Metformin Supplementation for Ovarian Cancer Prevention: A Prospective Preclinical Study

Ovarian cancer is the most lethal gynecological disease affecting women. The higher rate of mortality is attributed to the fact that women with ovarian cancer do not show symptoms at an early stage but are often (>85% of cases) diagnosed at an advanced stage of disease progression resulting in a poor (27%) 5-year survival rate. Cancer prevention strategies, therefore, assume a greater importance in reducing the incidence of ovarian cancer. Metformin, a generic anti-diabetic drug, has been used in the past for improving insulin sensitivity and to manage type 2 diabetes symptoms. Several retrospective surveys have found indirect clinical evidence that metformin intake is correlated with greater survival in cancer patients including ovarian cancer patients. However, there are no prospective clinical studies to suggest that metformin intake reduces the incidence and/or severity of ovarian cancer. We seek to address this critical gap in knowledge by conducting a pilot preclinical study utilizing a naturally and spontaneously occurring ovarian cancer model. Preliminary studies have revealed that in the preclinical chicken model, hens develop ovarian tumor naturally at a very high rate that exceeds 25% during 2-4 years of age. Metastatic ovarian cancer cells isolated from the chickens were found to be aggressive and invasive and expressed genes and proteins commonly found in human ovarian cancer cells. Ovarian cancer stem cells recovered from ascites formed extensive network of ovospheres and were found to be highly invasive. The proposed pilot study will be conducted with two specific aims: 1) determine if long term dietary metformin intake affects incidence and severity of ovarian cancer; and 2) determine the extent to which metformin affects invasiveness and viability of ovarian cancer stem cells. Under the first aim, chickens will be fed with a diet supplemented with various levels of metformin for 18 months. Under the second aim, ovarian cancer stem cells isolated from the hen model will be treated with various levels of metformin. This project is innovative because it uses a substantively different approach for preclinical testing of potential anti-cancer effects of metformin. Furthermore, this research will utilize ovarian cancer stems cells isolated from hens to test their susceptibility to metformin treatment. The proposed research is significant because a positive outcome of this pilot study would lead to further testing of metformin in a population of euglycemic women who are at risk for developing ovarian cancer. Furthermore, this pilot study would lead to elucidation of the ovosphere microenvironment and the vulnerability of ovospheres to cancer prevention strategies.