On the Path to Early Detection: Fox Chase & Sloan-Kettering Researchers Identify Early Ovarian Cancers

Researchers at the Fox Chase Cancer Center and the Memorial Sloan-Kettering Cancer Center discover early tumors and precancerous lesions in cysts that fold into the ovary from its surface, called inclusion cysts. “This is the first study giving very strong evidence that a substantial number of ovarian cancers arise in inclusion cysts and that there is indeed a precursor lesion that you can see, put your hands on, and give a name to,” says Jeff Boyd, PhD, Chief Scientific Officer at Fox Chase and lead author on the study …

Ovarian cancer kills nearly 15,000 women in the United States each year, and fewer than half of the women diagnosed with the disease survive five years. A screening test that detects ovarian cancer early, when it is still treatable, would likely reduce the high mortality, yet scientists have not known where the tumors originate or what they look like. Now, researchers at Fox Chase Cancer Center think they have answered both questions. The study, published on April 26th in PLoS ONE, reports that they have uncovered early tumors and precancerous lesions in cysts that fold into the ovary from its surface, called inclusion cysts.

Jeff Boyd, Ph.D., Professor, Chief Scientific Officer & Senior Vice President, The Robert C. Young, MD, Chair in Cancer Research, Fox Chase Cancer Center

“This is the first study giving very strong evidence that a substantial number of ovarian cancers arise in inclusion cysts and that there is indeed a precursor lesion that you can see, put your hands on, and give a name to,” says Jeff Boyd, PhD, Chief Scientific Officer at Fox Chase and lead author on the study, which also involved colleagues at the Memorial Sloan-Kettering Cancer Center. “Ovarian cancer most of the time seems to arise in simple inclusion cysts of the ovary, as opposed to the surface epithelium.”

Clinicians and researchers have been looking for early ovarian tumors and the precancerous lesions from which they develop for years without success. In this study, Boyd and colleagues used a combination of traditional microscopy and molecular approaches to reveal the early cancers.

“Previous studies only looked at this at the morphologic level, looking at a piece of tissue under a microscope,” Boyd says. “We did that but we also dissected away cells from normal ovaries and early stage cancers, and did genetic analyses. We showed that you could follow progression from normal cells to the precursor lesion, which we call dysplasia, to the actual cancer, and see them adjacent to one another within an inclusion cyst.”

To learn where and how the tumors arise, the team examined ovaries removed from women with BRCA mutations, who have a 40% lifetime risk of developing ovarian cancer, and from women without known genetic risk factors. In both groups, they found that gene expression patterns were dramatically different in cells in the inclusion cysts compared to the normal surface epithelium cells, including increased expression of genes that control cell division and chromosome movement.

Moreover, when they used a technique called FISH (fluorescence in situ hybridization), which can be used to identify individual chromosomes in cells, they saw that cells from very early tumors and precursor lesions frequently carried extra chromosomes. In fact, the team found that 9% of the normal cells isolated from the cysts had extra chromosomes, even though the tissue appeared completely benign under the microscope. By contrast, virtually none of the cells isolated from the surface of the ovary, which was previously thought to be the site of early ovarian cancers, carried extra chromosomes.

With these new data on the origin of ovarian cancer in hand, Boyd and others can now start to develop screening tests, perhaps based on molecular imaging, that could be used to detect early ovarian cancers in asymptomatic women.

Co-authors on the study include Bhavana Pothuri, Mario M. Leitao, Douglas A. Levine, Agnès Viale, Adam B. Olshen, Crispinita Arroyo, Faina Bogomolniy, Narciso Olvera, Oscar Lin, Robert A. Soslow, Mark E. Robson, Kenneth Offit, and Richard R. Barakat of Memorial Sloan-Kettering Cancer Center.

About the Fox Chase Cancer Center

Fox Chase Cancer Center is one of the leading cancer research and treatments centers in the United States. Founded in 1904 in Philadelphia as one of the nation’s first cancer hospitals, Fox Chase was also among the first institutions to be designated a National Cancer Institute Comprehensive Cancer Center in 1974. Fox Chase researchers have won the highest awards in their fields, including two Nobel Prizes. Fox Chase physicians are also routinely recognized in national rankings, and the Center’s nursing program has received the Magnet status for excellence three consecutive times. Today, Fox Chase conducts a broad array of nationally competitive basic, translational, and clinical research, with special programs in cancer prevention, detection, survivorship, and community outreach. For more information, call 1-888-FOX-CHASE or 1-888-369-2427.

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Princeton Scientists Find Way To Catalog All That Goes Wrong In A Cancer Cell

A team of Princeton University scientists has produced a systematic listing of the ways a particular cancerous cell has “gone wrong,” giving researchers a powerful tool that eventually could make possible new, more targeted therapies for patients.

A team of Princeton University scientists has produced a systematic listing of the ways a particular cancerous cell has “gone wrong,” giving researchers a powerful tool that eventually could make possible new, more targeted therapies for patients.

Saeed Tavazoie is a professor in the Princeton University Department of Molecular Biology & the Lewis-Sigler Institute for Integrative Genomics

“For a very long time, cancer therapies have been developed by trial and error to essentially kill a broad variety of rapidly dividing cells, good and bad — that’s why they have massive side effects,” said Saeed Tavazoie, a professor in the Department of Molecular Biology and the Lewis-Sigler Institute for Integrative Genomics, who led the research. “The goal of cancer biology is to come up with therapies that are much more rational in terms of attacking the pathways that have been co-opted by cancer cells. The big challenge is to discover these pathways so that we can restore them to their normal state.”

Writing in the Dec. 11 issue of Molecular Cell, Tavazoie, along with his colleagues Hani Goodarzi, a graduate student in molecular biology, and Olivier Elemento, a former postdoctoral researcher in the department, found they were able to systematically categorize and pinpoint the alterations in cancer pathways and to reveal the underlying regulatory code in DNA. Elemento is now on the faculty of Weill Cornell Medical College in New York.

“We are discovering that there are many components inside the cell that can get mutated and give rise to cancer,” Tavazoie said. “Future cancer therapies have to take into account these specific pathways that have been mutated in individual cancers and treat patients specifically for that.”

The researchers developed an algorithm, a problem-solving computer program that sorts through the behavior of each of 20,000 genes operating in a tumor cell. When genes are turned “on,” they activate or “expressproteins that serve as signals, creating different pathways of action. Cancer cells often act in aberrant ways, and the algorithm can detect these subtle changes and track all of them.

“At the present moment, we lump a lot of cancers together and use the same therapy,” Tavazoie said. “In the future, we are aiming to be much more precise about treating the exact processes that were perturbed by the mutations.”

Pathologists presently examining the tumors of sick patients analyze a small set of tumor characteristics in order to determine the diagnostic and prognostic class to which the cells belong. This new method could give practitioners an encyclopedic accounting of the alterations in problem cells, spelling out the nature of the disease in much greater detail.

The algorithm devised by the group scans the DNA sequence of a given cell — its genome — and deciphers which sequences are controlling what pathways and whether any are acting differently from the norm. By deciphering the patterns, the scientists can conjure up the genetic regulatory code that is underlying a particular cancer.

The scientists developed the technique by employing modern methods of systems biology, where researchers seek to understand how components of living systems like cells work together to orchestrate processes, using powerful computers to sort vast arrays of data.

“Part of the promise of genomics and systems biology is the discovery of specific pathways of disease and finding ways to target them precisely,” Tavazoie said. “We have focused on revealing what these pathways are.”

The challenge for others, he said, will be to design specific therapies for such diseases, a process that could take many years. “This is an important first step,” Tavazoie added.

The method ultimately could work for any type of cancer and paves the way for rational approaches to treating a host of other diseases from diabetes to neurological disorders, the scientists said.

The research was funded by the National Human Genome Research Institute of the National Institutes of Health.

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MAGP2 Gene Expression Signature: A Potential Ovarian Cancer Personalized Treatment Target

A multi-institutional study has identified a potential personalized treatment target for the most common form of ovarian cancer. In the December 8 issue of Cancer Cell, the research team describes finding that a gene called MAGP2 – not previously associated with any type of cancer – was overexpressed in papillary serous ovarian tumors of patients who died more quickly. They also found evidence suggesting possible mechanisms by which MAGP2 may promote tumor growth.

A multi-institutional study has identified a potential personalized treatment target for the most common form of ovarian cancer. In the December 8 issue of Cancer Cell, the research team describes finding that a gene called MAGP2 (microfibril-associated glycoprotein 2) – not previously associated with any type of cancer – was overexpressed in papillary serous ovarian tumors of patients who died more quickly. They also found evidence suggesting possible mechanisms by which MAGP2 may promote tumor growth.

Michael Birrer, MD, Ph.D., Professor, Department of Medicine, Harvard Medical School; Director GYN/Medical Oncology, Medicine, Massachusetts General Hospital

“Ovarian cancer is typically diagnosed at an advanced stage when it is incurable, and the same treatments have been used for virtually all patients,” says Michael Birrer, MD, PhD, director of medical gynecologic oncology in the Massachusetts General Hospital (MGH) Cancer Center, and the study’s corresponding author. “Previous research from my lab indicated that different types and grades of ovarian tumors should be treated differently, and this paper now shows that even papillary serous tumors have differences that impact patient prognosis.” Birrer was with the National Institutes of Health when this study began but later joined the MGH Cancer Center.

The fifth most common malignancy among U.S. women, ovarian cancer is expected to cause approximately 15,000 deaths during 2009. Accounting for 60 percent of ovarian cancers, papillary serous tumors are typically diagnosed after spreading beyond the ovaries. The tumors typically return after initial treatment with surgery and chemotherapy, but while some patients die a few months after diagnosis, others may survive five years or longer while receiving treatment.

To search for genes expressed at different levels in ovarian cancer patients with different survival histories, which could be targets for new treatments, the researchers conducted whole-genome profiling of tissue samples that had been microdissected – reducing the presence of non-tumor cells – from 53 advanced papillary serous ovarian cancer tumors. Of 16 genes that appeared to have tumor-associated expression levels, MAGP2 had the strongest correlation with reduced patient survival.

Further analysis confirmed that MAGP2 expression was elevated in another group of malignant ovarian cancer tumors but not in normal tissue. MAGP2 gene expression was also reduced in patients whose tumors responded to chemotherapy. Recombinant expression of MAGP2 in samples of the endothelial cells that line blood vessels caused the cells to migrate and invade normal tissue.  In addition, MAGP2 gene overexpression increased microvessel density — a measurement used to determine the extent of tumor angiogenesis. The latter two observations suggest a potential role for MAGP2 gene overexpression in the growth of an ovarian cancer tumor’s blood supply.

“By confirming that different ovarian tumors have distinctive gene signatures that can predict patient prognosis, this study marks the beginning of individualized care for ovarian cancer,” says Birrer, a professor of Medicine at Harvard Medical School. “MAGP2 and the biochemical pathways it contributes to are definitely targets for new types of therapies, and we plan to pursue several strategies to interfere with tumor-associated pathways. But first we need to validate these findings in samples from patients treated in clinical trials.”

About The Study

Co-lead authors of the Cancer Cell paper are Samuel Mok, M.D., M.D. Anderson Cancer Center, and Tomas Bonome, National Cancer Institute (NCI). Additional co-authors are Kwong-Kowk Wong, M.D. Anderson; Vinod Vathipadiekal, Aaron Bell, Howard Donninger, Laurent Ozbun, Goli Samimi, John Brady, Mike Randonovich, Cindy Pise-Masison, and Carl Barrett, NCI; Michael Johnson, Dong-Choon Park, William Welch and Ross Berkowitz, Brigham and Women’s Hospital; Ke Hao and Wing Wong, Harvard School of Public Health; and Daniel Yip, University of South Florida. The study was supported by grants from the National Institutes of Health, the Ovarian Cancer Research Fund and the National Cancer Institute.

About Massachusetts General Hospital

Massachusetts General Hospital, established 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 $600 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, systems biology, transplantation biology and photomedicine.

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Novel Targeted Gene Therapies Use Diphtheria Toxin To Fight Ovarian Cancer; One Clinical Trial Underway

Two separate research teams reported promising results last week based upon preclinical studies involving the use of diphtheria toxin to fight ovarian cancer. … A targeted gene therapy was utilized in both studies, wherein a gene fragment capable of producing diptheria toxin was combined with a nanoparticle which was targeted against a unique or overexpressed genetic characteristic of the ovarian cancer tumor cells. Both research teams reported significant reduction in ovarian cancer tumor mass and extended survival for the treated mice. Based upon these findings, one research team already announced the opening of a Phase I/II clinical trial which will test the novel therapy on patients with advanced stage ovarian cancer.

Targeted Gene Therapy In the Fight Against Ovarian Cancer

The peritoneal cavity is a common site of ovarian cancer and accompanying ascites caused by the disease. Ascites is an abnormal buildup of fluid in the peritoneal cavity that causes swelling.  Malignant tumor cells may be found in the ascites fluid in connection with late stage ovarian cancer.  Massive ascites and the related abdominal distention can cause anorexia, nausea, vomiting and respiratory difficulties, and negatively impact the patient’s quality of life. Ovarian cancer patients frequently experience disease involvement of the pelvic and retroperitoneal lymph nodes as well. The standard primary treatment of patients with advanced stage ovarian cancer is cytoreductive surgery followed by platinum drug and taxane drug doublet chemotherapy. Despite this aggressive approach, there is a high rate of disease recurrence. Although discovery of several other active nonplatinum cytotoxic agents has improved outcome, long-term survival rates are low. Success of traditional chemotherapy has been limited by drug resistance and lack of specificity with respect to disease formation and progression. Thus, novel “targeted” ovarian cancer therapies that achieve improved long-term disease control with lower toxicity are desperately needed.

A so-called “targeted therapy” utilizes drugs or other medically manufactured substances (e.g., small molecule drugs or monoclonal antibodies) to block the growth and spread of cancer by interfering with specific molecules involved in cancer tumor growth and progression.  By identifying and selectively focusing upon molecular and cellular changes or unique genetic characteristics that are specific to cancer, targeted cancer therapies may be more effective than other types of treatment, including chemotherapy, and less harmful to normal cells.

It is possible for a targeted therapy to incorporate a gene therapy. Gene therapy is an experimental treatment that involves the introduction of genetic material (DNA or RNA) into a human cell to fight a disease such as cancer.  When both therapeutic approaches are combined by researchers, a “targeted gene therapy” is the result.  A targeted gene therapy is an attractive approach to controlling or killing human cancer cells only if the therapy can selectively identify and exploit the genetic and epigenetic alterations in cancer cells, without harming normal cells that do not possess such alternations.

Two separate research groups reported promising results last week based upon preclinical studies involving the use of diphtheria toxin to fight ovarian cancer.  The toxin is produced by a deadly bacterium (Corynebacterium diphtheriae).  A targeted gene therapy was utilized in both studies, wherein a gene fragment capable of producing diptheria toxin was combined with a nanoparticle which was targeted against a unique or overexpressed genetic characteristic of the ovarian cancer tumor cells.  Both research teams reported significant reduction in ovarian cancer tumor mass and extended survival for the treated mice. Based upon these findings, one research team already announced the opening of a Phase I/II clinical trial which will test the novel therapy on patients with advanced stage ovarian cancer.

MIT-Lankenau Institute Researchers Use Diphtheria Toxin Gene Therapy To Target Overexpression Of The MSLN & HE4 Ovarian Cancer Genes.

anderson

Daniel Anderson, Ph.D., Research Associate, David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology

The first study, which appears in the August 1 issue of the journal Cancer Research, was conducted by a team of researchers from the Massachusetts Institute of Technology (MIT) and the Lankenau Institute of Medical Research (Lankenau Institute). In this study, the researchers used a nanoparticle as a delivery vehicle (or vector) for DNA that encodes a diphtheria toxin suicide protein (DT-A).  The novel nanoparticles are made with positively charged, biodegradable polymers known as poly(beta-amino esters). When mixed together, these polymers can spontaneously assemble with DNA to form nanoparticles. The polymer-DNA nanoparticle can deliver functional DNA when injected into or near the targeted tissue.

The nanoparticle carrying the DT-A is designed to target overexpression of two genes (mesothelin (MSLN) and HE4 (or WFDC2)) that are highly active in ovarian tumor cells, but not in normal cells. Once inside an ovarian cancer tumor cell, the DT-A disrupts the tumor cell’s ability to manufacture critical life sustaining proteins, thereby causing cell death.  Accordingly, the choice of the DT-A fragment of a diptheria toxin gene ensures high ovarian cancer cell killing activity.  It also avoids unintended toxicity to normal cells because the DT-A released from destroyed ovarian cancer cells is not able to enter normal neighboring tissue cells in the absence of the DT-B fragment which was excluded from the original nanoparticle delivery system or vector.

As part of this study, researchers administered DT-A nanoparticles directly into the peritoneal cavity – which encases abdominal organs such as the stomach, liver, spleen, ovaries and uterus – of mice xenografted with primary and metastatic ovarian tumors.  Ovarian cancer is known to initially spread throughout the peritoneal cavity, and current therapeutic approaches in humans include direct injection into the peritoneal space, thereby targeting the therapy to the ovaries and nearby tissues where tumors may have spread.

“… [The researchers] discovered that the intraperitoneal (IP) administration of DT-A nanoparticles resulted in a significant reduction in ovarian tumor mass and extended survival for the treated mice.  The researchers also found that the targeted gene-therapy treatment was as effective, and in some cases more effective, than the traditional chemotherapy combination of cisplatin and paclitaxel. …”

langerrobert

Robert S. Langer is the David H. Koch Institute for Integrative Cancer Research Professor (there are 14 Institute Professors at MIT; being an Institute Professor is the highest honor that can be awarded to a faculty member). Dr. Langer has written approximately 1,050 articles. He also has approximately 750 issued and pending patents worldwide. Dr. Langer’s patents have been licensed or sublicensed to over 220 pharmaceutical, chemical, biotechnology and medical device companies. He is the most cited engineer in history.

Sawicki

Janet Sawicki, Ph.D., Professor, Lankenau Institute of Medical Research. Dr. Sawicki also serves as an Associate Professor at the Kimmel Cancer Center of Thomas Jefferson University. Her ovarian cancer research is funded by the National Institutes of Health, the U.S. Department of Defense, the Sandy Rollman Foundation, the Teal Ribbon Ovarian Cancer Foundation, and the Kaleidoscope of Hope Foundation.

Daniel Anderson, Ph.D., research associate in the David H. Koch Institute for Integrative Cancer Research at MIT and a senior author of the paper, and others from MIT, including Institute Professor Robert Langer, along with researchers from the Lankenau Institute, led by Professor Janet Sawicki, discovered that the intraperitoneal (IP) administration of DT-A nanoparticles resulted in a significant reduction in ovarian tumor mass and extended survival for the treated mice.  The researchers also found that the targeted gene-therapy treatment was as effective, and in some cases more effective, than the traditional chemotherapy combination of cisplatin and paclitaxel. Furthermore, the novel therapy did not have the toxic side effects of chemotherapy because the diptheria toxin gene is engineered to function in ovarian cells but is inactive in normal cell types.

Based upon these finding, the MIT and Lankenau Institute researchers concluded that IP administration of DT-A nanoparticles, combined with designed targeting of those nanoparticles against ovarian tumor cell gene (MSLN & HE4) expression, holds promise as an effective therapy for advanced-stage ovarian cancer. According to Anderson, human clinical trials could start, after some additional preclinical studies, in about 1 to 2 years.  Currently ovarian cancer patients undergo surgery followed by chemotherapy. In many cases, the cancer returns after treatment.  Disease recurrence is problematic because there are no curative therapies for advanced-stage tumors.

For several years, the MIT-Lankenau Institute team worked to develop the DT-A nanoparticles as an alternative to viruses, which are associated with safety risks. In addition to ovarian cancer, these nanoparticles have demonstrated treatment potential for a variety of diseases, including prostate cancer and viral infection. “I’m so pleased that our research on drug delivery and novel materials can potentially contribute to the treatment of ovarian cancer,” Langer said. In future studies, the team plans to examine the effectiveness of nanoparticle-delivered diphtheria toxin genes in other types of cancer, including brain, lung and liver cancers.

Other MIT authors of the paper are recent MIT Ph.D. recipients Gregory Zugates and Jordan Green (now a professor at John’s Hopkins University), and technician Naushad Hossain. The research was funded by the Department of Defense and the National Institutes of Health.

Israeli Researchers Use Diphtheria Toxin Gene Therapy To Target Overexpression Of The H19 Ovarian Cancer Gene.

The second study was conducted by Israeli researchers and was published August 6 online ahead of print in the Journal of Translational Medicine.

In the provisional study report, the researchers note that based upon earlier studies from their team and others, the H19 gene has emerged as a candidate for cancer gene therapy. The H19 gene is expressed at substantial levels in ovarian cancer tumor cells, but is nearly undetectable in surrounding normal tissue cells.  Although the Israeli research team acknowledges that the exact function of H19 is the subject of past debate, it notes that recent data suggests a role for H19 in promoting cancer progression, angiogenesis and metastasis.

As a first step, Israeli researchers tested H19 gene expression in ovarian cancer cells obtained from the ascites fluid of 24 patients, and established that H19 expression levels were detected in 90% of the tested patients. Of those patients with positive H19 expression, 76% showed a moderate or high level of expression, while 24% showed a low level of expression.

Next, the researchers created a DT-A nanoparticle similar to the one created by the MIT/Lankenau research team as described above, except the Israeli nanoparticle was designed to target H19 overexpression within ovarian cancer cells.  The therapeutic effect of the DT-A/H19 nanoparticles was first tested in vitro against various ovarian cancer cell lines and cells obtained from patient ascites fluid.  The researchers determined that the DT-A/H19 nanoparticle therapy caused ovarian cancer cell death.  The therapeutic effect of the DT-A nanoparticles was tested in vivo by injecting the DT-A nanoparticles into mice xenografted with ovarian cancer tumors. The researchers estimate that the DT-A nanoparticle therapy reduced ovarian cancer tumor growth in the treated mice by 40%.

Based upon these finding, the researchers note that although the study report issued is provisonal, it is their working hypothesis that intraperitoneal administration of DT-A/H19 nanoparticles holds the potential to (1) reach ascites tumor cells, (2) deliver its intracellular toxin without targeting normal tissue cells, and (3) reduce tumor burden & fluid accumulation; and therefore, improve the patient’s quality of life, and hopefully, prolong her survival.

  • DT-A/H19 Nanoparticle Therapy Administered To An Israeli Patient On A Compassionate Use Trial Basis

In the provisional study report, the researchers state that the targeted gene therapy was administered to an Israeli patient with advanced, recurrent ovarian cancer, who qualified for compassionate use treatment under Israeli regulatory rules.  Specifically, the patient’s intraperitoneal ovarian cancer metastases and ascites were treated with the DT-A/H19 nanoparticle therapy after the failure of conventional chemotherapy. The results of the single patient compassionate use trial suggest that the drug caused no serious adverse events at any drug dosage level.  Moreover, the patient experienced (1) a 50% decrease in serum cancer marker protein CA-125, (2) a significant decrease in the number of cancerous cells in the ascites, and (3) a clinical improvement as reported by her doctors.  It is reported that the patient’s quality of life increased during the course of treatment and her condition continues to be stable, with no new cancerous growths.

  • Phase I/II Clinical Trial To Test DT-A/H19 Nanoparticle Therapy (BC-819) In the U.S. & Israel

The DT-A/H19 nanoparticle therapy is being developed commercially by BioCancell Therapeutics, Inc (BioCancell) Recently, BioCancell announced the opening of a clinical trial to test the DT-A/H19 nanoparticle therapy (also referred to as BC-819) in patients with advanced stage ovarian cancer.  The clinical trial is entitled, Phase 1/2a, Dose-Escalation, Safety, Pharmacokinetic, and Preliminary Efficacy Study of Intraperitoneal Administration of DTA-H19 in Subjects With Advanced Stage Ovarian Cancer, and the trial investigators are recruiting patients in the U.S. and Israel as indicated below.

University of Pennsylvania Medical Center [Abramson Cancer Center] (Recruiting)
Philadelphia, Pennsylvania, United States, 19104-6142
Contact: Lana E. Kandalaft, Pharm.D, PhD – 215-537-4782 (lknd@mail.med.upenn.edu)
Principal Investigator: George Coukos, M.D., Ph.D.

Massey Cancer Center (Not yet recruiting)
Richmond, Virginia, United States, 23298-0037
Contact: Jane W. Baggett, RN 804-628-2360 (jbaggett@mcvh-vcu.edu)
Principal Investigator: Cecelia H. Boardman, M.D.

The Edith Wolfson Medical Center (Recruiting)
Holon, Israel
Contact: Pnina Nir (972)-52-8445143 (pninanir@wolfson.health.gov.il)
Principal Investigator: Tally Levy, M.D.

Hadassah University Hospital (Recruiting)
Jerusalem, Israel
Contact: Zoya Bezalel (972)-2-6776725 (zoyab@hadassah.org.il)
Principal Investigator: David Edelman, MD

Meir Hospital (Recruiting)
Kfar Saba, Israel
Contact: Tal Naderi 09-7472213 (Ta.INadiri@clalit.org.il)
Principal Investigator: Ami Fishman, MD

In the provisional study report, the Israeli researchers discuss the importance of collecting data regarding the correlation between the level of ovarian cancer cell H19 expression and the efficacy of the treatment as part of the clinical trial discussed above.  Based upon accrued future clinical trial data, the researchers believe that they will be able to identify in advance patients that will respond to this novel therapy, as well as non-responders who are resistant to all known therapies, thereby avoiding treatment failure and unnecessary suffering and cost.

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Johns Hopkins Discovers a Protein That Contributes to Ovarian Cancer Recurrence By Causing Chemoresistance

” … Ground-breaking work on an ovarian cancer-related protein in the lab of Ie-Ming Shih at the [Johns Hopkins] School of Medicine is leading to new insights into cancer biology. … They have revealed a novel protein that creates cancer cells that are resistant to traditional cancer chemotherapies and partially revealed its mechanism of action. With all of this information, the team hopes to create drugs that can target these proteins or find out which chemotherapies currently on the market do not function in this pathway to create resistant cancer cells.”

“Ovarian cancer is a growing concern with more than 15,000 deaths occurring in 2007, making it the leading cause of death in gynecological diseases.

Ie-Ming Shih, M.D., Ph.D., Professor, Pathobiology Graduate Program, Department of Pathology, Johns Hopkins University, Baltimore, Maryland

Ie-Ming Shih, M.D., Ph.D., Professor, Pathobiology Graduate Program, Department of Pathology, Johns Hopkins University, Baltimore, Maryland

Ground-breaking work on an ovarian cancer-related protein in the lab of Ie-Ming Shih at the School of Medicine is leading to new insights into cancer biology.

The protein is nucleus accumbens-1, NAC-1, which is a transcription factor that regulates the expression of genes. Previous work has shown NAC-1 to be overexpressed in many types of cancer, specifically ovarian cancer that is resistant to chemotherapy.

A deeper understanding of its mechanism of action would allow scientists and physicians to make inroads into possibly curing the diseases.

In many cases, the first round of chemotherapy or treatment shrinks the tumor but does not cure the patient of the diseases. The cancer then grows back and can be resistant to a second round of the initial therapy.

Ovarian cancer cells that are resistant to chemotherapy have higher than normal levels of NAC-1. Shih and her [sic] team showed that the ovarian cancer cells, when exposed to a particular chemotherapy drug, were resistant compared to cancer cells with normal expression of NAC-1.

Upon further investigation into the biological pathways of interacting proteins in the nucleus, the team found that another protein [Gadd45-gamma-interacting protein 1 (Gadd45gip1)] is the target of NAC-1’s mechanism of action.

NAC-1 works by interacting with this other protein and stopping it from working and decreasing its expression inside the cell. So when NAC-1 expression is increased, the cancer cells are resistant to treatment, and the downstream target protein of NAC-1 is downregulated.

Performing further experiments, the researchers found that by making normal cancer cells overexpress the NAC-1 protein the cells were resistant to the chemotherapy drug, where previously they were not before the induced expression.

Also, the downstream target protein had reduced expression.

Conversely, if the researchers knocked down the expression of NAC-1 or increased the expression of its downstream target protein, then the cells were sensitive to cancer treatment, more so than normal cancer cells.

The scientists also wanted to uncover how the proteins interact structurally. Their work has revealed that NAC-1 is a homodimer protein, meaning it self-dimerizes – two copies of the protein come together to form the working product.

If the researchers formed a NAC-1 protein with only one of the units working properly, then the entire protein would not function and the ovarian cancer cells were sensitive to chemotherapy treatment.

Also, in this non-functional protein, it would induce the expression of its downstream target protein and increase that protein’s expression, thereby sensitizing the cells to chemotherapy.

Taken together, the researchers have paved new roads into the ever-complicating fight against cancer.

They have revealed a novel protein that creates cancer cells that are resistant to traditional cancer chemotherapies and partially revealed its mechanism of action.

With all of this information, the team hopes to create drugs that can target these proteins or find out which chemotherapies currently on the market do not function in this pathway to create resistant cancer cells.”

Source: Resistance to cancer chemotherapy is studied, by Neil Neumann, Science Section, The Johns Hopkins Newsletter, April 2, 2009 (discussing Jinawath N, Vasoontara C, Yap KL et al.  NAC-1, a potential stem cell pluripotency factor, contributes to paclitaxel resistance in ovarian cancer through inactivating Gadd45 pathwayOncogene. 2009 Mar 23. [Epub ahead of print]).

President of M.D. Anderson Outlines 10 Steps To Achieve Progress Against Cancer.

“The Houston Chronicle recently published a commentary by John Mendelsohn, M.D., president of M. D. Anderson, outlining actions the nation should take to achieve great progress against cancer. … Here are 10 steps we can take to ensure that deaths decrease more rapidly, the ranks of survivors swell, and an even greater number of cancers are prevented in the first place. …”

“Ten Pieces Help Solve Cancer Puzzle

John Mendelsohn, M.D., President, The University of Texas M.D. Anderson Cancer Center

John Mendelsohn, M.D., President, The University of Texas M.D. Anderson Cancer Center

The Houston Chronicle recently published a commentary by John Mendelsohn, M.D., president of M. D. Anderson, outlining actions the nation should take to achieve great progress against cancer.

An American diagnosed with cancer today is very likely to join the growing ranks of survivors, who are estimated to total 12 million and will reach 18 million by 2020. The five-year survival rate for all forms of cancer combined has risen to 66%, more than double what it was 50 years ago.

Along with the improving five-year survival rates, the cancer death rate has been falling by 1% to 2% annually since 1990.

According to the World Health Organization, cancer will be the leading worldwide cause of death in 2010. Over 40% of Americans will develop cancer during their lifetime.

While survival rates improve and death rates fall, cancer still accounts for one in every five deaths in the U.S., and cost this nation $89.0 billion in direct medical costs and another $18.2 billion in lost productivity during the illness in 2007, according to the National Institutes of Health.

Here are 10 steps we can take to ensure that deaths decrease more rapidly, the ranks of survivors swell, and an even greater number of cancers are prevented in the first place.

#1.  Therapeutic cancer research should focus on human genetics and the regulation of gene expression.

Cancer is a disease of cells that have either inherited or acquired abnormalities in the activities of critical genes and the proteins for which they code. Most cancers involve several abnormally functioning genes – not just one – which makes understanding and treating cancer terribly complex. The good news is that screening for genes and their products can be done with new techniques that accomplish in days what once took years.

Knowledge of the human genome and mechanisms regulating gene expression, advances in technology, experience from clinical trials, and a greater understanding of the impact of environmental factors have led to exciting new research approaches to cancer treatment, all of which are being pursued at M. D. Anderson:

  • Targeted therapies.  These therapies are designed to counteract the growth and survival of cancer cells by modifying, replacing or correcting abnormally functioning genes or their RNA and protein products, and by attacking abnormal biochemical pathways within these cells.
  • Molecular markers.  Identifying the presence of particular abnormal genes and proteins in a patient’s cancer cells, or in the blood, will enable physicians to select the treatments most likely to be effective for that individual patient.
  • Molecular imaging.  New diagnostic imaging technologies that detect genetic and molecular abnormalities in cancers in individual patients can help select optimal therapy and determine the effectiveness of treatment within hours.
  • Angiogenesis.  Anti-angiogenesis agents and inhibitors of other normal tissues that surround cancers can starve the cancer cells of their blood supply and deprive them of essential growth-promoting factors which must come from the tumor’s environment.
  • Immunotherapy. Discovering ways to elicit or boost immune responses in cancer patients may target destruction of cancer cells and lead to the development of cancer vaccines.

#2.  Better tests to predict cancer risk and enable earlier detection must be developed.

New predictive tests, based on abnormalities in blood, other body fluids or tissue samples, will be able to detect abnormalities in the structure or expression of cancer-related genes and proteins. Such tests may predict the risk of cancer in individuals and could detect early cancer years before any symptoms are present.

The prostate-specific antigen test for prostate cancer currently is the best known marker test to detect the possible presence of early cancer before it has spread. Abnormalities in the BRCA 1 and BRCA 2 genes predict a high risk for breast cancer, which can guide the decisions of physicians and patients on preventive measures. Many more gene-based predictors are needed to further our progress in risk assessment and early detection.

#3.  More cancers can and must be prevented.

In an ideal world, cancer “care” would begin with risk assessment and counseling of a person when no malignant disease is present. Risk factors include both inherited or acquired genetic abnormalities and those related to lifestyle and the environment.

The largest risk factor for cancer is tobacco smoking, which accounts for nearly one-third of all cancer deaths. Tobacco use should be discouraged with cost disincentives, and medical management of discontinuing tobacco use must be reimbursed by government and private sector payors.

Cancer risk assessment should be followed by appropriate interventions (either behavioral or medical) at a pre-malignant stage, before a cancer develops. Diagnosis and treatment of a confirmed cancer would occur only when these preventive measures fail.

A full understanding of cancer requires research to identify more completely the genetic, environmental, lifestyle and social factors that contribute to the varying types and rates of cancer in different groups in this country and around the world. A common cancer in Japan or India, for example, often is not a common cancer in the U.S. When prostate cancer occurs in African-Americans it is more severe than in Caucasians. A better understanding of the factors that influence differences in cancer incidence and deaths will provide important clues to preventing cancer in diverse populations worldwide.

#4.  The needs of cancer survivors must become a priority.

Surviving cancer means many things: reducing pain, disability and stress related to the cancer or the side effects of therapy; helping patients and their loved ones lead a full life from diagnosis forward; preventing a second primary cancer or recurrence of the original cancer; treating a difficult cancer optimally to ensure achieving the most healthy years possible, and more.  Since many more patients are surviving their cancers – or living much longer with cancer – helping them manage all the consequences of their disease and its treatment is critically important.  It is an area ripe for innovative research and for improvement in delivery of care.

#5.  We must train future researchers and providers of cancer care.

Shortages are predicted in the supply of physicians, nurses and technically trained support staff needed to provide expert care for patients with cancer.  On top of this, patient numbers are projected to increase.  We are heading toward a “perfect storm” unless we ramp up our training programs for cancer professionals at all levels.   The pipeline for academic researchers in cancer also is threatened due to the increasing difficulty in obtaining peer-reviewed research funding. We must designate more funding from the NIH and other sources specifically for promising young investigators, to enable them to initiate their careers.

#6.  Federal funding for research should be increased.

After growing by nearly 100% from 1998-2002, the National Cancer Institute budget has been in decline for the past four years. Through budget cuts and the effects of inflation, the NCI budget has lost approximately 12% of its purchasing power.  Important programs in tobacco control, cancer survivorship and support for interdisciplinary research have had significant cuts.  The average age at which a biomedical researcher receives his or her first R01 grant (the gold standard) now stands at 42, hardly an inducement to pursue this field. This shrinks the pipeline of talented young Americans who are interested in careers in science, but can find easier paths to more promising careers elsewhere.  Lack of adequate funding also discourages seasoned scientists with outstanding track records of contributions from undertaking innovative, but risky research projects.  The U.S. leadership in biomedical research could be lost.

Biomedical research in academic institutions needs steady funding that at least keeps up with inflation and enables continued growth.

#7.  The pace of clinical research must accelerate.

As research ideas move from the laboratory to patients, they must be assessed in clinical trials to test their safety and efficacy. Clinical trials are complicated, lengthy and expensive, and they often require large numbers of patients.  Further steps must be taken to ensure that efficient and cost-effective clinical trials are designed to measure, in addition to outcomes, the effects of new agents on the intended molecular targets. Innovative therapies should move forward more rapidly from the laboratory into clinical trials.

The public needs to be better educated about clinical trials, which in many cases may provide them with access to the best care available.  Greater participation in trials will speed up drug development, in addition to providing patients with the best options if standard treatments fail.  The potential risks and benefits of clinical trials must continue to be fully disclosed to the patients involved, and the trials must continue to be carefully monitored.

The issue of how to pay for clinical trials must be addressed. The non-experimental portion of the costs of care in clinical trials currently are borne in part by Medicare, and should be covered fully by all payors. The experimental portion of costs of care should be covered by the owner of the new drug, who stands to benefit from a new indication for therapeutic use.

#8.  New partnerships will encourage drug and device development.

One way to shorten the time for drug and device development is to encourage and reward collaboration among research institutions, and collaboration between academia and industry.  Increasingly, partnerships are required to bring together sufficient expertise and resources needed to confront the complex challenges of treating cancer. There is enormous opportunity here, but many challenges, as well.

Academic institutions already do collaborate, but we need new ways to stimulate increased participation in cooperative enterprises.

Traditionally, academic institutions have worked with biotech and pharmaceutical companies by conducting sponsored research and participating in clinical trials.  By forming more collaborative alliances during the preclinical and translational phases prior to entering the clinic, industry and academia can build on each other’s strengths to safely speed drug development to the bedside. The challenge is that this must be done with agreements that involve sharing, but also protect the property rights and independence of both parties.

The results of all clinical trials must be reported completely and accurately, without any influence from conflicts of interest and with full disclosure of potential conflicts of interest.

#9. We must provide access to cancer care for everyone who lives in the U.S.

More than 47 million Americans are uninsured, and many others are underinsured for major illnesses like cancer. Others are uninsurable because of a prior illness such as cancer.  And many are indigent, so that payment for care is totally impossible.

Depending on where they live and what they can afford, Americans have unequal access to quality cancer care. Treatment options vary significantly nationwide. We must find better ways to disseminate the best standards of high-quality care from leading medical centers to widespread community practice throughout the country.

Cancer incidence and deaths vary tremendously among ethnic and economic groups in this country. We need to address the causes of disparities in health outcomes and move to eliminate them.

We are unique among Western countries in not providing direct access to medical care for all who live here. There is consensus today among most Americans and both political parties that this is unacceptable.  Especially for catastrophic illnesses like cancer, we must create an insurance system that guarantees access to care.

A number of proposals involving income tax rebates, vouchers, insurance mandates and expanded government insurance programs address this issue. Whatever system is selected should ensure access and include mechanisms for caring for underserved Americans.  The solution will require give-and-take among major stakeholders, many of which benefit from the status quo.  However, the social and economic costs have risen to the point that we have no choice.

#10.  Greater attention must be paid to enhancing the quality of cancer care and reducing costs.

New therapies and medical instruments are expensive to develop and are a major contributor to the rising cost of medical care in the U.S.  The current payment system rewards procedures, tests and treatments rather than outcomes.  At the same time, cancer prevention measures and services are not widely covered.  A new system of payment must be designed to reward outcomes, as well as the use of prevention services.

Quality of care can be improved and costs can be reduced by increasing our efforts to reduce medical errors and to prescribe diagnostic tests and treatments only on the basis of objective evidence of efficacy.

A standardized electronic medical record, accessible nationwide, is essential to ensuring quality care for patients who see multiple providers at multiple sites, and we are far behind many other nations.  Beyond that, a national electronic medical record could provide enormous opportunities for reducing overhead costs, identifying factors contributing to many illnesses (including cancer), determining optimal treatment and detecting uncommon side effects of treatment.

What the future holds in store.

I am optimistic. I see a future in which more cancers are prevented, more are cured and, when not curable, more are managed as effectively as other chronic, life-long diseases. I see a future in which deaths due to cancer continue to decrease.

Achieving that vision will require greater collaboration among academic institutions, government, industry and the public.  Barriers to quality care must be removed.  Tobacco use must be eradicated.  Research must have increased funding.  Mindful that our priority focus is on the patient, we must continue to speed the pace of bringing scientific breakthroughs from the laboratory to the bedside.

M. D. Anderson resources:

John Mendelsohn, M.D.”

Primary SourceTen Pieces Help Solve Cancer Puzzle, by John Mendelsohn, M.D., Feature Article, The University of Texas M.D. Anderson Cancer Center Cancer News, Mar. 2009.