TGen-led Study Discovers Genetic Cause of a Rare Type of Ovarian Cancer

TGen-led study discovers genetic cause of a rare type of ovarian cancer. Scientific breakthrough could lead to new cancer treatments; study inspired by the memory of Taryn Ritchey, a 22-year-old patient who lost her battle to the disease.

The cause of a rare type of ovarian cancer that most often strikes girls and young women has been uncovered by an international research team led by the Translational Genomics Research Institute (TGen), according to a study published online recently by the renowned scientific journal, Nature Genetics. [1] In a scientific rarity, two additional studies with similar results were also published online on the same day in Nature Genetics, producing immediate validation and reflecting a scientific consensus that usually takes months or even years to accomplish. [2-3]

By applying its groundbreaking work in genomics, TGen led a study that included: Scottsdale Healthcare, Mayo Clinic, Johns Hopkins University, St. Joseph’s Hospital and Medical Center; Evergreen Hematology and Oncology, Children’s Hospital of Alabama, the Autonomous University of Barcelona, British Columbia Cancer Agency, University of British Columbia, and the University Health Network-Toronto.

The findings revealed a “genetic superhighway” mutation in a gene found in the overwhelming majority of patients with small cell carcinoma of the ovary, hypercalcemic type, also known as “SCCOHT.” This rare type of ovarian cancer is usually not diagnosed until it is in its advanced stages. It does not respond to standard chemotherapy, and 65 percent of patients with the disease die within 2 years. SCCOHT can affect girls as young as 14 months, and women as old as 58 years – with a mean age of only 24 years old. In this study, the youngest patient was 9 years old.

The three separate groups of international researchers reported strikingly similar scientific findings related to SCCOHT, as provided below.

• Identification of germline (i.e., inherited) and somatic (lifetime acquired) inactivating mutations in the SWI/SNF chromatin-remodeling gene SMARCA4 in 75% (9/12) of SCCOHT cases, in addition to SMARCA4 protein loss in 82% (14/17) of the SCCOHT tumors. Notably, only 0.4% (2/485) of the other primary ovarian tumors tested possessed similar genomic characteristics. [Ref. 1]

• Identification of recurrent inactivating mutations in the SMARCA4 gene in 12 of 12 SCCOHT tumor samples. [Ref. 2]

• Indentification of germline inactivating mutations in familial cases of SCCOHT. Through additional analysis of non-familial tumors, the researchers determined that nearly 100% of tumors carry SMARCA4 mutations, and 38 of 40 lack protein expression.[Ref. 3]

Collectively, these findings implicate inactivating mutations in the SMARCA4 gene as a major cause of SCCOHT, and may lead researchers to improvements in genetic counseling, as well as the development of new targeted therapy treatment approaches.

Dr. Jeffrey Trent, President and Research Director of TGen, is the study’s senior author.

“This is a thoroughly remarkable study. Many genetic anomalies can be like a one-lane road to cancer; difficult to negotiate. But these findings indicate a genetic superhighway that leads right to this highly aggressive disease,” said Dr. Jeffrey Trent, President and Research Director of TGen, and the study’s senior author. “The correlation between mutations in SMARCA4 and the development of SCCOHT is simply unmistakable.”

Dr. Trent added that while the breakthrough is for a relatively rare cancer, discovering the origins of this type of ovarian cancer could have implications for more common diseases.

Much of the work in this study was inspired by the memory of Taryn Ritchey, a 22-year-old TGen patient who in 2007 lost her battle with ovarian cancer, the 5th leading cause of cancer death among American women.

“Taryn would be incredibly excited about this amazing new study, and she would be glad and thankful that other young women like her might now be helped because of TGen’s ongoing research,” said Taryn’s mother Judy Jost of Cave Creek, Arizona. “My daughter never gave up, and neither has TGen.”

The SMARCA4 gene – previously associated with lung, brain and pancreatic cancer – was the only recurrently mutated gene in the study’s samples. The implications of this discovery, therefore, may be widespread.

“The findings in this study represent a landmark in the field. The work identifies SMARCA4 mutations as the culprit, and most future research on this disease will be based on this remarkable discovery,” said Dr. Bert Vogelstein, Director of the Ludwig Center at Johns Hopkins University, Investigator at the Howard Hughes Medical Institute, and pioneer in the field of cancer genomics. He did not participate in the study but is familiar with its findings.

“The past decade of research has taught us that cancer is a vastly complex disease. Profound patient-to-patient variability has made treatment and diagnosis for many tumor types at times very difficult. In this case, however, we have found a single genetic event driving SCCOHT in nearly every patient,” said Dr. William Hendricks, a TGen Staff Scientist and another author of the study.

“We have shown that loss of SMARCA4 protein expression is extremely specific to SCCOHT and can facilitate the diagnosis of SCCOHT,” said Dr. Anthony N. Karnezis, a fellow at the British Columbia Cancer Agency located in Vancouver, Canada, and one of the study’s authors.

Pilar Ramos, a TGen Research Associate, is the study’s lead author. “By definitively identifying the relationship between SMARCA4 and SCCOHT, we have high confidence that we have set the stage for clinical trials that could provide patients with immediate benefit.”

“By definitively identifying the relationship between SMARCA4 and SCCOHT, we have high confidence that we have set the stage for clinical trials that could provide patients with immediate benefit.”

“We set out to uncover any small sliver of hope for women afflicted with this rare cancer. What we found instead are the nearly universal underpinnings of SCCOHT,” said Pilar Ramos, a TGen Research Associate, and the study’s lead author. “By definitively identifying the relationship between SMARCA4 and SCCOHT, we have high confidence that we have set the stage for clinical trials that could provide patients with immediate benefit.”

The TGen-led study was supported by grants from: the Marsha Rivkin Center for Ovarian Cancer Research, the Anne Rita Monahan Foundation, the Ovarian Cancer Alliance of Arizona, the Small Cell Ovarian Cancer Foundation, and philanthropic support to the TGen Foundation. Further support was provided by the Terry Fox Research Initiative’s New Frontiers Program in Cancer, and the Canadian Institutes of Health Research.

For more information about TGen’s research into small cell carcinoma of the ovary (SCCO), or to participate in a future study, visit: www.tgen.org/scco.

About TGen

Translational Genomics Research Institute (TGen) is a Phoenix, Arizona-based non-profit organization dedicated to conducting cutting-edge genomic research to accelerate breakthroughs in healthcare. TGen is focused on helping patients with cancer, neurological disorders and diabetes, through cutting edge translational research (the process of rapidly moving research towards patient benefit). TGen physicians and scientists work to unravel the genetic components of both common and rare complex diseases in adults and children. Working with collaborators in the scientific and medical communities literally worldwide, TGen makes a substantial contribution to help our patients through efficiency and effectiveness of the translational process. For more information, visit: www.tgen.org.

References:

1./ Ramos P, et al.  Small cell carcinoma of the ovary, hypercalcemic type, displays frequent inactivating germline and somatic mutations in SMARCA4. Nature Genetics (published online 23 March 2014) doi:10.1038/ng.2928.

2./ Jelinic P, et al. Recurrent SMARCA4 mutations in small cell carcinoma of the ovary. Nature Genetics (published online 23 March 2014) doi:10.1038/ng.2922.

3./ Witkowski L, et al.  Germline and somatic SMARCA4 mutations characterize small cell carcinoma of the ovary, hypercalcemic type.  Nature Genetics (published online 23 March 2014) doi:10.1038/ng.2931

Additional Information:

• Ovarian cancer breakthrough discovered by Phoenix scientists, by Adam Longo, http://www.kptv.com, March 23, 2014. [Includes CBS5 video news story].

• Select SCCHOT PubMed Medical Study Citations

• Small Cell Ovarian Cancer Foundation

 

Tel Aviv University Researchers Target Drug-Resistant Ovarian Tumors with Nanotechnology

Tel Aviv University researchers devise a fast and effective nanotechnology — called “gagomers” — to combat drug-resistant ovarian cancer.

Professor Dan Peer of Tel Aviv University’s Department of Cell Research and Immunology has proposed a new strategy to tackle drug-resistant ovarian cancer using a new nanoscale drug-delivery system designed to target specific cancer cells. The study was published in February in the journal ACS Nano.

Nanotechnology usually refers to an object that is 1-to–100 nanometers in size. A nanometer is a billionth of a meter. By comparison, the width of a strand of hair is approximately 100,000 times larger than a nanometer.

Prof. Peer and his team — Keren Cohen and Rafi Emmanuel from Peer’s Laboratory of Nanomedicine and Einat Kisin-Finfer and Doron Shabbat, from TAU’s Department of Chemistry — devised a cluster of nanoparticles called “gagomers,” which are made from fats and coated with a kind of polysugar. When filled with chemotherapy drugs (in this case doxorubicin), these clusters accumulate in tumors, producing dramatic therapeutic benefits.

The objective of Peer’s research is two-fold: to provide a specific target for anti-cancer drugs to increase their therapeutic benefits, and to reduce the toxic side effects of anti-cancer therapies.

Why Chemotherapy Fails

According to Prof. Peer, traditional courses of chemotherapy are not an effective line of attack. Chemotherapy’s failing lies in the inability of the medicine to be absorbed and maintained within the tumor cell long enough to destroy it. In most cases, the chemotherapy drug is almost immediately ejected by the cancer cell, severely damaging the healthy organs that surround it, leaving the tumor cell intact.

Gagomers (labeled in color) accumulating on ovarian cancer cells.
(Credit: Image courtesy of American Friends of Tel Aviv University)

But with this new nanotechnology therapy, Peer and his colleagues saw a 25-fold increase in tumor-accumulated medication and a dramatic dip in toxic accumulation in healthy organs. Tested on laboratory mice, the gagomer affects a change in drug-resistant ovarian cancer tumor cells. Receptors on tumor cells recognize the sugar that encases the gagomer, allowing the binding gagomer to slowly release tiny particles of chemotherapy into the cancerous cell. As more and more of the drug accumulates within the tumor cell, the cancer cells begin to die off within 24-48 hours. In this preclinical setting, the doxorubicin encased gagomers even outperformed pegylated liposomal doxorubicin (Doxil) — a standard of care drug used to treat recurrent ovarian cancer.

“Tumors become resistant very quickly. Following the first, second, and third courses of chemotherapy, the tumors start pumping drugs out of the cells as a survival mechanism,” said Prof. Peer. “Most patients with tumor cells beyond the ovaries relapse and ultimately die due to the development of drug resistance. We wanted to create a safe drug-delivery system, which wouldn’t harm the body’s immune system or organs.”

A Personal Perspective

Prof. Peer chose to tackle ovarian cancer in his research because his mother-in-law passed away at the age of 54 from the disease. “She received all the courses of chemotherapy and survived only a year and a half,” Peer said. “She died from the drug-resistant aggressive tumors.”

“At the end of the day, you want to do something natural, simple, and smart. We are committed to try to combine both laboratory and therapeutic arms to create a less toxic, focused drug that combats aggressive drug-resistant cancerous cells,” said Prof. Peer. “We hope the concept will be harnessed in the next few years in clinical trials on aggressive tumors,” said Prof. Peer.

Sources:

• Researchers Devise a Fast and Effective Mechanism to Combat One of the Most Aggressive Cancers, American Friends of Tel Aviv University, Press Release, February 24, 2014. [PDF Full Text Version]

• Keren Cohen, et al. Modulation of Drug Resistance in Ovarian Adenocarcinoma Using Chemotherapy Entrapped in Hyaluronan-Grafted Nanoparticle Clusters. ACS Nano, 2014; 140206084950005 DOI: 10.1021/nn500205b

Novel “Jantibody Fusion Protein” Cancer Vaccine Holds Promise Against Ovarian Cancer

A novel approach to cancer immunotherapy – strategies designed to induce the immune system to attack cancer cells – may provide a new and cost-effective weapon against some of the most deadly tumors, including ovarian cancer and mesothelioma.

A novel approach to cancer immunotherapy – strategies designed to induce the immune system to attack cancer cells – may provide a new and cost-effective weapon against some of the most deadly tumors, including ovarian cancer and mesothelioma. Investigators from the Massachusetts General Hospital (MGH) Vaccine and Immunotherapy Center (VIC) report in the Journal of Hematology & Oncology that a protein engineered to combine a molecule targeting a tumor-cell-surface antigen with another protein that stimulates several immune functions prolonged survival in animal models of both tumors.

“Some approaches to creating cancer vaccines begin by extracting a patient’s own immune cells, priming them with tumor antigens and returning them to the patient, a process that is complex and expensive,” says Mark Poznansky, M.D., Ph.D., director of the MGH Vaccine and Immunotherapy Center and senior author of the report. “Our study describes a very practical, potentially broadly applicable and low-cost approach that could be used by oncologists everywhere, not just in facilities able to harvest and handle patient’s cells.”

The MGH team’s vaccine stimulates the patient’s own dendritic cells, a type of immune cell that monitors an organism’s internal environment for the presence of viruses or bacteria, ingests and digests pathogens encountered, and displays antigens from those pathogens on their surface to direct the activity of other immune cells. As noted above, existing cancer vaccines that use dendritic cells require extracting cells from a patient’s blood, treating them with an engineered protein or nucleic acid that combines tumor antigens with immune-stimulating molecules, and returning the activated dendritic cells to the patient.

Fusion protein activates immune cells against tumors. The Jantibody fusion protein, combining an antibody fragment targeting an antigen found on tumor cells with an immune-response-inducing protein (MTBhsp70), activates dendritic cells against several tumor antigens and induces a number of T-cell-based immune responses. (Jianping Yuan, PhD, MGH Vaccine and Immunotherapy Center)

The approach developed by the MGH team starts with the engineered protein, which in this case fuses an antibody fragment targeting a protein called mesothelin – expressed on the surface of such tumors as mesothelioma, ovarian cancer and pancreatic cancer – to a protein from the tuberculosis bacteria that stimulates the activity of dendritic and other immune cells. In this system, the dendritic cells are activated and targeted against tumor cells while remaining inside the patient’s body.

In the experiments described in the paper, the MGH team confirmed that their mesothelin-targeting fusion protein binds to mesothelin on either ovarian cancer or mesothelioma cells, activates dendritic cells, and enhances the cells’ processing and presentation of several different tumor antigens, inducing a number of T-cell-based immune responses. In mouse models of both tumors, treatment with the fusion protein significantly slowed tumor growth and extended survival, probably through the activity of cytotoxic CD8 T cells.

“Many patients with advanced cancers don’t have enough functioning immune cells to be harvested to make a vaccine, but our protein can be made in unlimited amounts to work with the immune cells patients have remaining,” explains study co-author Jeffrey Gelfand, MD, senior scientist at the Vaccine and Immunotherapy Center. “We have created a potentially much less expensive approach to making a therapeutic cancer vaccine that, while targeting a single tumor antigen, generates an immune response against multiple antigens. Now if we can combine this with newly-described ways to remove the immune system’s “brakes” – regulatory functions that normally suppress persistent T-cell activity – the combination could dramatically enhance cancer immunotherapy.”

Poznansky adds that the tumors that might be treated with the mesothelin-targeting vaccine – ovarian cancer, pancreatic cancer and mesothelioma – all have poor survival rates. “Immunotherapy is generally nontoxic, so this vaccine has the potential of safely extending survival and reducing the effects of these tumors, possibly even cutting the risk of recurrence. We believe that this approach could ultimately be used to target any type of cancer and are currently investigating an improved targeting approach using personalized antigens.” The MGH team just received a two-year grant from the Department of Defense Congressionally Directed Medical Research Program to continue their research.

Poznansky is an associate professor of Medicine, and Gelfand is a clinical professor of Medicine at Harvard Medical School. Jianping Yuan, Ph.D., of the MGH Vaccine and Immunotherapy Center (VIC) is the lead author of the Journal of Hematology and Oncology report. Additional co-authors include Pierre LeBlanc, Ph.D., Satoshi Kashiwagi M.D., Ph.D., Timothy Brauns, and Svetlana Korochkina, Ph.D., MGH VIC; and Nathalie Scholler, M.D., Ph.D., University of Pennsylvania School of Medicine.

The authors dedicate their report to Janet Gelfand, the wife of Jeffrey Gelfand, who died of ovarian cancer in 2006 and inspired their investigation. In her honor they named their tumor-targeting fusion protein “Jantibody.” Support for the study includes grants from the Edmund Lynch Jr. Cancer Fund, Arthur Luxenberg Esq., Perry Weitz Esq., the VIC Mesothelioma Research and Resource Program, and the Friends of VIC Fund.

Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $775 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, reproductive biology, systems biology, transplantation biology and photomedicine.

Sources:

• Novel cancer vaccine holds promise against ovarian cancer, mesothelioma — Antigen-targeting fusion protein should be less expensive, more accessible than current approaches, Massachusetts General Hospital, Press Release, March 5, 2014.

• Yuan J et al., A novel mycobacterial Hsp70-containing fusion protein targeting mesothelin augments antitumor immunity and prolongs survival in murine models of ovarian cancer and mesothelioma. J Hematol Oncol. 2014 Feb 24;7(1):15. doi: 10.1186/1756-8722-7-15. (Abstract – PMID: 24565018; Full Text – PMCID: PMC3943805)

U.S. President Barack Obama Proclaims September 2013 As National Ovarian Cancer Awareness Month — What Should You Know?

Yesterday, U.S. President Barack Obama designated September 2013 as National Ovarian Cancer Awareness Month. “… During National Ovarian Cancer Awareness Month, we lend our support to everyone touched by this disease, we remember those we have lost, and we strengthen our resolve to better prevent, detect, treat, and ultimately defeat ovarian cancer…. This month, we extend a hand to all women battling ovarian cancer. We pledge our support to them, to their families, and to the goal of defeating this disease. …”

Yesterday, U.S. President Barack Obama designated September 2013 as National Ovarian Cancer Awareness Month. The Presidential Proclamation is reproduced in full below.

During National Ovarian Cancer Awareness Month, Libby’s H*O*P*E*™ will honor the women who have lost their lives to the disease, support those who are currently battling the disease, and celebrate with those who have beaten the disease. This month, medical doctors, research scientists, and ovarian cancer advocates renew their commitment to develop a reliable early screening test, improve current treatments, discover new groundbreaking therapies, and ultimately, defeat the most lethal gynecologic cancer.

Let us begin this month with several important facts relating to ovarian cancer. Please take time to review these facts — they may save your life or that of a loved one.

Ovarian Cancer Facts

Lethality. Ovarian cancer causes more deaths than any other cancer of the female reproductive system.

Statistics. In 2013, the American Cancer Society (ACS) estimates that there will be approximately 22,240 new ovarian cancer cases diagnosed in the U.S. ACS estimates that 14,030 U.S. women will die from the disease, or about 38 women per day or 1-to-2 women every hour. This loss of life is equivalent to 28 Boeing 747 jumbo jet crashes with no survivors — every year.

Signs & Symptoms. Ovarian cancer is not a “silent” disease; it is a “subtle” disease. Recent studies indicate that women with ovarian cancer are more like to experience four persistent, nonspecific symptoms as compared with women in the general population, such as (i) bloating, (ii) pelvic or abdominal pain, (iii) difficulty eating or feeling full quickly, or (iv) urinary urgency or frequency. Women who experience such symptoms daily for more than a few weeks should seek prompt medical evaluation. Note: Several other symptoms have been commonly reported by women with ovarian cancer. These symptoms include fatigue, indigestion, back pain, pain with intercourse, constipation and menstrual irregularities. However, these additional symptoms are not as useful in identifying ovarian cancer because they are also found in equal frequency in women within the general population who do not have the disease.

Age. Although the median age of a woman with ovarian cancer at initial diagnosis is 63, the disease cancer can afflict adolescent, young adult, and mature women. Ovarian cancer does not discriminate based upon age.

Prevention. Pregnancy, breastfeeding, long-term use of oral contraceptives, and tubal ligation reduce the risk of developing ovarian cancer.

Risk Factors.

• BRCA Gene Mutations. Women who have had breast cancer, or who have a family history of breast cancer or ovarian cancer may have increased risk. Women who test positive for inherited mutations in the BRCA-1 or BRCA-2 gene have an increased lifetime risk of breast and ovarian cancer. A women can inherit a mutated BRCA gene from her mother or father. Women of Ashkenazi (Eastern European) Jewish ancestry are at higher risk (1 out of 40) for inherited BRCA gene mutations. Studies suggest that preventive surgery to remove the ovaries and fallopian tubes in women possessing BRCA gene mutations can decrease the risk of ovarian cancer.

• Lynch Syndrome. An inherited genetic condition called “hereditary nonpolyposis colorectal cancer” (also called “Lynch syndrome“), which significantly increases the risk of colon/rectal cancer (and also increases the risk of other types of cancers such as endometrial (uterine), stomach, breast, small bowel (intestinal), pancreatic, urinary tract, liver, kidney, and bile duct cancers), also increases ovarian cancer risk.

• Hormone Therapy. The use of estrogen alone menopausal hormone therapy may increase ovarian cancer risk. The longer estrogen alone replacement therapy is used, the greater the risk may be. The increased risk is less certain for women taking both estrogen and progesterone, although a large 2009 Danish study involving over 900,000 women suggests that combination hormone therapy may increase risk. Because some health benefits have been identified with hormone replacement therapy, a women should seek her doctor’s advice regarding risk verses benefit based on her specific factual case.

• Smoking. Smoking has been linked to an increase in mucinous epithelial ovarian cancer.

Early Detection. There is no reliable screening test for the detection of early stage ovarian cancer. Pelvic examination only occasionally detects ovarian cancer, generally when the disease is advanced. A Pap smear cannot detect ovarian cancer. However, the combination of a thorough pelvic exam, transvaginal ultrasound, and a blood test for the tumor marker CA-125 may be offered to women who are at high risk of ovarian cancer and to women who have persistent, unexplained symptoms like those listed above. This early detection strategy has shown promise in a 2013 University of Texas M.D. Anderson Cancer Center early detection study involving over 4,000 women. Importantly, another large ovarian cancer screening trial that is using similar early detection methods is under way in the United Kingdom, with results expected in 2015. The U.K. study is called “UKCTOCS” (UK Collaborative Trial of Ovarian Cancer Screening) and involves over 200,000 women aged 50-74 years.

Treatment.

• Treatment includes surgery and usually chemotherapy.

• Surgery usually includes removal of one or both ovaries and fallopian tubes (salpingo-oophorectomy), the uterus (hysterectomy), and the omentum (fatty tissue attached to some of the organs in the belly), along with biopsies of the peritoneum (lining of the abdominal cavity) and peritoneal cavity fluid.

• In younger women with very early stage tumors who wish to have children, removal of only the involved ovary and fallopian tube may be possible.

• Among patients with early ovarian cancer, complete surgical staging has been associated with better outcomes.

• For women with advanced disease, surgically removing all abdominal metastases larger than one centimeter (debulking) enhances the effect of chemotherapy and helps improve survival.

• For women with stage III ovarian cancer that has been optimally debulked, studies have shown that chemotherapy administered both intravenously and directly into the abdomen (intraperitoneally) improves survival.

• Studies have also found that ovarian cancer patients whose surgeries are performed by a board-certified gynecologic oncologist at a high quality/high surgical volume medical facility have more successful outcomes. Such medical facilities include National Cancer Institute-Designated Cancer Centers and member institutions of the National Comprehensive Cancer Network.

• Patients can enter clinical trials at the start of, during the course of, and even after, their ovarian cancer treatment(s).

• New types of treatment are being tested in ovarian and solid tumor clinical trials, including “biological therapy” and “targeted therapy.” For example, these types of treatment can exploit biological/molecular characteristics unique to an ovarian cancer patient’s specific tumor classification, or better “train” the patient’s own immune system to identify and attack her tumor cells, without harming normal cells.

Survival. 

• If diagnosed at the localized stage, the 5-year ovarian cancer survival rate is 92%; however, only about 15% of all cases are detected at an early stage, usually fortuitously during another medical procedure. The majority of cases (61%) are diagnosed at a distant or later stage of the disease.

• Overall, the 1-, 5-, and 10-year relative survival of ovarian cancer patients is 75%, 44%, and 34%, respectively.

• The 10-year relative survival rate for all disease stages combined is only 38%.

• Relative survival varies by age; women younger than 65 are twice as likely to survive 5 years (56%) following diagnosis as compared to women 65 and older (27%).

Help Spread the Word To “B-E-A-T” Ovarian Cancer

Please help us “B-E-A-T” ovarian cancer by spreading the word about the early warning signs & symptoms of the disease throughout the month of September.

B = bloating that is persistent and does not come and go

E = eating less and feeling fuller

A =abdominal or pelvic pain

T = trouble with urination (urgency or frequency)

Women who have these symptoms almost daily for more than a few weeks should see their doctor. Prompt medical evaluation may lead to detection at the earliest possible stage of the disease. As noted above, early stage diagnosis is associated with an improved prognosis.

__________________________________________________________

The White House

Office of the Press Secretary

For Immediate Release August 30, 2013

BY THE PRESIDENT OF THE UNITED STATES OF AMERICA

A PROCLAMATION

Each September, America calls attention to a deadly disease that affects thousands of women across our country. This year, over 22,000 women will develop ovarian cancer, and more than half that number of women will die of this disease. During National Ovarian Cancer Awareness Month, we lend our support to everyone touched by this disease, we remember those we have lost, and we strengthen our resolve to better prevent, detect, treat, and ultimately defeat ovarian cancer.

Because ovarian cancer often goes undetected until advanced stages, increasing awareness of risk factors is critical to fighting this disease. Chances of developing ovarian cancer are greater in women who are middle-aged or older, women with a family history of breast or ovarian cancer, and those who have had certain types of cancer in the past. I encourage all women, especially those at increased risk, to talk to their doctors. For more information, visit www.Cancer.gov.

My Administration is investing in research to improve our understanding of ovarian cancer and develop better methods for diagnosis and treatment. As we continue to implement the Affordable Care Act, women with ovarian cancer will receive increased access to health care options, protections, and benefits. Thanks to this law, insurance companies can no longer set lifetime dollar limits on coverage or cancel coverage because of errors on paperwork. By 2014, the health care law will ban insurers from setting restrictive annual caps on benefits and from charging women higher rates simply because of their gender. Additionally, insurance companies will be prohibited from denying coverage or charging higher premiums to patients with pre-existing conditions, including ovarian cancer.

This month, we extend a hand to all women battling ovarian cancer. We pledge our support to them, to their families, and to the goal of defeating this disease.

NOW, THEREFORE, I, BARACK OBAMA, President of the United States of America, by virtue of the authority vested in me by the Constitution and the laws of the United States, do hereby proclaim September 2013 as National Ovarian Cancer Awareness Month. I call upon citizens, government agencies, organizations, health care providers, and research institutions to raise ovarian cancer awareness and continue helping Americans live longer, healthier lives. I also urge women across our country to talk to their health care providers and learn more about this disease.

IN WITNESS WHEREOF, I have hereunto set my hand this thirtieth day of August, in the year of our Lord two thousand thirteen, and of the Independence of the United States of America the two hundred and thirty-eighth.

BARACK OBAMA

__________________________________________________________

Sources:

• Cancer Facts & Figures 2013. Atlanta: American Cancer Society; 2013 [PDF file].

• Presidential Proclamation — National Ovarian Cancer Awareness Month, 2013, Office of the Press Secretary, The White House, August 30, 2013.

Ovarian Cancer Survivor Seeks “Compassionate Use” Drug Exemption From BioMarin to Save Her Life

Andrea Sloan, a 7-year survivor of stage 3c ovarian cancer, is seeking a “compassionate use” exemption from pharmaceutical company BioMarin to save her life. Sloan is scheduled to start treatment at the M.D. Anderson Cancer Center on September 5 and would like to obtain access to the “PARP 1/2 inhibitor” drug known as “BMN 673” by that time. A robust grassroots campaign in support of Sloan has emerged on social media and Change.org in an effort to get an affirmative response from BioMarin.

Andrea Sloan, a 7-year, stage 3c survivor of ovarian cancer, is seeking a “compassionate use” investigational cancer drug exemption from pharmaceutical company BioMarin to save her life. Sloan, the executive director of a non-profit that advocates for survivors of domestic violence and abuse, now finds herself forced to publicly advocate for herself in a last chance effort to get the cancer treatment she needs.

Drugs that are being tested but have not yet been approved by the U.S. Food and Drug Administration (FDA) are called “investigational drugs.” These drugs are generally available only to people who are taking part in a clinical trial. The FDA “Expanded Access” protocol — sometimes referred to as a “compassionate use” exemption — involves the use of an investigational drug outside of a clinical trial to treat a patient with a serious or immediately life-threatening disease or condition, who has no comparable or satisfactory alternative treatment options.

FDA regulations allow access to investigational drugs for treatment purposes on a case-by-case basis for an individual patient, or for intermediate-size groups of patients with similar treatment needs who otherwise do not qualify to participate in a clinical trial. Before an investigational drug can qualify for compassionate use, the patient’s physician, the FDA, and the drug manufacturer must approve such use.

Unfortunately, drug manufacturers may not always be willing or able to provide access to a drug outside of their clinical trials. By law, drug companies are not required to make their drug available through the FDA expanded access protocol, or to make more of a drug for that purpose.

Andrea Sloan, a 7-year survivor of stage 3c ovarian cancer, is seeking a compassionate use exemption from pharmaceutical company BioMarin to save her life. Sloan is scheduled to start treatment at the University of Texas M.D. Anderson Cancer Center on September 5, and she would like to obtain access to the “PARP 1/2 inhibitor” drug known as “BMN 673” by that time. A robust grassroots campaign in support of Sloan has emerged on social media and Change.org in an effort to get an affirmative response from BioMarin.

“BioMarin’s BMN 673 offers me the best chance at a long life,” said Sloan. “My doctors and the FDA agree that I am an excellent candidate for this drug and meet the criteria for compassionate use exemption. However, BioMarin’s lack of a policy on compassionate use is preventing me from gaining access to the drug I need to save my life. I respectfully implore them to reconsider and make the ethical decision to help me.” [Emphasis added]

Sloan has endured two full rounds of chemotherapy, five surgeries, and a stem cell transplant. While her cancer remains responsive to treatment, her bone marrow can no longer tolerate traditional therapies. Her world-class oncology team at M.D. Anderson believes that BioMarin’s PARP inhibitor BMN 673, which is currently being tested in a phase I solid tumor clinical trial, is the best option for Sloan’s BRCA-1 gene-mutated form of ovarian cancer.

Unfortunately, Sloan hit a barrier in gaining access to BMN 673. Further enrollment of ovarian cancer patients in the phase I solid tumor trial is now closed, and the publicly announced portion of the trial that will be entering phase III testing is only open to BRCA gene-mutated breast (but not ovarian) cancer patients. Therefore, Sloan is left with the compassionate use exemption as her only option to access the drug she needs to fight her cancer. Based on FDA requirements, Sloan qualifies for the compassionate use exemption. Data emerging from the phase I BMN 673 study suggest that the drug is a safe and effective treatment option for patients with BRCA gene-mutated ovarian cancer.

Moreover, on August 16, 2013, BioMarin announced that its medical study abstract, entitled “PARP inhibition with BMN 673 in ovarian and breast cancer patients with deleterious mutations of BRCA1 and BRCA2,” has been selected as a “late breaking” abstract by the 17th ECCO — 38th ESMO — 32nd ESTRO European Cancer Congress, which will be held from September 27 through October 1, 2013 in Amsterdam, The Netherlands. BioMarin’s oral presentation at the European Cancer Congress (scheduled for September 29, 2013) will include data presented from 28 ovarian cancer patients with deleterious germline (inherited) BRCA gene mutations, including 17 patients from the phase I BMN 673 trial dose escalation cohort (range 100 µg to 1100 µg) and 11 patients from the dose expansion cohort. Presumably, the most recent ovarian cancer patient data to be presented at the European Cancer Congress will expand upon the positive data presented by the company at the 2013 Annual Meeting of the American Society of Clinical Oncology, which indicate that positive RECIST (“Response Evaluation Criteria in Solid Tumors“) and/or CA-125 ovarian cancer patient responses occurred at BMN 673 drug doses ≥ 100 µg/d in 11 out of 17 (64%) BRCA gene-mutated ovarian and peritoneal cancer patients. The positive RECIST medical imaging findings and the CA-125 blood test results highlight the promising effectiveness of BMN 673, albeit among a small group of ovarian cancer patients.

BMN 673 is a targeted therapy designed to disrupt the tumor without traditional chemotherapy drug side effects, thereby making it an optimal treatment for Sloan.

Despite Sloan’s best efforts, she has been unable to convince BioMarin to allow compassionate use of BMN 673. BioMarin, according to Sloan, has not been cooperative, merely citing their lack of a policy on the issue. Sloan, the executive director of a non-profit that advocates for survivors of domestic violence and abuse, now finds herself forced to publicly advocate for herself in a last chance effort to save her life. Sloan is committed to advocating for meaningful reform on this topic and hopes BioMarin will lead by example in starting a national dialogue.

If you would like to help Andrea Sloan obtain compassionate use of BMN 673, please click on this picture and sign her petition at Change.org.

For those interested in supporting Andrea Sloan, please sign her petition on Change.org that urges BioMarin to grant her a compassionate use investigational cancer drug exemption for BMN 673. Also, you can follow Andrea on Twitter at @andi_sloan.

Update:

Yesterday, BioMarin issued a statement to KXAN, an Austin, Texas local affilate of NBC, in response to a in-depth news story that KXAN aired tonight regarding Andrea Sloan’s dire situation. Effectively, BioMarin rejected Andrea Sloan’s request for compassionate use of BMN 673, although its statement was worded as a general drug “expanded access” policy explanation.

BioMarin acknowledged that it allowed preapproved expanded access to one of its investigational drugs which completed phase III clinical testing last year. In terms of general guidelines for its expanded access programs, the company stated:

“We implement these [expanded access] programs when we have sufficient scientific evidence to support both the safety and the efficacy of a product for an indication. Additionally, we implement these programs only when we can ensure that access will be provided equitably, ensuring that the process is appropriately blinded, and when we are confident that the expanded access will not inhibit our clinical trial plans or clinical trials for a disease generally.”

In terms of Andrea Sloan’s specific case, BioMarin stated that it does not comment on the status of individual patients. Apparently in a refusal to grant expanded access to any preapproved patient who requests compassionate use of BMN 673 prior to completion of phase III drug testing, the company stated:

“… However, we note that, although the current data [for BMN 673] that we have looks promising, there is no data at this point to support anything beyond dosing and some preliminary safety. It is too early to know if the experimental therapy is safe or effective, or will even prolong life, until we conduct the appropriate Phase 3 trials. The data that we have is from an ongoing early stage clinical trial, and it is the first trial that we have ever done with this therapy in humans.”

Accordingly, it appears that BioMarin’s current expanded access policy for its investigational drugs, such as BMN 673, will only extend to drugs that have already completed phase III clinical trial testing.

Sources:

• Ovarian Cancer Survivor Andrea Sloan Seeks Compassionate Use Exemption From BioMarin to Save Her Life, Press Release, Digital Journal, August 29, 2013.

• BioMarin Provides BMN 673 Program Update, BioMarin Pharmaceutical Inc, Press Release, July 25, 2013.

• De Bono JS et. al. First-in-human trial of novel oral PARP inhibitor BMN 673 in patients with solid tumors. J Clin Oncol 31, 2013 (suppl; abstr 2580).

• Shen Y. et al.  BMN 673, a novel and highly potent PARP-1/2 inhibitor for the treatment of human cancers with DNA repair deficiency. Clin Cancer Res. 2013 Jul 23. PMID: 23881923 [Epub ahead of print]

• A Phase 1, First in Human, Single-arm, Open-label Study of Once a Day, Orally Administered BMN 673 in Patients With Advanced or Recurrent Solid Tumors. ClinicalTrials.gov Identifier: NCT01286987.

• Advocate for others needs help in a fight for her life, by Shannon Wolfson & Joe Ellis, In-Depth Investigation, KXAN News, August 29, 2013.

• Statement From BioMarin on Expanded Access, August 28, 2013.

• BioMarin Announces Oral Presentation of BMN 673 Most Recent Data on Breast and Ovarian Cancers at the European Cancer Congress 2013, Press Release, August 16, 2013.

Inaugural World Ovarian Cancer Day: “World Embrace” to Learn, Educate, Fight & Inspire

May 8th, 2013, is the first World Ovarian Cancer Day. On this day, 26 ovarian cancer organizations from 17 countries around the world will unite to educate their communities about ovarian cancer and its symptoms. For women living with the disease, and their families and friends, World Ovarian Cancer Day will build a sense of solidarity in the fight against ovarian cancer.

“LEARN:” Inaugural World Ovarian Cancer Day — May 8, 2013

Ovarian cancer has the lowest survival rate of all gynecologic cancers, and is characterized around the world by a lack of awareness of symptoms and late stage diagnosis.

Today, May 8th, 2013, is the first World Ovarian Cancer Day (WOCD). On this day, ovarian cancer organizations from around the world will unite to educate their communities about ovarian cancer and its symptoms. For women living with the disease, and their families and friends, World Ovarian Cancer Day will build a sense of solidarity in the fight against the disease.

In 2009, representatives from patient organizations working in ovarian cancer around the globe came together for the first time in a two day workshop, to discuss the common issues they faced in their work.

Unlike more common cancers, there are significant challenges as the disease has been largely overlooked and underfunded to this point. Symptoms which are similar to those of less serious illnesses, the absence of an early detection test, and the resulting late diagnosis and poor outcomes means there are few survivors of the disease to become advocates. This initial meeting galvanized the community to begin thinking about what could be accomplished on a global level to begin changing this situation.

By coming together since that first meeting, the group has considered the many gaps in understanding and managing the disease, building awareness in the general public about symptoms and the importance of family history, and increasing funding for research .The idea of a Global Awareness Day for Ovarian Cancer was put forward and embraced by all participants as an important joint international action creating a powerful momentum.

A brand for World Ovarian Cancer Day, “World Embrace,” was developed and launched to the international group in March 2013 in preparation for this important day.

“EDUCATE:” Ovarian Cancer Facts:

Libby’s H*O*P*E* is dedicated to my 26-year old cousin, Elizabeth “Libby” Remick, who died from ovarian cancer in July 2008. Our mission is to educate ovarian cancer survivors and their families, as well as the general public, about ovarian cancer under the principle that “information is power.” The key to a significant reduction in deaths from ovarian cancer is early detection. Early detection is best achieved by having women listen to their bodies for the subtle, yet persistent, early warning signs & symptoms of the disease as described below. Together, we can raise money for a reliable early detection test, and ultimately a cure, for ovarian cancer.

Please take time to educate yourself with respect to the important ovarian cancer awareness facts provided below.

–Ovarian cancer causes more deaths than any other cancer of the female reproductive system.

–In 2012, the American Cancer Society (ACS) estimates that there will be approximately 22,280 new ovarian cancer cases diagnosed in the U.S. ACS estimates that 15,550 U.S. women will die from the disease, or about 43 women per day. The loss of life is equivalent to 28 Boeing 747 jumbo jet crashes with no survivors every year.

–Ovarian cancer is not a “silent” disease; it is a “subtle” disease. Recent studies indicate that some women may experience persistent, nonspecific symptoms, such as (i) bloating, (ii) pelvic or abdominal pain, (iii) difficulty eating or feeling full quickly, or (iv) urinary urgency or frequency. Women who experience such symptoms daily for more than a few weeks should seek prompt medical evaluation.

–Ovarian cancer can afflict adolescent, young adult, and mature women.

–Pregnancy and the long-term use of oral contraceptives reduce the risk of developing ovarian cancer.

–Women who have had breast cancer, or who have a family history of breast cancer or ovarian cancer may have increased risk. Inherited mutations in BRCA1/BRCA2 genes increase risk. Women of Ashkenazi Jewish ancestry are at higher risk for BRCA gene mutations.

–There is no reliable screening test for the detection of early stage ovarian cancer. Pelvic examination only occasionally detects ovarian cancer, generally when the disease is advanced. A Pap smear is used to detect cervical cancer, not ovarian cancer. However, the combination of a thorough pelvic exam, transvaginal ultrasound, and a blood test for the tumor marker CA125 may be offered to women who are at high risk of ovarian cancer and to women who have persistent, unexplained symptoms like those listed above.

–If diagnosed at the localized stage, the 5-year ovarian cancer survival rate is 92%; however, only about 19% of all cases are detected at this stage, usually fortuitously during another medical procedure.

–The 10-year relative survival rate for all disease stages combined is only 38%.

Please help us spread the word about the early warning signs & symptoms of ovarian cancer and raise money for ovarian cancer research. The life you save may be your own or that of a loved one.

“FIGHT:” The “Holy Trinity” of Major U.S. Ovarian Cancer Organizations

There are three major U.S. ovarian cancer organizations that are working to increase ovarian cancer awareness, and/or raise money to fight the disease. They are listed below. Please consider making a donation to one of these critically important nonprofit organizations.

• Ovarian Cancer Research Fund

The Ovarian Cancer Research Fund (OCRF) is the largest independent organization in the U.S. that is dedicated exclusively to funding ovarian cancer research– and to finding a cure. Through its three research programs, OCRF funds many of the best researchers and the most innovative projects.

Since 1998, OCRF has awarded 63 leading medical centers 195 grants for ovarian cancer research: an investment totaling over $50 million. OCRF researchers are taking on ovarian cancer from many angles:

— Developing innovative strategies for early detection;

— Discovering genetic polymorphisms that increase risk for ovarian cancer;

— Understanding the underlying genetics and molecular biology of ovarian cancer;

— Identifying new, better targets for treatment;

— Determining how to super-charge a woman’s immune response to better fight ovarian cancer; and

— Deciphering how and why ovarian cancer spreads, and how to stop it.

You can click here to make a donation to OCRF through the Libby’s H*O*P*E*’s donation page.

• Ovarian Cancer National Alliance

The Ovarian Cancer National Alliance (OCNA) is one of the foremost advocates for women with ovarian cancer in the U.S. To advance the interests of women with ovarian cancer, OCNA advocates at a national level for increases in research funding for the development of an early detection test, improved health care practices, and life-saving treatment protocols. OCNA also educates health care professionals and raises public awareness of the risks and symptoms of ovarian cancer.

To make a donation to OCNA, click here.

• National Ovarian Cancer Coalition

The mission of the National Ovarian Cancer Coalition (NOCC) is to raise awareness and promote education about ovarian cancer. NOCC is committed to improving the survival rate and quality of life for women with ovarian cancer.

Through national programs and local Chapter initiatives, the NOCC’s goal is to make more people aware of the early symptoms of ovarian cancer. In addition, the NOCC provides information to assist the newly diagnosed patient, to provide hope to survivors, and to support caregivers.

To make a donation to NOCC, click here.

“INSPIRE:” Everyday Heroes in the Fight Against Ovarian Cancer.

Nearly a quarter million women are diagnosed with ovarian cancer every year around the world, and the disease also affects their families and friends. Please take time to visit the WOCD website and read inspirational stories about survivors, volunteers, and family members who are overcoming ovarian cancer, as well as the endeavors people are taking on to raise awareness about the disease.

At Libby’s H*O*P*E*, we are amazed each and every day by the inspirational ovarian cancer survivors and family members that we hear about, correspond with, or meet. The stories below represent a small sample of incredible individuals who have successfully fought the disease, as well as those who are currently fighting the disease with courage and grace. There are also stories about women who have died from ovarian cancer, but contributed to ovarian cancer awareness in a unique and special way during life. In addition, there are stories about doctors, advocates, and other inspirational individuals who are clearly making a difference in the fight against the disease.

— “Bald is Beautiful,” March 20, 2008.

— “Patty Franchi Flaherty Loses Battle to Ovarian Cancer, But Deserves a Long Standing Ovation,” August 19, 2008.

— “Oscar Winner Kathy Bates Is an Inspirational Ovarian Cancer Survivor,” February 25, 2009.

— “Rare Form of Ovarian Cancer Not Getting Inspirational 13 Yr. Old Down; You Can Help!,” February 26, 2009.

— “Meet Laurey Masterton, 20-Year Ovarian Cancer Survivor Extraordinaire,” March 20, 2009.

— “The Rock Band ‘N.E.D.’: Their Medical Skills Save Many; Their Music Could Save Thousands,” March 29, 2009.

— “A Wish To Build A Dream On,” May 3, 2009.

— “Husband’s Love For Wife Inspires A 9,000 Mile Bike Trek To Raise Money For Ovarian Cancer Awareness & Cancer Prevention,” May 14, 2009.

— “Gloria Johns Was Told ‘Ovarian Cancer Patients Don’t Live Long Enough … To Have Support Groups;’ She Proved Otherwise,” June 5, 2009.

— “Vox Populi:* How Do Your Define “Tragedy?“, January 22, 2010.

— “Smile, Open Your Eyes, Love and Go On,” July 28, 2010.

— “PBS Documentary, ‘The Whisper: The Silent Crisis of Ovarian Cancer,'” September 21, 2010.

— “Determined Teen Loses Ovarian Cancer Battle, But Her Courage Inspires An Entire Community,” December 28, 2010.

— “Mrs. Australia Quest Finalist Veronica Cristovao Is Raising Ovarian Cancer Awareness ‘Down Under'”, February 28, 2011.

— “Whither Thou Goest, I Will Go …”, July 28, 2012.

— “Crowd Funding:” Paying Medical Bills With a Little Help From Your Friends (and Strangers Too!), January 17, 2013.

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For more information on World Ovarian Cancer Day visit: www.ovariancancerday.org

Facebook: www.facebook.com/WorldOvarianCancerDay

Twitter: @OvarianCancerDY

Pinterest: @OvarianCancerDY

Each participating country is linked through the dedicated website which has been established for World Ovarian Cancer Day. To find out more about activities in each country, please contact the local organization directly through the website at http://www.ovariancancerday.org/get-involved/

“Adoptive T-Cell” Immunotherapy Shows Activity Against Advanced Ovarian Cancer in Phase I Study

In a new study, researchers from the Perelman School of Medicine at the University of Pennsylvania School of Medicine show that a two-step personalized immunotherapy treatment — a dendritic cell vaccine using the patient’s own tumor followed by adoptive T cell therapy — triggers anti-tumor immune responses in advanced ovarian cancer patients.

Most ovarian cancer patients are diagnosed with late stage disease that is unresponsive to existing therapies. In a new study, researchers from the Perelman School of Medicine at the University of Pennsylvania School of Medicine show that a two-step personalized immunotherapy treatment — a dendritic cell vaccine using the patients’ own tumor followed by adoptive T cell therapy — triggers anti-tumor immune responses in these type of patients. Four of the six patients treated in the phase I trial responded to the therapy, the investigators report this month in OncoImmunology.

“What we proved in this study is that this is a safe treatment strategy,” says co-first author Lana Kandalaft, PharmD, MTR, Ph.D., research assistant professor of Obstetrics and Gynecology and director of clinical development in the Ovarian Cancer Research Center. “It is a walk in the park for patients, especially compared to standard chemotherapies and surgical treatments for ovarian cancer – literally, some patients left the clinic and went for a walk in a nearby park after their treatment.”

The findings follow research by the study’s senior author, George Coukos, M.D., Ph.D., director of the Ovarian Cancer Research Center at Penn, who showed in 2003 that women whose ovarian tumors were infiltrated by healthy immune cells, called T cells, tended to live longer than women whose tumors were devoid of T cells. That observation and other subsequent ones suggest the patient’s immune system is trying to fight off the disease but can’t quite muster the strength to beat it. Therefore, investigators have been trying to find ways using patients’ own tumor cells to boost the immune system’s power.

Adoptive T-Cell Therapy Approach

In the first segment of the study, the University of Pennsylvania researchers prepared an individualized dendritic cell vaccine for each ovarian cancer patient. (Photo Credit: Penn Medicine)

In the current study, Coukos, Kandalaft, co-first author Daniel J. Powell Jr., PhD, research assistant professor of Pathology and Laboratory Medicine, and colleagues treated six women with advanced ovarian cancer in a two-staged immunotherapy protocol in which they utilized a dendritic cell vaccine created from tissue in the patients’ own tumor, which was stored at time of surgery. All of these women’s cancers had progressed on standard of care chemotherapy.

In the first segment of the study, the team prepared an individualized dendritic cell vaccine for each patient. They harvested dendritic cells from each patient using apheresis, the same process volunteers go through when they donate platelets or other blood products such as those collected for stem cell transplants. Kandalaft and colleagues then exposed each patient’s dendritic cells to tumor extract produced from the woman’s ovarian cancer tumor, which teaches the dendritic cells who the enemy is. After this priming, the investigators vaccinated each patient with her own dendritic cells and gave them a combination chemotherapy regimen consisting of bevacizumab (Avastin) and  metronomic cyclophosphamide. Because dendritic cells are like the generals of the immune system, they then induce other immune cells to take up the fight.

Of the six advanced ovarian cancer patients who received the dendritic cell vaccine, four patients developed an anti-tumor immune response, indicating that the approach was working. One of those patients had no measurable disease at study entry because all of it had been successfully removed during surgery. She remains in remission today, 42 months following vaccine treatment. The remaining three who had an immune response to the vaccine still had residual disease and went on to the second segment of treatment.

In the second segment of the study, T cells were harvested from the ovarian cancer patients, grown in the laboratory, thereby expanding their numbers exponentially, and then were reintroduced into each patient after she underwent a lymphodepleting chemotherapy regimen. (Photo Credit: Penn Medicine)

In the second segment of the study, the team harvested T cells from each of the three women mentioned above. Using a technique developed at Penn, the researchers grew the cells in the laboratory, expanding their numbers exponentially, and then reintroduced them into each patient after she underwent a lymphodepleting chemotherapy regimen. Because the T cells had already been trained by the dendritic cell vaccine to attack the tumor cells, the adoptive T cell transfer amplifies the anti-tumor immune response.

Two of the women showed a restored immune response after the T cell transfer. One of the women continued to have stable disease, whereas the other had a complete response to the therapy.

The researchers say it is too early to say whether this type of therapy will be effective in a large number of ovarian cancer patients, but the early results are promising. First, and foremost, she notes, the two-step approach appears safe and well tolerated by the patients. Additionally, the team saw a correlation in both treatment steps between immune responses and clinical benefit, suggesting that it is, in fact, the immune response that is holding the disease in check.

With these encouraging results in hand, the team has opened a larger trial (UPCC-19809 & UPCC-26810; clinical trial protocols listed below) in which they have already enrolled about 25 women and aim for up to 30 more. The new protocol uses an improved vaccine platform and an optimized adoptive T cell transfer protocol. The prinicipal investigator of this study is Janos Tanyi, MD, PhD.

“Large clinical trials have shown that intensifying chemotherapy doesn’t improve outcomes for women with advanced ovarian cancer,” Coukos says. “So we need to explore other avenues. We think the combinatorial approach of both immune and chemotherapy is the way to go.”

Other co-authors from Penn include Cheryl L. Chiang, Janos Tanyi, Sarah Kim, Kathy Montone, Rosemarie Mick, Bruce L. Levine, Drew A. Torigian, and Carl H. June. Co-author Marnix Bosch is from Northwest Biotherapeutics in Bethesda, Maryland.

This study was supported by National Cancer Institute Ovarian SPORE grant P01-CA83638, National Institution of Health R01FD003520-02, and the Ovarian Cancer Immunotherapy Initiative. 

___________________________

Penn Medicine is one of the world’s leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation’s first medical school) and the University of Pennsylvania Health System, which together form a $4.3 billion enterprise.

The Perelman School of Medicine is currently ranked #2 in U.S. News & World Report’s survey of research-oriented medical schools. The School is consistently among the nation’s top recipients of funding from the National Institutes of Health, with $479.3 million awarded in the 2011 fiscal year.

The University of Pennsylvania Health System’s patient care facilities include: The Hospital of the University of Pennsylvania — recognized as one of the nation’s top “Honor Roll” hospitals by U.S. News & World Report; Penn Presbyterian Medical Center; and Pennsylvania Hospital — the nation’s first hospital, founded in 1751. Penn Medicine also includes additional patient care facilities and services throughout the Philadelphia region.

Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2011, Penn Medicine provided $854 million to benefit our community.

____________________________

Sources:

Kandalaft L, Powell D, Chiang C, et. al. Autologous lysate-pulsed dendritic cell vaccination followed by adoptive transfer of vaccine-primed ex vivo co-stimulated T cells in recurrent ovarian cancer. OncoImmunology 2013; 2:e22664; http://dx.doi.org.

Two-Step Immunotherapy Attacks Advanced Ovarian Cancer, Penn Medicine Researchers Report, Penn Medicine, Press Release, January 31, 2013.

Closed Clinical Trial Protocols (two study segments discussed above):

Study Segment One: A Phase I Clinical Trial of Autologous Dendritic Cell Vaccine Loaded With Autologous Tumor Cell Lysate for Recurrent Ovarian or Primary Peritoneal Cancer; ClinicalTrials.gov Identifier: NCT00683241; UPCC ID: 11807.

Study Segment Two: A Phase-I/II Randomized Trial of Maintenance Vaccination Combined With Metronomic Cyclophosphamide w/wo Adoptive Transfer of CD3/CD28-CoStimulated T-Cells for Recurrent Ovarian or Primary Peritoneal Cancer Previously Vaccinated DCVax-L; ClinicalTrials.gov Identifier: NCT00603460; UPCC ID: 10808

Open Clinical Trial Protocols (enrolling new patients, as of this writing):

A Pilot Clinical Trial of Dendritic Cell Vaccine Loaded With Autologous Tumor for Recurrent Ovarian, Primary Peritoneal or Fallopian Tube Cancer;  ClinicalTrials.gov ID: NCT01132014;  UPCC ID: 19809. [currently recruiting patients]

A Phase-1 Trial of Adoptive Transfer of Vaccine-Primed CD3/CD28-Costimulated Autologous T-Cells Combined With Vaccine Boost and Bevacizumab for Recurrent Ovarian Fallopian Tube or Primary Peritoneal Cancer Previously Vaccinated With Autologous Tumor Vaccine; ClinicalTrials.gov ID: NCT01312376;  UPCC ID: 26810. [currently recruiting patients]

Related Libby’s H*O*P*E* Articles:

Gene Transfer Therapy Destroys Tumors in Chronic Lymphocytic Leukemia Patients; Holds Promise For Ovarian Cancer, by Paul Cacciatore, August 11, 2011.

Penn’s Genetically Modified T Cells Create Antitumor Effect In Mice With Folate Positive Ovarian Cancer; Clinical Trial Pending, by Paul Cacciatore, August 17, 2011.

World Cancer Day 2013: Dispelling Myths & Misconceptions About “The Enemy Within”

1.5 million premature cancer deaths could be prevented each year if targets set to reduce non-communicable diseases are met by 2025.  Today, on World Cancer Day, the Union for International Cancer Control and the International Agency for Research on Cancer reveal the real life impact of achieving this goal.

World Cancer Day 2013

“… 1.5 million people saved from an early death due to cancer is equal to the entire populations of Philadelphia, Auckland, Barcelona or Maputo each and every year.”

World Cancer Day is the one initiative under which the entire world can unite in the fight against the global cancer epidemic.It takes place every year on February 4th. World Cancer Day aims to save millions of preventable deaths each year by raising awareness and education about cancer, and pressing governments and individuals across the world to take action against the disease.

World Cancer Day is an initiative of the Union for International Cancer Control (UICC), a leading international non-governmental organization dedicated to the prevention and control of cancer worldwide. Founded in 1933 and based in Geneva, UICC’s growing membership of over 765 organizations across 155 countries, features the world’s major cancer societies, ministries of health, research institutes, treatment centers, and patient groups. Additionally, the organization is a founding member of the NCD Alliance, a global civil society network that now represents almost 3,000 organizations in 170 countries.

Target “25 by 25:” Reduce 25% of Premature Non-Communicable Disease Deaths by 2025

The UICC and the International Agency for Research on Cancer (IARC) today announced that 1.5 million lives which would be lost to cancer, could be saved each year if decisive measures are taken to achieve the World Health Organization’s (WHO) “25 by 25” target; to reduce premature deaths due to non-communicable diseases (NCDs), including cancer, by 25% by 2025.

Currently, 7.6 million people die from cancer worldwide every year, out of which, 4 million people die prematurely (aged 30 to 69 years). So unless urgent action is taken to raise awareness about the disease and to develop practical strategies to address cancer, by 2025, this is projected to increase to an alarming 6 million premature cancer deaths per year.

“The estimate of 1.5 million lives lost per year to cancer that could be prevented must serve to galvanize our efforts in implementing the WHO’s ‘25 by 25’ target,” said Dr.  Christopher Wild, Director of IARC. “There is now a need for a global commitment to help drive advancements in policy and encourage implementation of comprehensive National Cancer Control Plans. If we are to succeed in this, we have a collective responsibility to support low- and middle-income countries who are tackling a cancer epidemic with insufficient resources.”

The 1.5 million lives lost per year represent 25% of the estimated 6 million premature cancer deaths that will occur by 2025, and the 6 million figure is itself based on population projections of current numbers and aging.

“Cancer — Did You Know?”

On World Cancer Day, UICC and its members are urging the public and governments alike to speak out with one voice to dispel damaging myths and misconceptions on cancer. Under the theme “Cancer – Did you know?” individuals and communities are encouraged to shed light on four key cancer “myths” and the corresponding “truth” via the UICC World Cancer Day Facebook App.

Myth #1: Cancer is just a health issue.

Truth #1: Cancer is not just a health issue. It has wide-reaching social, economic, development and human rights implications.

———-

Myth #2: Cancer is primarily a disease of the wealthy, elderly, and developed countries.

Truth #2: Cancer is a global epidemic, affecting all ages and socio-economic groups, with developing countries bearing a disproportionate burden.

———-

Myth #3: Cancer is a death sentence.

Truth #3: Many cancers that were once considered a death sentence can now be cured and for many more people their cancer can now be treated effectively.

———-

Myth #4: Cancer is my fate.

Truth #4: With the right strategies, at least 30% of cancer cases can be prevented based on current knowledge.

———-

Mr. Cary Adams, UICC Chief Exective Officer said:

“This World Cancer Day UICC, its members and partners urge everyone from individuals to governments to take a stand against damaging myths on cancer. By truly understanding this deadly disease, governments can develop appropriate strategies to reduce premature deaths and reach the WHO ‘25 by 25’ goal. The figures today announced by IARC and UICC reveal the fundamental human value of achieving this target. 1.5 million people saved from an early death due to cancer is equal to the entire populations of Philadelphia, Auckland, Barcelona or Maputo each and every year.”

What Can You Do?

In 2008, UICC developed the World Cancer Declaration as a tool to help bring the growing cancer crisis to the attention of government leaders and health policymakers. The 11 Declaration targets, designed to significantly reduce the global cancer burden by 2020, have served as the basis for UICC recommendations to the WHO. This year’s goal — #5 Declaration target — is to dispel damaging cancer myths and misconceptions. The Declaration, with more than half a million signatories, has also been instrumental in generating political will for cancer control targets both at the United Nations and grassroots levels. In close collaboration with the NCD Alliance, UICC played a key role recently in securing WHO’s global health target of a 25% reduction in premature deaths from NCDs by 2025 (known as “25 by 25”), at the World Health Assembly in May 2012 – demonstrating the important role advocacy plays in the global flight against cancer.

To sign the World Cancer Declaration, click here.

To download the World Cancer Day Facebook App, and play your part in reducing the unacceptable burden of cancer, visit https://apps.facebook.com/world_cancer_day.

Review and circulate the cancer truth fact sheets hyperlinked above under the “Cancer — Did You Know?” section of this article.

For more ideas on how you can get involved and take local action against the global crisis of cancer, visit worldcancerday.org.

Understanding Cancer:  “The Enemy Within” Documentary

In the documentary posted below, Vivienne Parry OBE tells the incredible story of our fight against cancer over the last 50 years. Through the eyes of scientists, researchers, and patients, we see how far we have come and how far we have yet to go, including contributions from Professor Robert Weinberg, Professor Umberto Veronesi, Lord Ara Darzi, Cancer Research UK, David Nathan, M.D., Brian Druker, M.D., and many more.

The film is a non-commercial, editorially independent piece of work which has been supported by Cancer Research UK and funded by an educational grant from Roche. The purpose is to educate and inform those who are affected by cancer. It’s now freely available to all who may want to use it, so please feel free to embed on your own websites and share as you see fit.

“Crowd Funding:” Paying Medical Bills With a Little Help From Your Friends (and Strangers Too!)

An interesting article appearing in USA Today on January 14, written by Cheryl Alkon, describes the use of “crowd funding” to assist individuals who may be experiencing tough financial times — or even bankruptcy — due to, among other things, medical costs, including those incurred to treat cancer.

What is “Crowd Funding?”

The term “crowd funding” describes the collective effort of individuals who network and pool their money, generally through the Internet, to support efforts initiated by other people or organizations. For example, crowd funding can be used to support disaster relief, citizen journalism, political campaigns, startup company funding, movie or software development, and scientific research.

Crowd funding is even taking on national significance through enacted federal legislation. In April 2012, President Obama signed the JOBS (Jumpstart Our Business Startups) Act, which enables entrepreneurs, start-ups, and small businesses to raise funds and gather investors through equity crowd funding.

An interesting article appearing in USA Today on January 14, written by Cheryl Alkon, describes the use of crowd funding to assist individuals who may be experiencing tough financial times — or even bankruptcy — due to, among other things, medical costs, including those incurred to treat cancer. The crowd funding websites listed by Alkon include: the Human Tribe Project (humantribeproject.com), GiveForward (giveforward.com), FundRazr (fundrazr.com), and GoFundMe (gofundme.com).

It is estimated that $2.8 billion was raised by all types of crowdfunding websites in 2012.

In an era when social media and networking reign supreme, most individuals have “friends,” and even “friends of friends.” At this point, you should be thinking about The Beatles song entitled, A Little Help From My Friends, which the group recorded on their Sgt. Pepper’s Lonely Hearts Club Band album in 1967. Or perhaps, you prefer Joe Cocker’s cover version of the song, which he sang at the Woodstock Music Festival in 1969. But, I digress. So, let’s turn to a great example of crowding funding used to support medical costs.

The Genesis of the Human Tribe Project

The Human Tribe Project Leadership Team: (left-to-right) Ryan Foutz, Jaclyn Foutz, Matt Foutz, and Steve Bever.

The concept of crowd funding within the context of cancer treatment is best understood through the genesis of The Human Tribe Project.

In early 2008, Jaclyn Foutz learned that her longtime friend, Kindra McLennan, had been diagnosed with a rare form of cervical cancer. Not knowing how to help Kindra, who lived 1,500 miles away, Jaclyn did what anyone thirty-something would do: she turned to Google®.

Her search turned up various websites listing ways to help support and encourage a friend through cancer, and of those, some even suggested fundraising ideas. Realizing that they could not be there to hold Kindra’s hand through the chemotherapy and radiation, Jaclyn and her friends decided to raise money for Kindra and her husband to relieve the financial burden associated with her cancer treatment. Jaclyn identified websites suggesting fundraising options, but all seemed too local and small in scope to have the kind of impact that she and her friends wanted. At the time, Jaclyn’s husband, Ryan Foutz, his brother, Matt Foutz, and Ryan’s childhood friend, Steve Bever, owned a wholesale jewelry company. They donated turquoise beads, and Jaclyn and her friends sold turquoise necklaces in support of Kindra. They sold the necklaces in-person to friends, relatives and coworkers, and by e-mail to people in Kindra’s support network all across the country.

The project was a huge success; they sold 350 necklaces and raised $10,000. They were inspired by the breadth of Kindra’s network of friends and the willingness of complete strangers to buy the necklaces.

Initially, Kindra refused to take handouts from her friends and family; however, when she knew her friends and family were receiving a necklace in return for their monetary donation, her concerns were alleviated. And, when Kindra saw everyone from her best friend to her chemotherapy nurse wearing the necklaces, she felt an emotional support as great as the financial support that she had received.

After extensive research, Jaclyn and Ryan learned that there were no resources available to do what they did on a larger, commercial scale. They found companies selling products in an effort to raise money for non-profits, foundations, or research institutions, but none raised money directly for individuals during their time of need.

During their research process, they were astonished to learn about the financial burden that individuals suffering from an illness often face. For example, with respect to breast cancer alone, it is estimated that out-of-pocket expenditures and lost-income costs for women with insurance coverage average $1,455.00 per month. The majority of those out-of-pocket costs are related to co-payments, hospitalizations, and specialist visits.

In 2006, twenty-five percent of cancer patients reported that they had to use all or most of their savings to deal with cancer treatment costs. Approximately fifty percent of all personal bankruptcies filed in the U.S. are filed due to medical expenses. Also, researchers have found that there is a strong connection between emotional support and healthcare outcomes. Jaclyn and Ryan found these statistics astounding; there was a better way to aid individuals and enhance the benefits of strong support networks.

Through all of this, Jaclyn, Ryan, Matt, and Steve saw firsthand the power of the humanitarian spirit and how that spirit connects us all. It was from this experience that Human Tribe Project was born.

Ultimately, Kindra McLennan used some of the funds raised on the website to take a trip to Las Vegas for her 30th birthday, four months before she died. “If that’s what you feel you need to use the money for, that’s one of the things you can do when you know the people who are donating to you,” Jaclyn Foutz says. The Human Tribe Project website launched  in early 2009, six months after McLennan’s death.

Not only were Kindra’s friends and family able to raise approximately $10,000 on her behalf, but Kindra could see their love and support in every necklace that was worn. The Human Tribe Project website is dedicated to Kindra’s memory.

After helping establish the Human Tribe project, Matt Foutz never anticipated using the service for his own family. Two years ago, Mathew’s daughter Mia was diagnosed with a brain tumor, called a “medulloblastoma,” at the age of five. Mia received surgery, months of chemotherapy, and radiation treatment, the net result of which was permanent memory, mobility and endocrine issues. Through crowd funding, Matthew Foutz has already raised $11,520 for Mia.

Thoughts From Those In the Field

The USA Today article cites several individuals who are actively involved, directly or indirectly, in the field of crowd funding.

Catherine Chapman, a philanthropic consultant with Fullanthropy, a Louisville, Ky., consulting firm that advises non-profits on charitable best practices said:

Crowd funding is doing what has always been done, but taking the technology we have to make it viral. People give on these sites often because they have been asked to do so by a friend or a friend of a friend. The personal element is a lot more compelling than sending a check to a charity. Doing that is anonymous and you can’t relate, but if it’s your friend who has cancer, you want to help.”

Daryl Hatton, the founder and CEO of FundRazr, said:

“People know who they are donating to, but one of the big surprises is that people saw how many complete strangers were donating to them. The message has to really resonate with your friends, or else it won’t go anywhere. If you don’t get that social proof, then people don’t get donations. Our natural skepticism kicks in, and they hold back on hitting that button.”

According to the USA Today article, it appears that scams are rare. “Scammers tend to lack social-media followings, as they don’t want to identify themselves,” said Hatton. “Those with integrity have networks. To give you scale, approximately one in 5,000 medical FundRazrs get shut down.”

In the end, a cancer patient can use a crowdfunding site to tell his or her story about why money is needed, using blogs and updates to keep potential donors informed. Most websites collect donations and forward them directly to the person in need. The websites can take out a small portion of the donation for administrative and other costs, which can range from 5%-20% of funds raised. It is important to note that most crowd funding websites are not tax-exempt, non-profit organizations, and therefore, donations are not considered tax-deductible.

The USA Today article provides a few common sense tips to those who may be interested in crowd funding: (i) perform thorough due diligence on various websites beyond looking for a nice appearance (i.e., evaluate news stories, customer reviews, complaints,  etc.); (ii) research online tips for writing a compelling narrative about yourself and the need for money; (iii) give frequent updates (as most blog writers learn quickly); and (iv) know that fundraising is time-consuming, but realize that you are your own best advocate.

There is a saying that “to the world you may only be one person, but to one person you may be the world.” For those of you who may be thinking about helping a cancer survivor through crowd funding, keep in mind that “grand” opportunities to help others seldom arise, but small, yet critical, opportunities surround us everyday.

Sources:

“Crowdfunding” sites pay medical bills, raise hopes, written by Cheryl Alkon, USA Today, January 14, 2013.

“Company Background,” Media Packet, The Human Tribe Project, www.humantribeproject.com.

ENMD-2076 Monotherapy Demonstrates Anti-Cancer Activity in Recurrent, Platinum-Resistant Ovarian Clear Cell Carcinoma

An Aurora A/angiogenic kinase inhibitor named “ENMD-2076” demonstrated anti-cancer activity in recurrent, platinum-resistant epithelial ovarian cancer patients, including three patients with a difficult-to-treat subtype of the disease referred to as “clear cell carcinoma.”

An Aurora A/angiogenic kinase inhibitor named “ENMD-2076” demonstrated anti-cancer activity in recurrent, platinum-resistant epithelial ovarian cancer patients, including three patients with a difficult-to-treat subtype of the disease referred to as “clear cell carcinoma.” The trial drug results were reported in connection with a phase II clinical trial testing of ENMD-2076. The findings associated with ENMD-2076 were published in the January 2013 edition of the European Journal of Cancer.

ENMD-2076 is an orally-active, Aurora A/angiogenic kinase inhibitor with a unique kinase selectivity profile and multiple mechanisms of action. ENMD-2076 has been shown to inhibit a distinct profile of angiogenic tyrosine kinase targets in addition to the Aurora A kinase. Aurora kinases are key regulators of mitosis (cell division), and are often over-expressed in human cancers. ENMD-2076 also targets the VEGFR, Flt-3 and FGFR3 kinases which have been shown to play important roles in the pathology of several cancers.

The phase II trial was an open-label, single-arm Phase II study of single agent ENMD-2076 taken daily (orally). The study enrolled 64 patients, and the progression-free survival (PFS) rate at 6 months was 22%, with a median time-to-progression of 3.6 months. The median number of prior treatment regimens per patient was two. The most common adverse events were fatigue, hypertension and diarrhea, with the most significant events being hypertension and fatigue. Unfortunately, none of the markers of mitotic index or angiogenesis evaluated in the archival tissue samples obtained were predictive of greater benefit or resistance to ENMD-2076 treatment.

Based on the foregoing results, the clinical investigators concluded that ENMD-2076 possesses anti-cancer activity in recurrent, platinum-resistant ovarian cancer, and they observed  toxicities were similar to other protein kinase inhibitors. The clinical investigators also noted that additional studies with ENMD-2076 are warranted, especially in combination with active chemotherapeutic agents in platinum-resistant patients. The investigators added that further work to determine appropriate biomarkers for ENMD-2076 should be incorporated into new clinical studies.

The co-authors of the article include clinical investigators from the Memorial Sloan-Kettering Cancer Center, Indiana University Simon Cancer Center, University of Colorado, and University of Chicago in the U.S., as well as the Princess Margaret Hospital and Campbell Family Institute for Cancer Research in Toronto, Canada.

Ursula A. Matulonis, M.D., Medical Director, Gynecologic Oncology, Dana-Farber Cancer Institute

Lead study author Dr. Ursula A. Matulonis, who is the medical director of Gynecologic Oncology at the Dana-Farber Cancer Institute, commented on the publication as follows:

“Epithelial ovarian cancer represents the 4th leading cause of cancer deaths among women in the United States. There is unmet medical needs to develop new drugs with fewer side effects and/or better efficacy to improve the quality and duration of life of the patients, especially those whose cancer is resistant to platinum treatment.

ENMD-2076 is a novel small molecule kinase inhibitor with unique combination of mechanisms of action that involve inhibition of several pathways key to tumor growth and survival including angiogenesis, proliferation, and the cell cycle. Based on pre-clinical and Phase 1 clinical studies of ENMD-2076, we believed that the drug candidate may play a role in fitting some of the unmet medical needs. This Phase 2 trial further demonstrates the anti-cancer activity of ENMD-2076 in yet a difficult to treat patient population of platinum-resistant ovarian cancer with tolerable side effects.”

Notably, Dr. Matulonis also commented on the anti-cancer activity of ENMD-2076 in three ovarian clear cell carcinoma patients as follows:

“ENMD-2076 also showed anti-cancer activities in patients with clear cell carcinoma [CCC], a histological subtype considered as chemo-resistant. Two of three [CCC] patients recruited had longer PFS than the median with one patient in stable disease for over two years. As recent reports suggest VEGF is frequently expressed in clear cell cancers, this subtype might be particularly responsive to therapies that incorporate VEGF inhibition. Further clinical evaluations of ENMD-2076 may therefore be warranted in this patient subset either as a single agent or in combinations.” [emphasis added]

Ken Ren, Ph.D., EntreMed’s Chief Executive Officer, further commented:

“We are very pleased and honored to have this Phase 2 trial data published in such an esteemed journal. This is a further endorsement of the global medical and science community on the clinical and scientific value of ENMD-2076 in ovarian cancer treatment. We truly believe that ENMD-2076 may potentially offer unique and competitive advantages for unmet medical needs in such difficult to treat oncology indications including platinum-resistant and/or clear cell ovarian cancer in improving the patients’ quality and duration of life. We are committed to the global clinical development of ENMD-2076 for cancer patients who might benefit from its therapy. With the support of clinical investigators like Dr. Matulonis, their commitment and dedication, and the support from our long term shareholders, we are confident that we can achieve our goal.”

About EntreMed

EntreMed, Inc. is a clinical-stage pharmaceutical company employing a drug development strategy primarily in the United States and China to develop targeted therapeutics for the global market. Its lead compound, ENMD-2076, a selective angiogenic kinase inhibitor, has completed several Phase 1 studies in solid tumors, multiple myeloma, and leukemia, and is currently completing a multi-center Phase 2 study in ovarian cancer. EntreMed, Inc. recently initiated a dual-institutional Phase 2 study of ENMD-2076 in triple-negative breast cancer. Additional information about EntreMed is available on the Company’s web site at www.entremed.com.

About ENMD-2076

ENMD-2076 is an orally-active, Aurora A/angiogenic kinase inhibitor with a unique kinase selectivity profile and multiple mechanisms of action. ENMD-2076 has been shown to inhibit a distinct profile of angiogenic tyrosine kinase targets in addition to the Aurora A kinase. Aurora kinases are key regulators of mitosis (cell division), and are often over-expressed in human cancers. ENMD-2076 also targets the VEGFR, Flt-3 and FGFR3 kinases which have been shown to play important roles in the pathology of several cancers. ENMD-2076 has shown promising activity in Phase 1 clinical trials in solid tumor cancers, leukemia, and multiple myeloma. ENMD-2076 is currently completing a Phase 2 trial for ovarian cancer. EntreMed, Inc. recently initiated a dual-institutional Phase 2 study of ENMD-2076 in triple-negative breast cancer.

ENMD-2076 received orphan drug designation from the United States Food and Drug Administration (FDA) for the treatment of ovarian cancer, multiple myeloma and acute myeloid leukemia (AML). In the United States, the Orphan Drug Act is intended to encourage companies to develop therapies for the treatment of diseases that affect fewer than 200,000 people in this country. Orphan drug designation provides seven years of market exclusivity that begins once ENMD-2076 receives FDA marketing approval. It also provides certain financial incentives that can help support the development of ENMD-2076.

Citation:

Matulonis UA, Lee J, Lasonde B, et. al. ENMD-2076, an oral inhibitor of angiogenic and proliferation kinases, has activity in recurrent, platinum resistant ovarian cancer. Eur J Cancer. 2013 Jan;49(1):121-31.doi:10.1016/j.ejca.2012.07.020. PubMed PMID: 22921155.

Additional Source:

Dana-Farber Cancer Institute’s Ursula A. Matulonis, M.D. Article on EntreMed’s ENMD-2076 Published in the European Journal of Cancer, EntreMed, Inc. Press Release, Sept. 6, 2012.

ENMD-2076 Phase II Ovarian Cancer Clinical Trial Protocol Summary:

A Phase 2 Study of Oral ENMD-2076 Administered to Patients With Platinum Resistant Ovarian Cancer, ClinicalTrials.gov Identifier: NCT01104675 (study ongoing, but not recruiting patients).

Glimmer of Hope: Johns Hopkins Uses Pap Smear Test Cervical Fluid to Detect Ovarian & Endometrial Cancers

Using cervical fluid obtained during routine Pap tests, scientists at the Johns Hopkins Kimmel Cancer Center have developed a test to detect ovarian and endometrial cancers. The investigators note that larger-scale studies are needed prior to clinical use on women. 

Using cervical fluid obtained during routine Pap tests, scientists at the Johns Hopkins Kimmel Cancer Center have developed a test to detect ovarian and endometrial cancers. Results of the experiments are published in the January 9 issue of the journal Science Translational Medicine.

In a pilot study, the “PapGene” test, which relies on genomic sequencing of cancer-specific mutations, accurately detected all 24 (100 percent) endometrial cancers and nine of 22 (41 percent) ovarian cancers. The endometrial cancers may have been easier to find because cells from those tumors do not have as far to travel as ovarian cancer cells. The Hopkins researchers will study whether inserting the Pap brush deeper, testing during different times of the menstrual cycle, or other factors might improve detection of ovarian cancer.

The investigators note that larger-scale studies are needed prior to clinical use on women, but they believe the test has the potential to pioneer genomic-based, cancer screening tests. [Emphasis added]

The Papanicolaou (Pap) test, during which cells collected from the cervix are examined for microscopic signs of cancer, is widely and successfully used to screen for cervical cancers. Today, many women’s Paps undergo an additional DNA-based test to see if they harbor the human papillomavirus (HPV), which can spur cervical cancer. However, no routine screening method is available for ovarian or endometrial cancers.

Luis Alberto Diaz, M.D.

Since the Pap test occasionally contains cells shed from the ovaries or endometrium, cancer cells arising from these organs could be present in the fluid as well, says Luis Diaz, M.D., associate professor of oncology at Johns Hopkins, as well as director of translational medicine at the Ludwig Center for Cancer Genetics and Therapeutics and director of the Swim Across America Laboratory, also at Johns Hopkins. The laboratory is sponsored by a volunteer organization that raises funds for cancer research through swim events. “Our genomic sequencing approach may offer the potential to detect these cancer cells in a scalable and cost-effective way,” adds Diaz.

Hear Dr. Diaz discuss the PapGene test research in this hyperlinked podcast, courtesy of the American Association for the Advancement of Science.

Cervical fluid of patients with gynecologic cancer carries normal cellular DNA mixed together with DNA from cancer cells, according to the investigators. The investigators’ task was to use genomic sequencing to distinguish cancerous from normal DNA.

The scientists had to determine the most common genetic changes in ovarian and endometrial cancers in order to prioritize which genomic regions to include in their test. They searched publicly available genome-wide studies of ovarian cancer, including those done by other Johns Hopkins investigators, to find mutations specific to ovarian cancer. Such genome-wide studies were not available for the most common type of endometrial cancer, so they conducted genome-wide sequencing studies on 22 of these endometrial cancers.

From the ovarian and endometrial cancer genome data, the Johns Hopkins-led team identified 12 of the most frequently mutated genes in both cancers and developed the PapGene test with this insight in mind.

The investigators then applied PapGene on Pap test samples from ovarian and endometrial cancer patients at The Johns Hopkins Hospital, Memorial Sloan-Kettering Cancer Center, the University of São Paulo in Brazil and ILSbio, a tissue bank. The new test detected both early- and late-stage disease in the endometrial and ovarian cancers tested. No healthy women in the control group were misclassified as having cancer.

Animation of PapGene:

Looking ahead, the investigators’ next steps include applying PapGene on more samples and working to increase the test’s sensitivity in detecting ovarian cancer. “Performing the test at different times during the menstrual cycle, inserting the cervical brush deeper into the cervical canal, and assessing more regions of the genome may boost the sensitivity,” says Chetan Bettegowda, M.D., Ph.D., assistant professor of neurosurgery at Johns Hopkins and a member of the Ludwig Center as well.

Together, ovarian and endometrial cancers are diagnosed in nearly 70,000 women in the United States each year, and about one-third of them will die from it. “Genomic-based tests could help detect ovarian and endometrial cancers early enough to cure more of them,” says graduate student Yuxuan Wang, who notes that the cost of the test could be similar to current cervical fluid HPV testing, which is less than $100.

PapGene is a high-sensitivity approach for the detection of cancer-specific DNA mutations, according to the investigators; however, false mutations can be erroneously created during the many steps — including amplification, sequencing and analysis — required to prepare the DNA collected from a Pap test specimen for sequencing. This required the investigators to build a safeguard into PapGene’s sequencing method, designed to weed out artifacts that could lead to misleading test results.

“If unaccounted for, artifacts could lead to a false positive test result and incorrectly indicate that a healthy person has cancer,” says graduate student Isaac Kinde.

Kinde added a unique genetic barcode — a random set of 14 DNA base pairs — to each DNA fragment at an initial stage of the sample preparation process. Although each DNA fragment is copied many times before eventually being sequenced, all of the newly copied DNA can be traced back to one original DNA molecule through their genetic barcodes. If the copies originating from the same DNA molecule do not all contain the same mutation, then an artifact is suspected and the mutation is disregarded. However, bonafide mutations, which exist in the sample before the initial barcoding step, will be present in all of the copies originating from the original DNA molecule.

The Johns Hopkins test results demonstrate that DNA from most endometrial and a fraction of ovarian cancers can be detected in a standard liquid-based Pap smear specimen obtained during routine pelvic examination. Although improvements need to be made before applying this test in a routine clinical manner, it represents a promising first step toward a broadly applicable screening methodology for the early detection of gynecologic malignancies.

“This is very encouraging, and it shows great potential,” said American Cancer Society genetics expert Michael Melner.

“We are a long way from being able to see any impact on our patients,” cautioned Dr. Shannon N. Westin of the University of Texas MD Anderson Cancer Center. Dr. Westin reviewed the research in an accompanying editorial, and said the ovarian cancer detection would need improvement if the test is to work. But Dr. Westin noted that ovarian cancer has poor survival rates because it’s rarely caught early. “If this screening test could identify ovarian cancer at an early stage, there would be a profound impact on patient outcomes and mortality,” Westin said.

More than 22,000 U.S. women are diagnosed with ovarian cancer each year, and more than 15,000 die. Symptoms such as bloating and pelvic or abdominal pain are seldom obvious until the cancer is more advanced, and numerous attempts at screening tests have failed.

Endometrial cancer affects about 47,000 U.S. women a year, and kills about 8,000. There is no screening test for it either, but most women are diagnosed early because of postmenopausal bleeding.

___________________________

Funding for the research was provided by Swim Across America, the Commonwealth Fund, the Hilton-Ludwig Cancer Prevention Initiative, the Virginia & D.K. Ludwig Fund for Cancer Research, the Experimental Therapeutics Center of the Memorial Sloan-Kettering Cancer Center, the Chia Family Foundation, The Honorable Tina Brozman Foundation, the United Negro College Fund/Merck Graduate Science Research Dissertation Fellowship, the Burroughs Wellcome Career Award for Medical Scientists, the National Colorectal Cancer Research Alliance and the National Institutes of Health’s National Cancer Institute (N01-CN-43309, CA129825, CA43460).

In addition to Kinde, Bettegowda, Wang and Diaz, investigators participating in the research include Jian Wu, Nishant Agrawal, Ie-Ming Shih, Robert Kurman, Robert Giuntoli, Richard Roden and James R. Eshleman from Johns Hopkins; Nickolas Papadopoulos, Kenneth Kinzler and Bert Vogelstein from the Ludwig Center at Johns Hopkins; Fanny Dao and Douglas A. Levine from Memorial Sloan-Kettering Cancer Center; and Jesus Paula Carvalho and Suely Kazue Nagahashi Marie from the University of São Paulo.

Papadopoulos, Kinzler, Vogelstein and Diaz are co-founders of Inostics and Personal Genome Diagnostics. They own stocks in the companies and are members of their Scientific Advisory Boards. Inostics and Personal Genome Diagnostics have licensed several patent applications from Johns Hopkins. These relationships are subject to certain restrictions under The Johns Hopkins University policy, and the terms of these arrangements are managed by the university in accordance with its conflict-of-interest policies.

____________________________

Citations:

I. Kinde, C. Bettegowda, Y. Wang, J. et. al. Evaluation of DNA from the Papanicolaou Test to Detect Ovarian and Endometrial Cancers. Sci. Transl. Med. 5, 167ra4 (2013).

S. N. Westin, G. B. Mills, A. P. Myers, Repurposing the Pap Smear: One Step Closer to Gynecologic Cancer Screening. Sci. Transl. Med. 5, 167ps1 (2013).

Additional Sources:

Johns Hopkins Scients Use Pap Test Fluid to Detect Ovarian, Endometrial Cancers, John Hopkins Medicine, Press Release, January 9, 2013.

Retooling Pap Test To Spot More Kinds Of Cancer, The Associated Press via National Public Radio, January 9, 2013.

“Whither Thou Goest, I Will Go …”

Today, we celebrate the life of Elizabeth (“Libby”) Remick on the fourth anniversary of her passing — July 28, 2008.

Elizabeth Kay Remick (1982 – 2008)

Today, we celebrate the life of Elizabeth (“Libby”) Remick on the fourth anniversary of her passing — July 28, 2008. Libby was only 26 years old when she died from ovarian clear cell cancer. The Libby’s H*O*P*E* website is dedicated to Elizabeth’s memory.

Some people come into our lives and quickly go.
Some people stay for awhile,
and move our souls to dance.
They awaken us to a new understanding,
leave footprints on our hearts,
and we are never, ever the same.
— Flavia Weedn

As many of you know, we consider Libby the driving force and inspiration behind our ongoing support work for ovarian cancer survivors and their families. Libby’s spirit inspires us on a daily basis. We believe that Libby’s eternal love and support of ovarian cancer survivors and their families are limitless; this is especially true when the situation is labeled “hopeless.” We were reminded of this fact earlier this week after coming across a touching story dating back to 1940, which epitomizes the close and unbreakable bond between the U.S. and Great Britain — quite apropos given the opening of the 2012 Summer Olympics in London yesterday.

Between September 7, 1940 and May 16, 1941, the German Luftwaffe (air force) engaged in a bombing campaign designed to demoralize the British people into surrender while destroying the country’s economic war production. At one point, London (and 16 other British cities) were bombed on 57 consecutive nights during the German air campaign. As a result of the German raids, more than 40,000 civilians (almost half of them in London) were killed, and more than one million London homes were destroyed or damaged.  The history books simply refer to this desperate and seemingly hopeless time period in England as “the Blitz” (derived from the German word “blitzkrieg,” meaning “lighting war”).

During this extremely difficult time period, Winston Churchill, England’s Prime Minister, knew that he had to rouse the British people to resist Adolf Hitler’s armed forces. Churchill also understood that England alone could not defeat Germany, and he recognized early on that the assistance of the U.S. would be necessary for ultimate victory. Churchill eagerly sought out U.S. assistance, and ultimately, American participation in support of England’s war effort.

The actions taken by Churchill to encourage U.S. assistance included welcoming the emissaries that were sent by President Franklin D. Roosevelt; foremost among them was Harry L. Hopkins. As Roosevelt’s closest wartime aide, Harry Hopkins played a crucial role in nurturing the Anglo-American partnership. At the direction of President Roosevelt, Harry Hopkins journeyed to England in the midst of the Blitz, and he later convinced the U.S. President that Churchill and the British people would fight on to the end, and therefore, must be supported at any cost.  During Hopkins’ visit, he spoke directly to Churchill about America’s strong support of England, regardless of the circumstances.

In January 1941, at the end of his visit with Churchill, Harry Hopkins summarized American support, as part of a dinner toast, by referencing the unbreakable bond of loyalty cited in the Book of Ruth 1:16, which begins with Ruth’s plea to a close family relative during difficult times: ” Intreat me not to leave thee, or to return from following after thee …”  In his toast, and with a deeply emotional tone, Hopkins simply recited the remainder of that biblical verse:

“‘Whither thou goest, I will go; and where thou lodgest, I will lodge: thy people shall be my people, and thy God my God’ — even to the end.”

According to those present at the dinner, Hopkins’ vow of American loyalty reduced the English Prime Minister to tears. Winston Churchill knew exactly what Hopkins meant, and he later stated: “Harry Hopkins’ impromptu sermon seemed like a rope thrown to a drowning man.” In the end, Hitler’s Blitz did not achieve its intended goal of demoralizing the British people into surrender; rather, it caused them to unite among themselves and forge an unbreakable bond with the U.S., which led to ultimate victory.

We know that if Libby were alive today, she would extend the same loyalty, perseverance, hope, and support towards ovarian cancer survivors and their families, similar to that cited in The Book of Ruth 1:16.  Libby’s H*O*P*E* represents the physical manifestation of Libby’s spirit, including the steadfast support of all ovarian cancer survivors and their families during difficult times.

Although Libby is no longer physically present among us, a traditional Native American Prayer reminds us that she remains forever present in our lives:

I give you this one thought to keep –
I am with you still – I do not sleep.
I am a thousand winds that blow,
I am the diamond glints on snow,
I am the sunlight on ripened grain,
I am the gentle autumn rain.
When you awaken in the morning’s hush,
I am the sweet uplifting rush,
of quiet birds in circled flight.
I am the soft stars that shine at night.
Do not think of me as gone –
I am with you still in each new dawn.

— Traditional Native American Prayer

Libby, we love you, miss you, and will never forget you. We do not think of you “as gone,” and we know that you are with us “in each new dawn.” Thank you for your life and eternal inspiration.

___________________

Related Libby’s H*O*P*E*™ Postings:

• The Mirror: “What is the Meaning of Life?”, by Paul Cacciatore, July 28, 2011.

• “Smile, Open Your Eyes, Love and Go On.,” by Paul Cacciatore, July 28, 2010.

• Vox Populi*: Libby, We’ll Be Missing You, by Paul Cacciatore, July 28, 2009.

• A Requiem Hallelujah, But Don’t Let There Be a Hole in the World Tomorrow, by Paul Cacciatore, July 28, 2008.

Proposed Federal Gov’t Rule Adds Ovarian Cancer to 9/11 World Trade Center Health Program List of Covered Conditions

On June 13, 2012, the federal government will publish a proposed rule that will add ovarian cancer to the list of conditions covered by the World Trade Center Health Program. It is anticipated that the proposed rule will take several months to finalize prior to becoming effective. The WTC Health Program was established by the James Zadroga 9/11 Health and Compensation Act of 2010, which provides health benefits and financial compensation to those harmed by the attacks of September 11th and its aftermath.

The World Trade Center Health Program (WTC Health Program) was established by the James Zadroga 9/11 Health and Compensation Act of 2010, which provides health benefits and financial compensation to those harmed by the attacks of September 11th and its aftermath.

The WTC Health Program provides services to responders, workers, and volunteers who helped with rescue, recovery, and cleanup at the World Trade Center and related sites located within the defined “New York City disaster area.” It also provides services for survivors who lived, worked, or were attending school in the area. The WTC Health Program will also be serving responders to the 9/11 attacks at the Pentagon in Arlington, Virginia, and the Flight 93 crash site in Shanksville, Pennsylvania

The WTC Health Program is administered by the National Institute for Occupational Safety and Health (NIOSH). After conducting a long-term study, NIOSH stated in a recent administrative filing that it favored a major expansion of the existing $4.3 billion WTC Health Program to include eligible individuals with 50 types of cancer, covering 14 broad categories of the disease. The specifics underlying NIOSH’s administrative decision will be published on June 13, 2012 in the Federal Register as a Notice of Proposed Rulemaking, entitled World Trade Center Health Program; Addition of Certain Types of Cancer to List of WTC-Related Health Conditions. Within the proposed rule, ovarian cancer (i.e., “malignant neoplasms of the ovary”) is listed as one of the enumerated cancer types.

Pursuant to NIOSH’s proposed rule, the WTC Health Program will provide medical testing and care for specific symptoms and illnesses related to being exposed to the disaster sites. The services will be provided by clinics and hospitals that have expertise in the diagnosis and treatment of 9/11-related health conditions.

It is important to note that NIOSH’s proposed rule does not represent a final administrative determination. The Notice of Proposed Rulemaking is subject to public review and a 30-day comment period. Once public comment is received, NIOSH will consider and address those comments as appropriate before issuing a final ruling. The proposed rule may change prior to finalization, or it may not be finalized at all.

If NIOSH determines that it is appropriate to issue a final rule to cover select cancer types, and a final rule is published, additional steps would be necessary before an eligible responder or survivor could receive care and treatment under the WTC Health Program. The physician diagnosing the cancer would be responsible for reviewing the individual’s exposure history to determine whether her cancer could be related to a 9/11 exposure; the individual’s diagnosis must then be certified by NIOSH before care and treatment can begin.

Sources:

• Statement from WTC Program Administrator John Howard, M.D., The National Institute for Occupational Safety and Health, Centers for Disease Control & Prevention, U.S. Department of Health & Human Services, June 8, 2012.

• World Trade Center Health Program.

• World Trade Center Health Program; Addition of Certain Types of Cancer to List of WTC-Related Health Conditions, Federal Register Notice of Proposed Rulemaking, June 13, 2012. (Pre-publication PDF copy)

Preclinical Testing Suggests That Apoptosis Protein Inhibitor AT-406 Is Effective Against Ovarian Cancer; Initial Phase I Solid Tumor Clinical Trial Ongoing

In preclinical testing, Mount Sinai School of Medicine researchers demonstrated the anti-ovarian cancer effectiveness of AT-406, an inhibitor of apoptosis proteins, as a single agent and in the combination with carboplatin.  As of this writing, Ascenta Therapeutics is conducting an open and ongoing phase I clinical study in patients with advanced solid tumors and lymphomas.

Apoptosis Proteins: A Promising Target For Cancer Therapeutics?

Apoptosis increasing from normal cells (top) to apoptotic ones (bottom). (Photo: Wikipedia)

Human cells are programmed to survive, die or proliferate through a complex system of regulatory controls.  Apoptosis — also know as “programmed cell death” — is a precisely regulated, complex process through which normal cells in the body die after a given life span, ensuring that defective, damaged, or redundant cells are eliminated.

The human body use apoptosis, or programmed cell death, to eliminate abnormal or unwanted cells. As a result of accumulated genomic alterations, it seems that cancer cells often fail to execute an apoptotic program, which allows them to live indefinitely and grow uncontrollably. The breakdown of the cellular apoptosis regulatory machinery is sometimes a dominant characteristic of cancer. Many current cancer therapies, including chemotherapeutic agents, radiation, and immunotherapy, work by inducing apoptosis in cancer cells. However, because the normal apoptotic biological pathways are sometimes defective, many cancer cells are inherently resistant or develop resistance to various therapies.  An emerging direction for drug development involves the direct targeting of apoptotic proteins to induce cell death and/or reduce treatment resistance.

AT-406 — A New Inhibitor of Apoptosis Proteins — is Effective in Preclinical Testing Against Ovarian Cancer.

(Photo: University of Michigan Heath System)

AT-406 is a novel and orally-active small molecule drug designed to promote programmed cell death (apoptosis) in tumor cells by blocking the activity of inhibitors of apoptosis proteins (IAPs), including XIAP, c-IAP1, c-IAP2, and ML-IAP, to create conditions in which apoptosis can proceed.  Based on this designed activity, AT-406 is best described as a multi-IAP inhibitor. IAPs are key components of the complex cascade of protein signaling that activates enzymes (called “caspases“) to initiate the breakdown of the cancer cell. AT-406 is thought to mimic the activity of Smac (second mitochondria-derived activator of caspases) by binding to XIAP and preventing it from inhibiting caspase activation. Upon binding to cIAP1 and cIAP2, AT-406 induces rapid degradation of these proteins and promotes apoptosis through activation of the death-receptor complex and caspase 8.

Ascenta Therapeutics (Ascenta), the developer of AT-406, reported that the drug has already demonstrated single-agent antitumor activity in multiple preclinical xenograft models of human cancer, including breast cancer, pancreatic cancer, prostate cancer, and lung cancer. Ascenta also noted that AT-406 has also been shown to work synergistically with conventional chemotherapeutic and targeted agents (such as TRAIL and tyrosine kinase inhibitors) in preclinical tumor models.

Mount Sinai School of Medicine researchers evaluated AT-406 in ovarian cancer cells as a single agent, and in the combination with carboplatin, for therapeutic effectiveness and mechanism of action. The researchers reported that AT-406 had significant single agent activity in 60% of the human ovarian cancer cell lines examined in vitro, and inhibited ovarian cancer progression in vivo. Notably, three of the five carboplatin-resistant cell lines tested sensitive to AT-406, thereby highlighting the therapeutic potential of AT-406 for patients with inherent or acquired platinum drug resistance.

Additionally, the researchers also determined that AT-406 enhanced carboplatin-induced ovarian cancer cell death and increased the survival of the experimental in vivo test mice. This result suggests a synergy created by this two drug  combination, whereby AT-406 sensitizes the response of these cancer cells to carboplatin. From a mechanism of action perspective, the researchers demonstrated that AT-406 induced apoptosis correlated with the drug’s ability to down-regulate XIAP,  whereby AT-406 induces cIAP1 degradation in both AT-406 sensitive and resistant cell lines. Collectively, these results demonstrate, for the first time, the anti-ovarian cancer efficacy of AT-406 as a single agent and in the combination with carboplatin. The researchers believe that AT-406 may represent a novel therapy for ovarian cancer patients, especially for patients exhibiting resistance to the platinum-based therapies.

Initial Phase I Clinical Study of AT-406 in Patients With Advanced Solid Tumors & Lymphomas

Ascenta is currently conducting clinical trials of AT-406 within the U.S. in patients with a variety of solid tumors and lymphomas. As of this writing, Ascenta is conducting a phase I, dose-escalation, open-label, multi-center study (University of Michigan Comprehensive Cancer Center, Mayo Clinic, and Duke University Medical Center) in patients with advanced solid tumors and lymphomas to evaluate the safety, tolerability and pharmacology of AT-406 when administered orally. The ClinicalTrials.gov Identifier Number for this trial is NCT01078649.

It is important to note that phase I trials usually enroll a small numbers of patients who have advanced cancer that cannot be treated effectively with standard treatments, or for which no standard treatment exists. Although evaluating the effectiveness of a drug is the primary goal of a phase II (not phase I) clinical study, medical investigators do look for evidence that the study treatment might be useful in a phase I clinical study.

Sources:

• Brunckhorst MK, et al. AT-406, an orally active antagonist of multiple inhibitor of apoptosis proteins, inhibits progression of human ovarian cancer. Cancer Biol Ther. 2012 Jul 1;13(9). [Epub ahead of print] PMID: 22669575.

• AT-406 Clinical Trial Protocol Summary: A Phase I, Open Label, Multi-Center, Dose Escalation Study of the Safety, Tolerability, Pharmacodynamic and Pharmacokinetic Properties of Orally Administered AT-406 in Patients With Advanced Solid Tumors and Lymphomas; ClinicalTrials.gov Identifier: NCT01078649.

U.S. Food & Drug Administration Acts to Bolster Supply of Critically Needed Cancer Drugs Including Doxil

The U.S. Food and Drug Administration today announced a series of steps to (i) increase the supply of critically needed cancer drugs, and (ii) build upon President Obama’s Executive Order to help prevent future drug shortages.  To alleviate the Doxil cancer drug shortage, the FDA approved  the temporary importation of a replacement drug named “Lipodox” (doxorubicin hydrochloride liposome injection), with the expectation of  ending the U.S. shortage and fully meeting patient needs in the coming weeks. Doxil is an important weapon in the fight against recurrent ovarian cancer.

The U.S. Food and Drug Administration today announced a series of steps designed to increase the supply of critically needed cancer drugs, and build upon President Obama’s Executive Order, dated October 31, 2011 (No. 13588), in an attempt to prevent future drug shortages.

Margaret Hamburg, M.D., Commissioner, U.S. Food & Drug Administration

“A drug shortage can be a frightening prospect for patients and President Obama made it clear that preventing these shortages from happening is a top priority of his administration,” said FDA Commissioner Margaret A. Hamburg, M.D. “Through the collaborative work of the FDA, industry, and other stakeholders, patients and families waiting for these products or anxious about their availability should now be able to get the medication they need.”

In response to the critical shortage of the cancer drug Doxil (doxorubicin hydrochloride liposome injection) and rapidly declining supplies of methotrexate, the FDA took proactive steps needed to increase available supply for patients in the U.S.

For Doxil, there will be temporary importation of a replacement drug named “LipoDox” (doxorubicin hydrochloride liposome injection), which is expected to end the shortage and fully meet patient needs in the coming weeks.

For methotrexate, in addition to already announced actions, the FDA approved a new manufacturer of preservative-free formulation of methotrexate that is expected to further bolster supply and help avert a shortage of this lifesaving medicine. the FDA expedited review of the application to help address this potential shortage.

In response to President Obama’s Executive Order #13588 regarding prescription drug shortages, the FDA today issued draft guidance to industry which provides detailed requirements for both mandatory and voluntary notifications to the FDA of issues that could result in a drug shortage or supply disruption. Because of President Obama’s Executive Order #13588 and the FDA’s letter to manufacturers on the same day, increased awareness of the importance of early notification has resulted in a sixfold increase in voluntary notifications by industry of potential shortages. In 2011, there were a total of 195 drug shortages prevented. Since the issuance of Presidential Executive Order #13588, the FDA has prevented 114 drug shortages.

Under the FDA’s exercise of enforcement discretion, the chemotherapeutic drug LipoDox will be imported as an alternative to Doxil. Doxil is used in multiple treatment regimens, including treatment of ovarian cancer after failure of platinum-based chemotherapy (e.g., carboplatin or cisplatin). The drug is also indicated for use in AIDS-related Kaposi’s sarcoma and multiple myeloma. The FDA anticipates that the incoming supply of LipoDox will be able to fully meet patient needs.

The FDA’s exercise of enforcement discretion for Lipodox is a temporary, limited arrangement specific to Sun Pharma Global FZE (a United Arab Emirates entity) and its authorized distributor, Caraco Pharmaceutical Laboratories Ltd. (a U.S. subsidiary of Sun Pharmaceutical Industries Ltd., a leading Indian pharmaceutical company).

Temporary importation of unapproved foreign drugs is considered in rare cases when there is a shortage of an approved drug that is critical to patients and the shortage cannot be resolved in a timely fashion with FDA-approved drugs.

When a company is identified that is willing and able to import the needed drug product, the FDA evaluates the foreign-approved drug to ensure that it is of adequate quality and that the drug does not pose significant risks for U.S. patients. Only after successful evaluation of these factors does the FDA exercise its enforcement discretion for the temporary importation of an overseas drug into the U.S. market.

Methotrexate is a drug that is needed for the treatment of many forms of cancer and other serious diseases. For example, preservative-free methotrexate is needed for the intrathecal (injection into the fluid surrounding the brain and spinal cord) treatment of children with acute lymphocytic leukemia (ALL), as well as high-dose therapy of osteosarcoma.

To alleviate the shortage of methotrexate, the FDA has successfully engaged several firms to assist in maintaining supplies to meet all patient needs. First, the FDA has prioritized the review and approval of a preservative-free methotrexate generic drug manufactured by APP Pharmaceuticals (APP) and expects that product to become available in March 2012 and continue indefinitely. Second, Hospira expedited release of additional methotrexate supplies, resulting in 31,000 vials of new product – enough for more than one month’s worth of demand – being shipped to hundreds of U.S. hospitals and treatment centers today. The FDA is actively working with other manufacturers of methotrexate who have also stepped up to increase drug production for the purpose of meeting patient needs, including Mylan and Sandoz Pharmaceuticals.

APP’s application for preservative-free methotrexate is a supplement to its already approved generic drug application that the firm had previously discontinued. When the FDA became aware of potential problems with the supply of the drug (attributable to the voluntary plant closing of the largest methotrexate manufacturer, Ben Venue Laboratories), the agency reached out to other firms to see how the FDA could assist to meet the shortfall.

Prior to the approval of APP’s application, and the subsequent Ben Venue Laboratories’ voluntary shutdown, the FDA worked with Ben Venue on release of already manufactured preservative-free methotrexate, following its confirmation of the safety of remaining drug inventory. This supply is available already and will provide emergency supplies as the other firms also work to increase production of methotrexate in response to requests by the FDA and the public.

On October 31, 2011, the Obama Administration also announced its support for bipartisan legislation that would (i) require all prescription drug shortages to be reported to the FDA, and (ii) give the FDA new authority to enforce these requirements. While additional manufacturing capacity is necessary to fully address the drug shortage problem, additional early notification to the FDA can have a significant, positive impact on addressing the incidence and duration of drug shortages.

For more FDA information relating to the U.S. drug shortage, please click on the topics listed below:

Drug Shortages

Drug Shortage Guidance (“Guidance for Industry — Notification to FDA of Issues that May Result in a Prescription Drug or Biological Product Shortage – Draft Guidance,” dated February 2012)

Labeling for Doxil (doxorubicin hydrochloride liposome injection)

Letter from Sun Pharma Global FZE to healthcare professionals regarding doxorubicin, dated January 27, 2012.

FDA letter to Industry regarding drug shortage, dated October 31, 2011.

Labeling for methotrexate

Consumer Inquiries: 888-INFO-FDA

About the U.S. Food & Drug Administration (FDA)

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The FDA is also responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

Source: FDA acts to bolster supply of critically needed cancer drugs, FDA News Release, U.S. Food & Drug Administration, February 21, 2012.