The Emerging Field of Oncofertility

“Welcome to the burgeoning world of oncofertility. As cancer survival rates climb and patients focus on quality-of-life issues, especially fertility, Dauer and others like her are forcing two very different medical specialties-oncology and assisted reproduction-to come together. ‘The narrative of cancer is no longer that it’s a death sentence; it’s a bump in your medical history that you overcome and go back to what we hope is a healthy lifestyle,’ says Teresa Woodruff of Northwestern University’s Feinberg School of Medicine …”

“When Annie Dauer’s oncologist told her she’d need a stem-cell transplant to cure her non-Hodgkin’s lymphoma, Dauer’s first thought wasn’t about death but about life. ‘I asked what would happen to my fertility,’ she says. Her oncologist dismissed the question: ‘Honey, you’re fighting for your life; forget the fertility at this point,’ she told me. But Dauer, then 30 and newly married, pressed the subject until the oncologist referred her to a fertility specialist. Since Dauer’s chemotherapy regimen would most likely destroy her body’s egg supply, the specialist, in an experimental procedure, removed one of her ovaries, froze it and reimplanted it when Dauer recovered. Three years later, Dauer, now cancer-free, and her husband, Greg, have a 2-year-old daughter, Sienna, and a second baby on the way.

Welcome to the burgeoning world of oncofertility. As cancer survival rates climb and patients focus on quality-of-life issues, especially fertility, Dauer and others like her are forcing two very different medical specialties-oncology and assisted reproduction-to come together. ‘The narrative of cancer is no longer that it’s a death sentence; it’s a bump in your medical history that you overcome and go back to what we hope is a healthy lifestyle,’ says Teresa Woodruff of Northwestern University‘s Feinberg School of Medicine, who last fall received a first-of-its-kind $21 million NIH grant to develop ways of protecting cancer patients’ reproductive health.

Of the 125,000 people under the age of 45 who are diagnosed with cancer each year, roughly half will receive treatments that will affect their fertility. The cancers that most commonly strike the young-leukemias, lymphomas and breast cancers-require some of the most toxic forms of chemotherapy, which target rapidly growing and fragile cells like hair follicles, sperm and eggs. The good news: patients who would like to become parents have a growing array of options. Men are benefiting from a procedure that allows urologists to find a single live sperm to bank, which can then be used in an in vitro fertilization method that requires just one sperm. Women can freeze eggs or ovarian tissue, though success rates are still low. Those with partners (or donor sperm) can freeze embryos, the procedure with the best track record, though, like egg freezing, it’s available only to patients who have two to six weeks before starting treatment. On the horizon are less toxic chemotherapy agents as well as methods of shielding eggs and sperm from harm.

Up to now, few oncologists passed this vital information to patients, either because they were not aware of fertility advances, or because they were understandably preoccupied with saving lives. As the field grows (at least 50 centers now provide oncofertility services), more cancer docs are tackling the issue, and even altering treatments to aid fertility. Advocacy groups like Fertile Hope, which educate cancer patients about assisted reproduction, deserve credit for spreading the word. ‘It’s being talked about more,’ says Nancy Lin, an oncologist at Boston’s Dana-Farber Cancer Institute. ‘There’s a growing awareness among doctors, and patients are more proactive.’

Two years after Dauer completed her cancer treatment, her doctor, Kutluk Oktay, founder of New York City’s Institute for Fertility Preservation, sutured a one-inch strip of ovary, containing tens of thousands of microscopic eggs, under the skin just below Dauer’s belly button. ‘Every month, I would feel little eggs, sometimes pea-sized, sometimes as big as a quarter,’ says Dauer. Normally, Oktay, who pioneered this procedure, would have harvested mature eggs, fertilized them with Greg’s sperm and implanted them into Dauer’s uterus. But in an unexpected development, Dauer became pregnant naturally; somehow, the implanted ovary jump-started her remaining, inactive ovary and she began to ovulate. Oktay is at a loss for an explanation. ‘The healthy ovary may contain signals or hormones that may enable the [dormant] ovary to regenerate eggs,’ says Oktay. ‘That’s the theory, other than a miracle.’

When cancer’s involved, even joy can be shadowed by uncertainty. Ronny Villarreal, 32, survived breast cancer, then, with her oncologist’s OK, stopped a common hormone-suppressing treatment early in order to conceive. Unfortunately, the cancer recurred during her second trimester of pregnancy. Villarreal’s daughter, Maddy Hunt, now 4 months old, is healthy, but Villarreal is facing more chemotherapy and a cloudy prognosis. ‘We are trying our hardest to stay positive,’ she says. ‘We have so much to live for.’ More, certainly, than if she never had the chance to get pregnant at all.”

Quoted Source: Survive Cancer, Have Baby – The emerging field of oncofertility offers hope to patients who worried that they couldn’t conceive, by Anna Kuchment, Medicine, Newsweek Magazine, Published July 26, 2008 (From the magazine issue dated Aug 4, 2008).

Additional Resources:

Non-Platinum Topotecan Drug Combination Therapy Provides No Survival Advantage Over Topotecan Monotherapy

“In women with recurrent ovarian cancer, treatment with topotecan along with etoposide or gemcitabine offers no survival advantage over topotecan monotherapy, German and Austrian researchers report in the July 1st issue of the Journal of Clinical Oncology.”

“In women with recurrent ovarian cancer, treatment with topotecan along with etoposide or gemcitabine offers no survival advantage over topotecan monotherapy, German and Austrian researchers report in the July 1st issue of the Journal of Clinical Oncology.

‘Combination therapies,’ lead investigator Dr. Jalid Sehouli told Reuters Health, ‘were associated with higher toxicity, but progression-free survival and overall survival were not significantly different.’

Dr. Sehouli, of Humboldt University in Berlin, and colleagues explain in their paper that although topotecan monotherapy is an established treatment, there was evidence to suggest that combination therapy may provide better results.

To investigate further, the researchers studied 502 women in whom ovarian cancer recurred following primary surgery and platinum-based chemotherapy. They were randomized to receive either topotecan alone or in combination with etoposide or gemcitabine.

Median overall survival was not significantly different among the groups: 17.2 months with topotecan alone, 17.8 months with the etoposide combination and 15.2 months with the gemcitabine combination. There were no differences in either median progression-free survival or objective response rates.

The researchers note that the incidence of thrombocytopenia was lower with monotherapy (13.5%) than with the etoposide combination (21.5%) or gemcitabine combination (31.3%), and they conclude that combination therapy increases toxicity and does not provide a survival advantage.

‘Based on our results,’ Dr. Sehouli warns, ‘physicians should not harm their patients with such combination regimens.’”

Quoted Source: Topotecan Combo No Extra Help in Ovarian Cancer, by David Douglas, Matria Healthcare News, July 28, 2008 (summarizing the findings of Nonplatinum topotecan combinations versus topotecan alone for recurrent ovarian cancer: results of a phase III study of the North-Eastern German Society of Gynecological Oncology Ovarian Cancer Study Group; Sehouli J et. al., J Clin Oncol. 2008 July;26(19):3176-82.

Additional Information:

A Requiem Hallelujah, But Don’t Let There Be a Hole in the World Tomorrow

As many of you know, the H*O*P*E*™ weblog is dedicated to Libby, my 26 year old cousin. Libby was diagnosed with ovarian clear cell carcinoma in January 2007. I am deeply saddened to inform you that Libby lost her ovarian cancer battle this morning with her family at her side. Libby leaves behind her loving spouse, Steve, her mother Kathy, her father Dennis, and her sister Sara.

Libby and Steve are the inspiration behind H*O*P*E*™, and its contining campaign to make all women aware of the early warning signs and symptoms of ovarian cancer, as well as significant treatment developments relating to the disease. Upon hearing of Libby’s death this morning, my initial thought was to allow H*O*P*E*™ to go “dark” (from a post reporting perspective) for the next week in her honor. Immediately after that initial thought, two classic songs came to mind as a better way to honor Libby. I believe the song choices were inspired by Libby from a much better place.

The first song is a gospel ballad entitled “Hallelujah.” “Hallelujah” was written by Canadian singer-songwriter Leonard Cohen, who originally released it on his 1984 studio album entitled “Various Positions.” A general translation of the word “Hallelujah” in the Jewish and Christian faiths is “Great Praise to God.” The song “Hallelujah” is frequently used in television shows and movies during scenes involving death or heartbreak. The reason for this, I believe, is that the song evokes strong emotions that capture the struggle to love, pray, and live with faith in the midst of tragic human suffering. Libby experienced that same struggle throughout her treatment, yet continued her fight to the end with grace and courage.

“Hallelujah” has been covered by various singers more than 120 times (counting only recorded, not live, versions). American singer-songwriter Jeff Buckley recorded one of the best-known and emotionally moving covers of “Hallelujah” for his 1994 studio album entitled “Grace.” Buckley, not wholly satisfied with any one take, recorded the song more than twenty times. In September 2007, a poll of fifty songwriters conducted by Q Magazine listed “Hallelujah” among the all-time “Top 10 Greatest Tracks,” with John Legend calling Buckley’s version “as near perfect as you can get.” A hyperlink to Jeff Buckley’s cover version of “Hallelujah” is provided below as an acknowledgment of Libby’s courageous fight against ovarian cancer.

Jeff Buckley-Hallelujah

CLICK HERE TO VIEW VIDEO

The second song is “[There’s a] Hole in the World [Tonight], which was recorded by The Eagles, a legendary U.S. rock band. In August 2001, The Eagles returned to the U.S. upon completion of a successful European tour to record a new album. The band was scheduled to begin recording on September 11, 2001. “Hole in the World” was written by the band in five part harmony to express the fear, sorrow, and future hope stemming from that tragic day. The lyrics set forth in the first verse of the song are as follows:

“There’s a hole in the world tonight.
There’s a cloud of fear and sorrow.
There’s a hole in the world tonight.
Don’t let there be a hole in the world tomorrow.”

I believe that Libby would abide by the message set forth in the last two sentences of that verse. Today, our family has a hole in its world as a result of Libby’s death, but H*O*P*E*™ cannot allow that fear and sorrow to create a hole in the world of another woman and her family through the failure to move ahead with its educational mission. Libby would tell you that “education increases survival.”

A video of The Eagles singing “Hole in the World” is provided below, as inspiration for all individuals who are involved in the fight against ovarian cancer. This fight will require perseverance through medical research, advocacy, education and fundraising until ovarian cancer is vanquished.

As an enduring tribute to Libby, H*O*P*E*™ revised the weblog homepage caption to read “Libby’s H*O*P*E*™.” We love you Libby and will forever miss you, but we will continue the fight against ovarian cancer on your behalf.

The Eagles – Hole In the World

Source: Wikipedia descriptions of the word “Hallelujah,” and Leonard Cohen’s song entitled “Hallelujah.”

From Zero to Hero: HMGB1 Protein Found to Promote DNA Repair, Prevents Cancer

“An abundant chromosomal protein [HMGB1] that binds to damaged DNA prevents cancer development by enhancing DNA repair, researchers at The University of Texas M. D. Anderson Cancer Center report online this week in the Proceedings of the National Academies of Science.”

“An abundant chromosomal protein that binds to damaged DNA prevents cancer development by enhancing DNA repair, researchers at The University of Texas M. D. Anderson Cancer Center report online this week in the Proceedings of the National Academies of Science.

The protein, HMGB1 [High mobility group box 1] , was previously hypothesized to block DNA repair, said senior author Karen Vasquez, Ph.D., associate professor in M. D. Anderson’s Department of Carcinogenesis at the Science Park – Research Division in Smithville, Texas.

Identification and repair of DNA damage is the frontline defense against the birth and reproduction of mutant cells that cause cancer and other illnesses.

Pinpointing HMGB1’s role in repair raises a fundamental question about drugs under development to block the protein, Vasquez said. The protein also plays a role in inflammation, so it’s being targeted in drugs under development for rheumatoid arthritis and sepsis.

‘Arthritis therapy involves long-term treatment,’ Vasquez said. ‘Our findings suggest that depleting this protein may leave patients more vulnerable to developing cancer.’

Long known to attach to sites of damaged DNA, the protein was suspected of preventing repair. ‘That did not make sense to us, because HMGB1 is a chromosomal protein that’s so abundant that it would be hard to imagine cell repair happening at all if that were the case,’ Vasquez said.

In a series of experiments reported in the paper, Vasquez and first author Sabine Lange, a doctoral candidate in the Graduate School of Biomedical Sciences, tracked the protein’s impact on all three steps of DNA restoration: access to damage, repair and repackaging of the original structure, a combination of DNA and histone proteins called chromatin.

First, they knocked out the [HMGB1] gene in mouse embryonic cells [HMGB1 knockout cells] and then exposed cells to two types of DNA-damaging agents. One was UV light, the other a chemotherapy called psoralen that’s activated by exposure to darker, low frequency light known as UVA. In both cases, the cells survived at a steeply lower rate after DNA damage than did normal cells.

Next they exposed HMGB1 knockout cells and normal cells to psoralen and assessed the rate of genetic mutation. The knockout cells had a mutation frequency more than double that of normal cells, however, there was no effect on the types of mutation that occurred.

Knock out and normal cells were then exposed to UV light and suffered the same amount of damage. However, those with HMGB1 had two to three times the repair as those without. Evidence suggests that HMGB1 works by summoning other DNA repair factors to the damaged site, Vasquez said.

The last step in DNA repair is called chromatin remodeling. DNA does not exist in a linear structure in the chromosome, but wraps around specialized histone proteins. This chromatin structure permits access to DNA when it is loose, or opened up, and blocks access when it is more tightly wrapped. Presence of HMGB1 resulted in a much higher rate of chromatin assembly in both undamaged and UVC-damaged cells.

Lange and Vasquez hypothesize that HMGB1 normally binds to the entrance and exit of DNA nucleosomes, so is nearby when DNA damage occurs. It then binds to and bends the damaged site at a 90-degree angle, a distortion that may help DNA repair factors recognize and repair the damage. After repair it facilitates restructuring of the chromatin.

Co-author with Lange and Vasquez is David Mitchell, Ph.D., professor of carcinogenesis.

The research was supported by grants from the National Cancer Institute and the National Institute of Environmental Health Sciences as well as an American Legion Auxiliary fellowship. 07/21/08”

Quoted Source: Once Suspect Protein Found to Promote DNA Repair, Prevent Cancer – M. D. Anderson scientists caution against targeting HMGB1 to treat other disease, M. D. Anderson News Release, July 21, 2008.

Fashion Really Can Make a Statement In the Fight Against Ovarian Cancer

Kelly Ripa and Molly Sims are fighting for a cure by doing something they love — shop! It’s all a part of Super Saturday Live on QVC. QVC will offer designer clothing, jewelry, beauty products, and accessories at 30% to 50% off of the manufacturer’s suggested retail price. All of the net proceeds benefit the Ovarian Cancer Research Fund (OCRF).

The QVC Super Saturday Live event will take place on Saturday, July 26, 2008 from 2:00 P.M. to 4:00 P.M. E.D.T. In its 11th year, the QVC Super Saturday Live event program will be hosted in the Hamptons, which is a summer playground in New York for the rich and famous. Dubbed the “Rolls Royce of Garage Sales” by The New York Times, Super Saturday 11 promises an exciting line up of over 200 top designers. It is being broadcast live for the second year on QVC.

The Super Saturday Live product line will be available through QVC by calling (800) 345-1515 or visiting www.QVC.com while supplies last.  To read ovarian cancer survivor stories on the QVC Super Saturday blog, click here.

As an organization committed to finding better ways to detect, treat, and ultimately cure ovarian cancer, the OCRF believes that future advances in ovarian cancer research lie in the hands of researchers. To promote research advancement, the OCRF sponsors young researchers with promising projects. Since 1998, the OCRF has awarded over $23 million grants to 128 of the brightest women and men in the field today at over 40 leading medical centers across the country. A brief video that describes the OCRF is provided below.

Ovarian Cancer Research Fund

TP53 Gene Mutation Found in 80% of High Grade Ovarian Serous Carcinomas; TP53 Not Directly Involved In The Development of Drug Resistance

“… [T]he [Johns Hopkins] research team concluded that the frequency of TP53 gene mutations using purified tumor DNA from ovarian serous carcinomas was 80.3%, which is much higher than previously reported in the medical literature. Furthermore, the research team found that TP53 is not directly involved in the development of drug resistance in high-grade ovarian serous carcinomas.”

The TP53 gene mutation frequency in ovarian serous carcinomas has been reported to range between 50% and 80%. A research team working at the The Sidney Kimmel Comprehensive Cancer Center of The Johns Hopkins Medical Institutions (Johns Hopkins) made several important findings regarding TP53 gene mutations with respect to high grade ovarian serous carcinoma, as reported in the International Journal of Gynecological Cancer. Ovarian serous carcinoma is the most common tumor subtype within the epithelial ovarian cancer histological classification.

According to the Johns Hopkins research team, a stringent analysis of the TP53 gene using purified epithelial tumor samples has not been performed to accurately assess the TP53 gene mutation frequency and its correlation to tumor histologic grade. The research team assessed the TP53 gene mutational profile in a relatively large series of high-grade (53 primary tumors and 18 recurrent tumors) and 13 low-grade ovarian serous tumors. All samples were affinity purified, and the tumor DNA was analyzed for TP53 mutations in exons 4 through 9. In addition, the ovarian serous tumors were subjected to in vitro drug resistance testing. In vitro drug resistance assays were performed on the same tumor samples using carboplatin, cisplatin, paclitaxel, and taxotere, and the results were correlated with the TP53 mutation status.

The reported study findings are as follows:

  • TP53 mutations were detected in 57 (80.3%) of 71 high-grade carcinomas and in one (7.8%) of 13; low-grade serous tumors (an invasive low-grade serous carcinoma);
  • The mutations were predominantly missense mutations (59.6%);
  • TP53 mutations were associated with high-grade serous carcinomas and recurrent disease; and
  • There was no statistically significant correlation between TP53 mutation status and drug resistance assays or clinical stage.

Accordingly, the research team concluded that the frequency of TP53 gene mutations using purified tumor DNA from ovarian serous carcinomas was 80.3%, which is much higher than previously reported in the medical literature. Furthermore, the research team found that TP53 was not directly involved in the development of drug resistance in high-grade ovarian serous carcinomas.

Source: Assessment of TP53 mutation using purified tissue samples of ovarian serous carcinomas reveals a higher mutation rate than previously reported and does not correlate with drug resistance; Salani R, et. al., Int J Gynecol Cancer. 2008 May-Jun;18(3):487-91. Epub 2007 Aug 10.

P.O.V. Documentary “In the Family”: One Woman’s Journey Through the Unpredictable World of Predictive Genetic Testing

“At the age of 27, filmmaker Joanna Rudnick tested positive for the BRCA mutation. Joanna now faces an impossible decision: remove her healthy breasts and ovaries or risk incredible odds of developing cancer. Armed with a positive test result that leaves her essentially “a ticking time bomb,” she balances dreams of having her own children with the unnerving reality that she is risking her life by holding on to her fertility. IN THE FAMILY follows Joanna as she takes us on a journey through the unpredictable world of predictive genetic testing.

Turning the camera on herself, Joanna bares her conflicting emotions about preventative surgery and the potential consequences. Turning the camera on her new relationship, she and her partner capture a young couple falling in love in the shadow of the mutation. Turning the camera on the company that owns the patents to the BRCA genes, she questions their control over access to the test. Along the way, she looks to other women and families dealing with the same unbelievable information.

Intensely personal and timely, IN THE FAMILY is a groundbreaking investigation that attempts to answer the question: How much do you sacrifice to survive?”

_________________________________

Producer/Director: Joanna Rudnick

Co-production: Kartemquin Films and the Independent Television Service (ITVS).

Date of Completion: February 2008

Running Time: 90 Minutes

US Broadcast: PBS/P.O.V. will air the film on Wednesday, October 1, 2008 at 10:00 P.M. (to have a reminder sent to you by email, click here, then click on the “Send Me A Reminder” link)

Filmmaker’s Website: http://inthefamily.kartemquin.com

_________________________________

Quoted Source: IN THE FAMILY – How much do you sacrifice to survive? (Synopsis), Press Kit, IN THE FAMILY website, accessed July 16, 2008 (Adobe Reader PDF document).

Comment: Visit the filmmaker’s website for more information about the film and upcoming screenings, by clicking on the link above. A brief video excerpt of IN THE FAMILY is provide below.

POV Website Note: “Want to hold a screening of In the Family in your community? If you are an organizer, a teacher, a young person using media to reach your peers or a PBS station employee interested in planning free local screenings of P.O.V. films, apply through P.O.V.’s Community Network and we’ll loan you a copy of the film (for free!) along with a toolkit including a discussion guide.”

Additional Resources:

P.O.V. – In the Family by Joanna Rudnick | PBS 2008

M.D. Anderson Identifies TG2 As a Potential Target in Chemo-Resistant Ovarian Cancer

“Scientists from The University of Texas M. D. Anderson Cancer Center have found overexpression of tissue type transglutaminase (TG2) in ovarian cancer is associated with increased tumor cell growth and adhesion, resistance to chemotherapy and lower overall survival rates. When researchers targeted and silenced TG2 in animal models, cancer progression was reversed, suggesting the protein may also provide a novel therapeutic approach for late-stage ovarian cancer.”

“Scientists from The University of Texas M. D. Anderson Cancer Center have found overexpression of tissue type transglutaminase (TG2) in ovarian cancer is associated with increased tumor cell growth and adhesion, resistance to chemotherapy and lower overall survival rates. When researchers targeted and silenced TG2 in animal models, cancer progression was reversed, suggesting the protein may also provide a novel therapeutic approach for late-stage ovarian cancer.

These findings in the July 15th issue of Cancer Research by a team of researchers led by Anil K. Sood, M.D., professor in the Departments of Gynecologic Oncology and Cancer Biology, and Kapil Mehta, Ph.D., professor in the Department of Experimental Therapeutics at M. D. Anderson, are among the first to explore TG2’s functionality in ovarian cancer.

‘TG2 appears to fuel different types of cancer through multiple molecular pathways, making it an important therapeutic target,’ said Mehta, whose lab also has connected TG2 overexpression to drug-resistant and metastatic melanoma, breast cancer and pancreatic cancer.

‘Drug resistance and metastasis are major impediments to the successful treatment of ovarian cancer and until now we had little information about the role TG2 played in ovarian cancer,’ Sood said. ‘We began to see its story unfold as we translated this data from tissue samples to cell lines to animal models.’

The American Cancer Society estimates 15,000 U.S. women will die from ovarian cancer this year. Most patients present with advanced stage disease that has spread beyond the primary tumor site. More than 70 percent of ovarian cancer patients will suffer a recurrence and eventually succumb to the disease.

Higher TG2, lower survival

The study, which examined 93 ovarian cancer samples of ranging stages, found that high levels of TG2 corresponded with significantly lower patient survival than those with low levels of TG2. Sixty-nine percent of high-stage ovarian cancers overexpressed TG2 compared with 30 percent of low-stage cancers. In-depth analysis demonstrated that tumors which overexpressed the protein tended to have an increased ability to invade healthy tissue and to survive or avoid the affects of chemotherapy.

‘From this investigation it became clear that TG2 activates the survival pathway p13K/Akt in these tumors, explaining the adverse, resistant behavior we observed on a molecular level,’ said Sood. ‘We then focused on whether silencing TG2 would block these effects.’

Researchers shut off TG2 with a small interfering RNA strand (TG2 siRNA) targeted to the protein, reducing the ability of the tumor cells to invade and killing them through programmed cell death, or apoptosis. ‘When exposed to this potent targeted therapy, ovarian cancer cells greatly reduced cancer cell proliferation and blood vessel development, while increasing apoptosis,’ said Sood.

Mouse model studies of chemotherapy-sensitive and chemotherapy-resistant models showed considerable antitumor activity both with TG2 siRNA alone and in combination with docetaxel chemotherapy. The combination therapy of TG2 siRNA with docetaxel reduced tumor weight by 86 percent, proving to have the greatest efficacy compared to control groups or those without chemotherapy.

‘While it remains to be seen if these results will translate in humans, looking ahead long term, it will be an attractive option against advanced ovarian cancer,’ said co-author Gabriel Lopez-Berestein, M.D. professor in the Department of Experimental Therapeutics at M. D. Anderson.

TG2 fuels pancreatic cancer differently

Sood and Lopez-Berestein, have developed siRNA therapy by packaging the gene-silencing strips of RNA in a fatty nanoparticle called a liposome and delivering it intravenously. TG2 is the third protein they have targeted in preclinical research. Sood and Mehta are moving TG2 siRNA toward Phase I clinical trials for ovarian and pancreatic cancers.

TG2 acts through different pathways in other types of cancer, Mehta noted. For example, TG2 overexpression causes the degradation of the tumor-suppressing protein PTEN in pancreatic cancer, Mehta and colleagues reported in Clinical Cancer Research in April. With PTEN out of the picture, pancreatic cancer is protected from a separate type of cell death called autophagy. In a separate paper, they showed that silencing TG2 with the siRNA liposome reduced tumor size, slowed metastasis and enhanced the effect of gemcitabine chemotherapy.

‘This aberrant protein is doing so many different things, you would have to develop a small-molecule drug to block each function,’ Mehta said. ‘Liposomal siRNA is exciting because it takes out TG2 completely, blocking everything that it does.’

Research was funded by grants from the National Cancer Institute, including M. D. Anderson’s Specialized Program in Research Excellence in Ovarian Cancer grant, a program project development grant from the Ovarian Cancer Research Fund, Inc., and the Zarrow Foundation.

In addition to Sood, Mehta and Lopez-Berestein, authors include Jee Young Hwang, M.D., Lingegowda S. Mangala, Ph.D., co-first authors, and Yvonne G. Lin, M.D., William M. Merritt, M.D., Whitney A. Spannuth, M.D., Alpa M. Nick, M.D., Derek J. Fiterman, M.D., and Robert L. Coleman, M.D., all of M. D. Anderson’s Department of Gynecologic Oncology; Jansina Y. Fok, also a co-first author, and Pablo E. Vivas-Mejia, Ph.D., both of the Department of Experimental Therapeutics; and Michael T. Deavers, M.D., of M. D. Anderson’s Department of Pathology. Hwang is also with the Department of Obstetrics and Gynecology, Dongguk University of College of Medicine, Kyung-ju, Korea. 07/15/08”

Quoted Source: TG2 Identified as Potential Target in Chemo-Resistant Ovarian Cancer – M. D. Anderson team silences protein with siRNA, implicates TG2 in fourth cancer, The University of Texas, M.D. Anderson Cancer Center News Release, July 15, 2008 (summarizing the findings of Clinical and biological significance of tissue transglutaminase in ovarian carcinoma; Sood, AK et. al,  Cancer Res. 2008 Jul 15;68(14):5849-58.)

Additional Information:

Understanding Cancer: A TV News Magazine

Yesterday, we came across an informative online cancer TV news magazine entitled “Understanding Cancer.” Based upon its mission statement, the Understanding Cancer website provides:

  • Empowerment through reliable, understandable information about cancer and its treatment;
  • Inspiration through the stories of cancer survivors and their cancer journeys;
  • Information about community oncology practitioners who are dedicated to outstanding patient care;
  • Stress relief through a “Meditation Room;”
  • Tips for managing symptoms;
  • Tools for living life to its fullest;
  • Compassion and understanding;
  • Relaxation through its “Mindless Distractions” which include online games, and crafts;
  • And most of all…Hope!

If you would like to learn more about Understanding Cancer TV, click here to watch the Understanding Cancer Welcome video located under the H*O*P*E*™ Ovarian Cancer Video Archive posting dated July 10, 2008, or visit the Understanding Cancer website by clicking on the banner below.


www.UnderstandingCancer.tv

U.S. News & World Report Issues 2008 Best U.S. Hospitals List

On July 10, 2008, U.S. News & World Report issued its 2008 list of the best U.S. hospitals (for adults). The University of Texas, M.D. Anderson Cancer Center was rated #1 in Cancer, Brigham and Women’s Hospital was rated #1 in gynecology, and Johns Hopkins was rated #1 overall. If you would like more information regarding the 2008 U.S. News & World Report best U.S. hospitals ranking, click here. To read “Your ‘Best Hospitals’ Questions Answered,” written by U.S. News & World Report’s Avery Comarow, click here.  U.S. News & World Report issued its 2008 “America’s Best Children’s Hospitals” last month.  If you would like to review the 2008 “America’s Best Children’s Hospitals” List, click here.

Top 10 U.S. Hospitals: Cancer

Top 10 U.S. Hospitals: Gynecology

Top 10 U.S. Hospitals (highest scores in at least six medical specialties)

1. Univ. of Texas M.D. Anderson Cancer Center, Houston, Texas Brigham and Women’s Hospital, Boston, Massachusetts Johns Hopkins Hospital, Baltimore, Maryland
2. Memorial Sloan-Kettering Cancer Center, New York, New York Johns Hopkins Hospital, Baltimore, Maryland Mayo Clinic, Rochester, Minnesota
3. Johns Hopkins Hospital, Baltimore, Maryland Mayo Clinic, Rochester, Minnesota Ronald Reagan UCLA Medical Center, Los Angeles
4. Mayo Clinic, Rochester, Minnesota Duke University Medical Center, Durham, North Carolina Cleveland Clinic, Cleveland, Ohio
5. Dana-Farber Cancer Institute, Boston, Massachusetts Univ. of California, San Francisco (UCSF) Medical Center Massachusetts General Hospital, Boston, Massachusetts
6. University of Washington Medical Center, Seattle, Washington New York-Presbyterian Univ. Hospital of Columbia & Cornell, New York, New York New York-Presbyterian Univ. Hospital of Columbia & Cornell, New York, New York
7. Massachusetts General Hospital, Boston, Massachusetts Magee-Womens Hospital of Univ. of Pittsburgh Medical Center, Pittsburgh, Pennsylvania Univ. of California, San Francisco (UCSF) Medical Center
8. Univ. of California, San Francisco (UCSF) Medical Center Cleveland Clinic, Cleveland, Ohio -Brigham and Women’s Hospital, Boston, Massachusetts/-Duke University Medical Center, Durham, North Carolina
9. Stanford Hospital and Clinics, Stanford, California Vanderbilt Univ. Medical Center, Nashville, Tennessee
10. Ronald Reagan UCLA Medical Center, Los Angeles Ronald Reagan UCLA Medical Center, Los Angeles Hospital of the Univ. of Pennsylvania, Philadelphia, Pennsylvania/-University of Washington Medical Center, Seattle, Washington

Increased Worldwide Focus on the Safety of Drugs Used To Treat Chemotherapy-Related Anemia

Over the past month, there was considerable press coverage regarding the safety and proper use of epoetin alfa (marketed as Epogen® & Procrit®) and darbepoetin (marketed as Aranesp®). Both drugs are erythropoiesis-stimulating agents (ESAs).

This controvery began between December 2006 and February 2007, when the U.S. Food and Drug Administration (FDA) was made aware of several studies in cancer patients that showed higher mortality or shorter time to tumor progression in patients randomized to receive an ESA as compared to placebo. Some of the trials dosed patients in the ESA treatment group to achieve hemoglobin levels ≥ 12 g/dl (higher than recommended on the ESAs drug box labeling). Other trials included anemic patients who were not on chemotherapy or radiotherapy. These studies were discussed at a May 10, 2007 meeting of the Oncology Drug Advisory Committee of the FDA (ODAC). The ODAC recommended additional restrictions in the labeling for ESAs including: (i) specific tumor types for which adverse safety signals were observed with the use of an ESA, (ii) instructions for hemoglobin trigger level-based dose modification/suspension, and (iii) instruction to discontinue use of ESAs upon completion of chemotherapy.

With respect to cancer the FDA recommendations to healthcare professionals include the following:

  • ESAs shortened the overall survival and/or time-to-tumor progression in patients with various cancers;
  • Risks of shortened survival and tumor progression have not been excluded when ESAs are dosed with the intent to achieve hemoglobin levels <12g/dL;
  • Use the lowest dose of [Aranesp/EPOGEN/PROCRIT] needed to avoid red blood cell transfusions. Do not exceed the upper safety limit for hemoglobin levels of 12 g/dL;
  • Reduce the ESA dose by 25% when hemoglobin reaches a level needed to avoid transfusion;
  • Withhold dosing with an ESA when hemoglobin level exceeds 12 g/dL;
  • Restart dosing at 25% below the previous dose when the hemoglobin approaches a level where transfusions may be required;
  • Discontinue treatment with an ESA following the completion of a course of chemotherapy; and
  • Use of ESAs in cancer patients have not been demonstrated in controlled clinical trials to improve the symptoms of anemia, quality of life, fatigue, or well-being.

The FDA also provided patient counseling guidance to healthcare professionals with respect to the use of ESAs. As part of a risk minimization plan, the FDA announced that it is developing a patient “Medication Guide” to better communicate the risks and benefits of ESA use to patients. Physicians and other healthcare professionals were advised by the FDA to discuss the following talking points with their patients:

  • The primary goal of treatment with erythropoiesis stimulating agents (ESA) is to increase the number of red blood cells in order to avoid receiving blood transfusions.
  • ESAs require at least 2 weeks of treatment before there is an increase in the number of red blood cells and the dose may be adjusted periodically but not more often than every 4 weeks.
  • ESAs increase the patient’s chance of blood clots and the risk of dying may be greater in certain circumstances
  • Patients should keep appointments for blood tests so hemoglobin levels can be monitored.
  • Patients need to monitor their blood pressure and contact their doctor if there are any changes outside of the range that has been established for them.
  • Patients should contact their doctor if they experience any of the following symptoms:

o Pain and/or swelling in the legs;
o Worsening in shortness of breath;
o Increases in blood pressure;
o Dizziness or loss of consciousness;
o Extreme tiredness; and
o Blood clots in hemodialysis vascular access ports

On June 26, 2008 -in a surprising announcement – the European Medicines Agency (EMEA) urged oncologists to favor blood transfusions over ESAs. Although these popular drugs have been used to treat cancer-related anemia for close to 20 years and have become a mainstay of therapy, the new recommendation is encouraging clinicians to reverse this common practice. The EMEA committee for Medicinal Products for Human Use (CHMP) recommendation is based upon its review of new data from studies that showed an increased risk for tumor progression, venous thromboembolism, and shorter overall survival in patients who received ESAs. “In cancer patients with a reasonably long life expectancy, the benefit of using epoetins does not outweigh the risk of tumor progression and shorter overall survival,” the committee noted in a statement. There are many U.S. doctors who believe that there is simply not enough data to conclude that ESAs are unsafe. Despite that fact, the ESA controversy is likely to continue until definitive fact-based evidence is fully developed.

Sources:

The “Fight Back Express” – A Mobile Petition To Fight Cancer

“The Fight Back Express is rolling across the nation, carrying the mobile message that Americans have the power to fight cancer in this country with their voices. The American Cancer Society Cancer Action Network (ACS CAN) is sponsoring the 6-month bus tour to highlight the crucial role elected officials play in supporting laws and policies that help people fight cancer. The ACS CAN Fight Back Express kicked off in Ohio in early May and will travel across the 48 continental United States through Election Day, Nov. 4 [2008].”

“The Fight Back Express is rolling across the nation, carrying the mobile message that Americans have the power to fight cancer in this country with their voices. The American Cancer Society Cancer Action Network (ACS CAN) is sponsoring the 6-month bus tour to highlight the crucial role elected officials play in supporting laws and policies that help people fight cancer. The ACS CAN Fight Back Express kicked off in Ohio in early May and will travel across the 48 continental United States through Election Day, Nov. 4 [2008].

‘If one person can fight cancer, then a nation can rise up and defeat it,’ said Daniel E. Smith, president of ACS CAN, the sister advocacy organization of the American Cancer Society. ‘As an essential partner in the fight against cancer, government has a critical role to play in enacting laws and policies that help people battle a disease that will kill an estimated 565,650 people in America this year.’ Scientific discovery alone will not defeat cancer. The federal government is by far the largest source of cancer research funding, but years of budget freezes and cuts are impeding progress.

Through the bus tour, ACS CAN is working to make cancer a higher national priority by educating the public, lawmakers, candidates and the media about the importance of government’s role in defeating cancer. Cancer patients, survivors, caregivers and their families gather at each stop to share their experience with the disease and to voice the need to make dramatic changes in this country’s approach to cancer. ‘We can make this disease history,’ said Bob Willman, an ACS CAN State Lead Ambassador Volunteer from Springfield, Ohio. ‘We know what we need to do to win the war on cancer. Now we need our elected officials to join us and support laws and policies that will help defeat this disease.’

The ACS CAN Fight Back Express is a mobile action center. At each bus stop visitors have the chance to share their story with their Members of Congress through the Picture A Cure program and sign a petition to support access to quality health care for all Americans. The ACS CAN Fight Back Express bus tour comes on the heels of a major public education campaign by ACS CAN and the American Cancer Society, raising awareness about the critical need for access to quality healthcare for all Americans. There has been tremendous progress in the fight against cancer, as evidenced by the reduction in death rates from cancer every year since 1991. But continued success is at risk if Americans don’t have access to cancer prevention, early detection and treatment. More than 47 million people in America are uninsured and countless millions more are underinsured, making them more likely to be diagnosed at later stages when cancers are more deadly. Too often, lifesaving cancer prevention, early detection, and treatment programs are not available to patients who need care the most.

ACS CAN supports evidence-based policy and legislative solutions for a number of cancer-related issues including:

  • Prevention and Early Detection: Regular screenings can catch cancer at its earliest, most treatable stages, but a federal program that offers low-income and uninsured women screenings for breast and cervical cancer only covers 1 in 5 eligible women. A similar program for colon cancer is now pending before Congress and needs to be created immediately as both of these programs have the potential to save lives.
  • Increased Funding for Cancer Research: Medical research could lead to the discovery of prevention and early detection tools for the most deadly cancers such as pancreatic and ovarian cancer, but federal research funding has been frozen or cut in recent years, threatening progress.
  • Tobacco Control: Tobacco is responsible for approximately one-third of all cancer deaths, but the federal government still lacks the ability to regulate tobacco products. At the state and local level, strong smoke-free policies could significantly reduce the number of tobacco-related cancer cases by protecting workers and patrons from the hazards of secondhand smoke.

The Fight Back Express is made possible by the contributions of millions of American Cancer Society and ACS CAN donors across the country whose lives have been touched by cancer. Additionally, the bus tour is made possible by a generous contribution from Pharmaceutical Research and Manufacturers of America (PhRMA). “Incredible progress has been made in recent years in the battle against cancer,” said PhRMA President and CEO Billy Tauzin. ‘America’s pharmaceutical research companies work hard every day to develop new medicines that will enable cancer patients to live longer, healthier, more productive lives. However, scientific research isbut one piece of the puzzle; improved prevention, early detection and access to quality healthcare are equally critical. Together, we can win this fight.’

To find out more about the ACS CAN Fight Back Express and how to make cancer a national priority log on to www.acscan.org. ACS CAN, the nonprofit, nonpartisan advocacy partner of the American Cancer Society, supports evidence-based policy and legislative solutions designed to eliminate cancer as a major health problem. ACS CAN works to encourage elected officials and candidates to make cancer a top national priority. ACS CAN gives ordinary people extraordinary power to fight cancer with the training and tools they need to make their voices heard. For more information, visit www.acscan.org.”

Quoted Source: National Bus Tour Rolls Across the Nation Urging Americans to Join the Fight to Defeat Cancer – American Cancer Society Cancer Action Network Effort Highlighting the Role of Elected Officials in the Fight Against Cancer, American Cancer Society Cancer Action Network Press Release, undated.

Comment: For additional information regarding the Fight Back Express including: (i) the purchase of miles to keep the bus on the road; (ii) the upcoming Fight Back Express stop locations; and (iii) stories from the roadtrip, please click here. A YouTube video regarding the ACS CAN Fight Back Express bus tour is provided below.

ACS CAN Fight Back Express Bus Tour

IL-7 Boosts Immune Response in Cancer Patients

” … [Recombinant human interleukin-7] rhIL-7 appears to be an effective T cell growth factor with “immune rejuvenating” properties, suggesting that it is effective in augmenting immune reactivity in hosts with impaired immunity due to any number of factors, including age, chemotherapy, and infectious disease, the authors note. In patients with both intact and deficient immune systems, the capacity of rhIL-7 to augment responses to weak antigens and to increase T cell cycling without expanding T regulatory cells might be clinically exploitable in the context of immunotherapy regimens for cancer and/or chronic infection, they write.”

“Data from a preliminary study suggest that recombinant human interleukin (r-hIL)-7 can enhance and broaden immune responses in patients with impaired immunity due to lymphocyte depletion.

The results of the phase 1 trial, published online June 23 in The Journal of Experimental Medicine, showed that when given to cancer patients, rhIL-7 induced a dramatic polyclonal prolonged expansion of CD4+ and CD8+ T cells, which in turn caused a significant broadening of circulating T cell receptor repertoire diversity. These effects were mediated primarily through an increase in peripheral T cell cycling and augmented cell survival.

Lymphopenia induced by cytotoxic chemotherapy, or pathologies such as HIV infection, can significantly weaken immune function; as a physiologic immuno-enhancer, IL-7 can enhance the restoration of T cells. CD4+ T cell recovery in adults who have experienced severe depletion requires the reemergence of a pool of naive T cells, which generally takes 18 to 24 months and might only occur in people younger than 40 to 45 years. Thus, the authors note, a strategy that can accelerate or promote the recovery of a widely diverse T cell repertoire in older people might be useful for a large number of clinical applications.

‘We know that IL-7 can enhance tumor vaccines in animals, so that would be a clear avenue of research,’ said lead author Claude Sportès, MD, senior staff clinician at the National Cancer Institute‘s Center for Cancer Research, Experimental Transplantation and Immunology Branch, in Bethesda, Maryland. ‘But it wouldn’t only have to be tumor vaccines. Hopefully we will have a trial underway in the not-too-distant future looking at how it can enhance anti-viral and other immunizations, particularly in the elderly.’

Treatment with IL-7 therapy exerted a marked effect on T cell immune reconstitution during preliminary trials with animal models. It also appeared to augment effector and memory responses to vaccination in mice; in preclinical models, IL-7 therapy was able to augment anti-tumor responses that might improve survival when combined with anti-tumor vaccines.

‘In older individuals, therapy with IL-7 could lead to a rejuvenation of the phenotype,’ explained Dr. Sportès in an interview. ‘This in turn can lead to better vaccine responses in general and, in oncology, better tumor vaccine responses.’

The implications for rhIL-7 are potentially vast, and there are many promising therapeutic avenues. ‘But as often happens in medicine,’ he cautioned, ‘things can be very promising at this stage and then fizzle out.’

First Human Trial

In this phase 1 dose-escalation study, the first initiated in a human population, Dr. Sportès and colleagues evaluated the effects of IL-7 therapy on human lymphocytes in 16 patients, between the ages of 20 to 71 years, with nonhematologic, nonlymphoid refractory cancer. The doses, extrapolated from previous mouse and primate studies, were 3, 10, 30, and 60 μg/kg, and were administered by subcutaneous injection every other day for 14 days, for a total of 8 doses.

They found that after a very transient decrease, the numbers of circulating lymphocytes and CD4+ and CD8+ T cells increased in a dose-dependent manner. At the highest dose levels, increases approached 300% for CD4+ and exceeded 400% for CD8+ T cells. Overall, the treatment induced widespread T cell cycling and was able to expand the T cell pool in human patients while preserving T cell function.

Treatment with rhIL-7 also seems to have advantages over rhIL-2, explained Dr. Sportès. The expanded T cells retained significant functional capacity, and the CD4+ T cell expansion was not accompanied by a disproportionate increase in T regulatory cells, a phenomenon that has been observed after rhIL-2 therapy. Previous data have shown that in vivo IL-2 administration in humans has minimal effects on CD8+ T cell numbers, whereas rhIL-7 effects on CD8+ T cell expansion are at least comparable to the effects on CD4+ T cells.

The researchers noted that rhIL-7 increases T cell receptor repertoire diversity, and that although it appears to selectively expand CD4+ recent thymic emigrants, naive cells, and central-memory populations, it did not have the same effect on effector T cells.

The details of the clinical trial will be the focus of a separate paper, said Dr. Sportès. ‘But it was well tolerated and we went to full-dose escalation.’

“Immune Rejuvenating” Properties

rhIL-7 appears to be an effective T cell growth factor with “immune rejuvenating” properties, suggesting that it is effective in augmenting immune reactivity in hosts with impaired immunity due to any number of factors, including age, chemotherapy, and infectious disease, the authors note.

In patients with both intact and deficient immune systems, the capacity of rhIL-7 to augment responses to weak antigens and to increase T cell cycling without expanding T regulatory cells might be clinically exploitable in the context of immunotherapy regimens for cancer and/or chronic infection, they write.”

[Quoted Source: IL-7 Therapy Boosts Immune Response in Cancer Patients, by Roxanne Nelson, Medscape Medical News, Medscape Today, July 4, 2008 (summarizing the findings of Administration of rhIL-7 in humans increases in vivo TCR repertoire diversity by preferential expansion of naive T cell subsets; Sportes, C. et. al., J Exp Med. 2008 Jun 23. Epub ahead of print]