Cancer is a disease of the genome, and genetic alterations drive cancer progression by enhancing the growth "fitness" properties of cancer cells. The growth "fitness" resulting from genetic alterations could also create an "Achilles' heel" or a vulnerability in cancer. New generations of chemotherapies are beginning to exploit these vulnerabilities in cancer by targeting the metaphorical Achilles' heel. This approach of targeting cancer is exemplified by PARP inhibitors that specifically target genetic defects in homology repair pathway in ovarian cancer.

A cancer cell with mutated genome is similar to Jenga structure with several missing blocks. Just as the entire structure can collapse with the removal of a critical block, cancer cells can be killed when a critical gene in cancer is disrupted. To extend this analogy further, similar to a fully stacked Jenga structure that can tolerate removal of a few blocks, normal cells with fully functional genome can tolerate such disruption, thereby allowing a strategy to specifically target cancer cells while minimizing the harm to normal cells. To identify these weaknesses in cancer that are harmful to cancer cells but tolerated in normal cells, several groups have developed methods to disrupt genes in cancer cells systematically and characterized which disruption killed cancer cells. Three separate groups identified genes involved in protein quality control as critical genes in ovarian cancer cells. In particular, the disruption of a gene called VCP was detrimental specifically to ovarian cancer cells but not to other cancer cell types. VCP acts as a quality control in protein production, and it is needed to remove misfolded proteins that can be toxic to cancer cells. In addition, many proteins involved in DNA repair are dependent on the protein quality control to function properly. When drugs, like bortezomib, inhibit this pathway, expression of DNA repair genes are reduced, thereby enhancing the effectiveness of chemotherapies like cisplatin or olaparib.

My laboratory group is advancing the development of VCP inhibitors as potential chemotherapeutic agents for ovarian cancer. In particular, we tested two VCP inhibitors in ovarian cancer cell lines, and these drugs are effective in killing cancer cells. Using these two drugs as a base, a pharmaceutical company, Cleave Bioscience, has further developed a more potent drug that can be taken orally. Researchers at Cleave Bioscience have shown that their compound, CB-5083, interfered with protein quality control in cancer cells and inhibited tumor growth in mouse models. Our preliminary results indicate that these drugs induce unfolded protein response and activate programmed cell death in cancer cells. In addition, our preliminary results indicate that these drugs can be combined with other agents that disrupt protein quality control to enhance the cytotoxic effect of VCP inhibition in cancer cells. Because this pathway is essential for ovarian cancer cells, we will determine how best to target this pathway using VCP inhibitors in combination with other agents that disrupt important components of this pathway. We will determine what effect these agents have on the expression of DNA repair genes and how these agents enhance chemotherapies that cause DNA damage. Successful completion of proposed studies will allow us to develop novel therapies to treat cisplatin-resistant ovarian cancer or to extend the effectiveness of currently available chemotherapies that include platinum agents and PARP inhibitors.