Cancer predisposition resulting from the presence of a specific gene variant shows a strong gender bias, researchers at the University of Cincinnati (UC) have demonstrated.

In addition, the research indicates that the risk for development of cancer in individuals harboring the gene variant can be further increased as a result of environmental exposure.

Peter Stambrook, PhD, a professor in the department of molecular genetics, biochemistry and microbiology, and colleagues report their findings this week in Proceedings of the National Academy of Sciences (PNAS). Coauthors include researchers from Wright State University and the Laboratory for Health Protection Research, National Institute of Public Health and the Environment, the Netherlands.

Stambrook says the gene CHEK2 is part of a DNA damage response pathway that can have an impact on whether or not cancers develop. A CHEK2 variant, CHEK2*1100delC, is associated with increased risk of cancer.

“Women who carry this particular gene variant are predisposed to developing breast or ovarian cancer,” says Stambrook, “while men have a higher risk of developing prostate cancer.”

Stambrooks team has produced a mouse model in which the CHEK2 gene was replaced by the variant and found that the overwhelming majority of mice that developed cancer were female about 80 percent, as opposed to slightly more than 15 percent for males. This contrasts sharply with the incidence of cancer in wildtype mice (those with the normal CHEK2 gene), in which male and female mice developed cancer to about the same extent but at a much lower frequency.

Stambrook says his team will be exploring possible reasons behind the difference, looking at hormonal involvement and possible interactions between the gene variant and estrogen receptors or estrogen itself.

By using a known carcinogen, dimethyl benzanthracene, the researchers also determined that mice that harbor the variant are more susceptible to an environmental challenge than those that dont. The compound was administered orally to female mice.

“When they delivered the compound, the lifespan of the mice was reduced significantly they developed breast cancer as well as other types of cancers,” Stambrook says. “In addition, the mice that harbored this variant were more susceptible in other words, they developed tumors more quickly than wildtype mice.”

Stambrook says that by learning more about the signaling pathway of the CHEK2 gene, researchers can explore ways to “rescue” it and identify potential therapeutic targets.

“Its an interesting gene,” says Stambrook, “and there are a lot of interesting directions that this finding will take us.”

The work was supported in part by grants from the National Institutes of Health and UCs Center for Environmental Genetics.

Keith Herrell Keith Herrell

Tikcro Technologies (PK TIKRF) announced that the United States (”US”) Department of Health and Human Services (”HHS”) has granted orphan drug status to BioCancells BC819 drug, currently in Phase I/IIa clinical trials, for its use in treating ovarian cancer.

Tikcro holds 36% of Biocancell (after conversion of notes and exercise of warrants), and 27% on a fully diluted basis.

The US Food and Drug Administration (”FDA”) defines an orphan drug as one that treats a disease affecting less than 200,000 people each year. The main benefit received under orphan drug status is the right to market the drug exclusively for 7 years from the date it is approved. Additional benefits include certain tax benefits and waived FDA fees.

The first patient in a Phase I/IIa clinical trial for advanced ovarian cancer using BC819 began treatment in the second quarter of 2009. The trial addresses patients suffering from advanced ovarian cancer characterized by ascites, peritoneal cavity fluid containing cancerous cells that did not previously respond to standard treatment for the disease. The trial is expected to include a total of 12 patients, each receiving nine weekly treatments.

The University of Pennsylvania Medical Center in the US and three centers in Israel the Wolfson Medical Center in Holon, the Meir Medical Center in Kfar Saba and the Hadassah Medical Center in Jerusalem, are recruiting patients for the trial. The Massey Cancer Center of Virginia Commonwealth University in the US is expected to begin recruitment pending certain local regulatory approvals.

This Phase I/IIa trial follows a compassionate use trial conducted in Israel with a patient suffering from ovarian cancer characterized by intraperitoneal distribution of metastases and ascites, who failed conventional chemotherapy treatment. The results of the compassionate trial showed that the drug caused no serious adverse events (”SAEs”) at any dosage. Additionally, the patients blood showed a 50% decrease of the ovarian cancer marker protein CA125, and a significant decrease in the number of cancerous cells in the ascites was measured. Clinical improvement was reported in the patients condition.

Source

Ovarian cancer kills approximately 15,000 women in the United States every year, and more than 140,000 women worldwide. Most deaths from ovarian cancer are caused by tumors of the serous histological type, which are rarely diagnosed before the cancer has spread.

In order to better understand the early natural history and to guide rational design of an early detection strategy for these cancers, Patrick Brown and colleagues from Stanford University developed models for the growth, progression, and detection of these cancers, in order to define what properties a biomarkerbased screening test would require in order to be clinically useful.

Funding This work was funded by the Canary Foundation and the Howard Hughes Medical Institute. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing Interests
The authors have declared that no competing interests exist.

Citation
“The Preclinical Natural History of Serous Ovarian Cancer Defining the Target for Early Detection.”
Brown PO, Palmer C (2009)
PLoS Med 6(7) e1000114. doi10.1371/journal.pmed.1000114

Researchers from the Centers for Disease Control and Prevention (CDC) found that survival among women with ovarian cancer is influenced by age of menarche and total number of lifetime ovulatory cycles.

This finding suggests that hormonal activity over the course of a womans lifetime may influence the prognosis after an ovarian cancer diagnosis. Results of this study are published in Cancer Epidemiology, Biomarkers & Prevention, a journal of the American Association for Cancer Research.

Results of previous studies indicated that fewer lifetime ovulatory cycles, higher parity, oral contraceptive use, hysterectomy and tubal ligation are associated with decreased risk of developing this form of cancer, according to the researchers. However, little is known about the influence of these factors on a patients survival after a diagnosis of ovarian cancer.

Cheryl L. Robbins, Ph.D., an epidemiologist at the CDC, and colleagues sought to explore whether these reproductive factors influence ovarian cancer survival.

“Ovarian cancer is the fifth leading cause of cancer mortality in women. It accounts for more deaths than any other gynecologic cancer,” said Robbins, also a researcher on the study. “Although we have relatively good knowledge about the influence of reproductive factors on the risk of developing ovarian cancer, knowledge is rather limited regarding the reproductive factors that may influence survival after diagnosis with this serious disease.”

Robbins and colleagues conducted a longitudinal analysis of 410 women, aged 20 to 54 years. All participants were previously enrolled in the 19801982 Cancer and Steroid Hormone (CASH) study as incident ovarian cancer cases.

After a followup of about 17 years, 221 women died; findings showed that overall 15year survival among the study population was 48 percent. Lifetime ovulatory cycle and age at menarche were two factors that played a key role in predicting death from ovarian cancer.

Women with the most lifetime ovulatory cycles had poorer survival compared with those who had fewer lifetime ovulatory cycles. Robbins explained that the number of lifetime ovulatory cycles a woman has is affected by her use of oral contraceptives, pregnancy and breastfeeding, all of which temporarily cause ovulation to cease and reduces the total number of cycles.

Furthermore, the researchers determined that those with the youngest age at menarche also had poorer survival. After diagnosis of ovarian cancer, participants whose menarche began before age 12 were more likely to die compared with those whose menarche began at age 14 or older.

“We now have evidence that higher numbers of lifetime ovulatory cycles may play a role in the development of ovarian cancer as well as the risk of death after being diagnosed with the disease,” Robbins concluded.

This study points to some important future directions of research for better understanding the influence of reproductive factors on ovarian cancer survival.

Mary B. Daly, M.D., Ph.D., director of the Personalized Cancer Risk Assessment Program at the Fox Chase Cancer Center in Philadelphia, said these results raise the question “can the amount and/or duration of reproductive hormones to which women are exposed affect the aggressiveness of ovarian cancer and/or its resistance to treatment, and if so, by what mechanism?”

“The significance of this paper is in suggesting new research directions, not in any immediate treatment changes,” said Daly, who is also an editorial board member for Cancer Epidemiology, Biomarkers & Prevention. “The next steps would be to study this association in a prospective study, then to characterize molecular and genetic profiles of ovarian tumors and compare these profiles among different levels of exposure to reproductive hormones.”