Recurrent chemoresistant ovarian cancer is a lethal disease for which no effective therapies currently exist. Improved management of these cancers requires new therapeutic strategies that (1) target novel pathways of ovarian cancer cells and (2) can be used in combination treatments leading to effective tumor response with limited toxicities.

Standard of care for the treatment of ovarian cancer uses drugs inducing DNA damage that will ultimately kill the tumor cells. A recently approved therapy for chemoresistant recurrent ovarian cancer exploits the incapacity of ovarian cancer cells to repair DNA damages due to mutations in the BRCA genes. These drugs target the "poly ADP ribose polymerase" enzyme (PARP), which is used by the cells to repair DNA. These DNA breaks are normally repaired by the products of the BRCA genes, which are frequently found to be altered in patients with ovarian cancer. Thus, cells that receive PARP inhibitors and have mutated BRCA genes will develop non-repairable DNA breaks that will lead to the cells death. The currently approved drug that acts through this mechanism, Olaparib, was shown to induce a tumor response in 30% of ovarian cancer patients with mutation in the BRCA genes. Unfortunately however, its effect in overall survival has not been validated and it is known that this drug is not effective in the majority of the patients, i.e., the ones that do not have a mutation in the BRCA genes. Efforts are ongoing to identify therapeutics that could provide a synergistic treatment effect when combined with PARP inhibitors.

CB-839 is a new drug that targets metabolic alterations of cancer cells. Its toxicity and maximum tolerated dose were established in Phase 1 trials for multiple cancers. This drug targets the enzyme glutaminase-1, which allows the use of an important molecule, glutamine, as a source of nutrients (required for the cell survival) and of nucleotides (required for DNA repair and replication). Translational studies performed by our group have observed that, by inhibiting the use of glutamine, CB-839 not only starves ovarian cancer cells to death, but will also induce the formation of DNA breaks that will sensitize the cells to Olaparib. The goal of this proposal is to test this therapeutic paradigm through a small, proof-of-concept clinical trial that tests the efficacy of CB-839 against ovarian cancer when used as solo agent and in combination with a PARP inhibitor. To verify that CB-839 can sensitize ovarian cancer cells to a PARP inhibitor by inducing DNA damage, we will select only patients that have no BRCA mutations, i.e., patients with tumors that do not respond to a PARP inhibitor. We will then leverage the tissues collected through this clinical trial to perform translational studies aimed at understanding the mechanisms leading to sensitivity versus resistance of ovarian cancer cells to CB-839.

If successful, these studies will open a new avenue for the treatment of ovarian cancer targeting a pathway that has been completely unexploited till now. The will provide (1) the rationale for testing such combination treatment in a larger cohort and in patients with mutated BRCA genes through multi-institutional trial(s) and (2) new exploratory translational studies for the development of novel therapeutics acting through mechanisms that are not targeted by current drugs.