Clear Cell Ovarian Carcinoma (CCOC) is one of the most clinically challenging types of ovarian cancer. The current standard-of-care consists in surgical resection and platinum therapy. The latter is a type of chemotherapy that causes changes in the DNA structure that result in cancer cell death. Unfortunately, platinum-based therapies are toxic and tumors frequently develop resistance to this type of treatment, leaving no good therapeutic alternatives. Thus, there is an urgent need for innovative research in this area.
Recently published data from our lab has led to the identification of a subset of CCOC patients that express high levels of an enzyme called APOBEC3B and are exquisite responders to platinum therapy. APOBEC3B is usually active as a part of our natural defense against viral infections. It attacks the genome of viruses by mutating their DNA, which in turn corrupts viral proteins and impairs virus replication and pathogenesis. However, in CCOC and other cancer types, APOBEC3B becomes activated without a viral infection and starts to attack and damage cellular chromosomal DNA. The cells in our body are equipped with machinery that recognizes this DNA damage and tries to repair it, yet many lesions escape repair and accumulate as mutations and DNA structural changes. Therefore, in CCOC tumors treated with platinum therapy there is a toxic accumulation of DNA damage caused by both the treatment and APOBEC3B activity. This simultaneous perturbation results in preferential death of the CCOC tumor cells (i.e. synthetic lethality). Thus, I hypothesize that the aberrant activation of APOBEC3B in CCOC makes these tumors dependent upon the proper functioning of cellular DNA repair machinery. Thus, inhibition of this machinery is predicted to lead to the selective death of CCOC tumor cells expressing APOBEC3B.
In this proposed research project, I will pursue two goals: Aim 1- Identify inhibitors (already in drug development pipelines) of the DNA repair machinery that kill CCOC tumor cells even more efficiently than platinum therapy when APOBEC3B is active. Aim 2- Identify the components of the DNA repair machinery responsible for the accumulation of DNA damage in CCOC patients treated with platinum therapy and active APOBEC3B. The results of these studies have the potential to identify new therapeutic opportunities for CCOC.