More than 22,000 women develop ovarian cancer each year in the United States. Despite substantial improvements in surgery and chemotherapy, the disease still proves lethal in 70% of cases. The persistence of dormant, drug-resistant cancer cells after primary surgery and chemotherapy is a major factor contributing to poor outcomes for ovarian cancer patients. Poly (ADP) ribose polymerase inhibitors (PARPi) are promising agents for the treatment of recurrent ovarian cancers. However, acquired drug resistance to PARPi decreased the clinical efficacy of these agents and the mechanism(s) of resistance in ovarian cancer is poorly understood. I have found that four different PARP inhibitors induce a process called autophagy or “self-eating” and that autophagy induces PARPi resistance in ovarian cancer cells. Through autophagy, cancer cells consume their own parts to generate energy in order to survive under stressful conditions. I have also shown that the addition of the autophagy inhibitor, chloroquine (CQ), can overcome resistance and enhance the anti-cancer activity of PARP inhibitors in different ovarian cancer models.
Our group has sought drugs that are selectively toxic for autophagic ovarian cancer cells and that might enhance sensitivity to PARP inhibitors. We have found that the FDA-approved ALK inhibitor, crizotinib, exhibited significantly greater toxicity after induction of autophagy, suggesting that autophagic ovarian cancer cells are selectively sensitive to ALK inhibition and that crizotinib might provide an effective agent to eliminate autophagic, ovarian cancer cells that remain after surgery and chemotherapy. As the PARP inhibitor olaparib induces autophagy in ovarian cancer cells and crizotinib selectively target autophagic cancer cells, my project will test the ability of crizotinib to improve the therapeutic efficacy of olaparib in ovarian cancer cells in xenografts models and define the mechanism(s) by which the combination of olaparib and crizotinib induces autophagy and increases cell death.
This grant is made possible in part by a generous donation from Joseph and Angela Campolo, in memory of Phebe Aubry.
Dr. Janice M. Santiago-O’Farrill is currently a postdoctoral fellow in the laboratory of Dr. Robert C. Bast at MD Anderson Cancer Center. Dr. Santiago-O’Farrill completed her B.S. from the University of Puerto Rico in 2008, where she was recipient of the National Smart Scholarship. Subsequently, she completed an M.S. in Pharmaceutical Sciences from the School of Pharmacy, University of Puerto Rico-Medical Sciences Campus. As a master’s student, she had the opportunity to participate in a summer research training program at MD Anderson Cancer Center through the University of Puerto Rico (UPR)/MD Anderson Cancer Center U54 Partnership for Excellence in Cancer Research Program. This experience confirmed her commitment to continue to work in cancer research. For this reason, after completing her master’s degree, she earned a Ph.D. in Cancer Biology from The University of Texas MD Anderson / UTHealth Graduate School of Biomedical Sciences. Her doctoral studies were conducted in the laboratory of Dr. Eugenie S. Kleinerman and focused on autophagy as a mechanism implicated in osteosarcoma resistance to chemotherapy. This research stimulated her interest in autophagy and her passion for cancer research.In 2015, Dr. Santiago-O’Farrill joined Dr. Bast’s laboratory, which has a strong background and expertise in the field of autophagy and ovarian cancer. She has found that olaparib, an FDA-approved PARP inhibitor, induces autophagy that enhances drug resistance in ovarian cancer cells. Having elucidated the mechanism by which olaparib induces autophagy, she is currently combining olaparib with FDA approved drugs that are selectively toxic for autophagic cancer cells, producing additive and synergistic antitumor activity. Dr. Santiago-O’Farrill received several awards for her graduate work including a First Place Research Award from the University of Puerto Rico- Medical Sciences Campus, and a Keystone Symposia National Institute of General Medical Sciences (NIGMS) Ancillary Training Program Scholarship. For her postdoctoral work, she has been awarded an AACR Minority Cancer Research Award. She is also a recipient of the NCI Research Diversity Supplement Award. The OCRA Ann and Sol Schreiber Mentored Investigator Award will help Dr. Santiago-O’Farrill to further growth as a translational scientist and better prepare her for an independent career with the goal of improving outcomes for women with ovarian cancer.