Site:  Northwestern University

Rationale

The five-year relative survival rate of cancer patients has improved from 50 to 68% in the last thirty years. The survival rate of pediatric cancers has reached 80%, and the NCI predicts that 1 out of every 250 adults will be a survivor of childhood cancer by 2015. As the number of cancer survivors increases, so does the concern for their quality of life post-treatment.

One of the most serious problems associated with radiation and chemotherapy is the off-target effect on germ cells. For young women, this is a particularly serious concern because the immature oocytes that comprise the ovarian reserve are highly sensitive to chemo/radiation therapies.

Since the ovarian reserve represents ALL the follicles available for future fertility as well as endocrine function, the loss of immature oocytes and subsequent sex steroid deficiency have significant physical and psychological consequences. The goal of this project is to better understand the mechanisms associated with survival and death of immature oocytes caused by cancer treatments, and in doing so, identify “neo-adjuvant” medical approaches for preserving fully functional ovaries in young women undergoing treatment.

The overall hypothesis of this proposal is that the balance between survival and death of oocytes in primordial and primary follicles is controlled by the interaction between p53 family members, and thus the p53 family members are targets for fertoprotective agents. 

The objectives of this project are to:

  • Elucidate the mechanism through which p53 family members are activated by chemotherapy.
  • Dissect the molecular pathways involved in the death of immature oocytes by applying in vitro culture and subrenal grafting of mouse ovaries to genetically engineered mouse models.

The results of these proposed studies will be critically important for understanding the mechanisms that underlie physiologic and iatrogenic follicle death and may reveal new strategies for protecting the fertility of young women diagnosed with cancer.