Ovarian cancer is the most lethal of the gynecological malignancies. Ovarian tumors can be particularly difficult to treat as they are often not responsive to the chemotherapeutics that are currently in use for the treatment of ovarian cancer. Recently, it was found that some types of ovarian cancer have mutations in the ARID1A gene and lack ARID1A protein expression. These mutations were found in tumors, but not in normal tissue from the same patient, suggesting a causal link between loss of ARID1A protein and tumor initiation or growth. Paradoxically, loss of ARID1A causes growth arrest and cell death, not the uncontrolled cell division that occurs in cancer. Thus, there must be mutations in other proteins that cooperate with mutations in ARID1A to drive tumor formation. Recent data suggests that mutations in ARID1A are most often paired with mutations in an enzyme called PI 3-Kinase for which drugs have been developed. This proposal aims to understand how cells respond to mutations in these two different proteins to become cancerous. With this mechanistic understanding, we hope to determine how this class of ovarian tumors responds to PI 3-Kinase inhibitors with the aim of providing better, more personalized chemotherapeutic treatment.
This grant was made possible through the generous support of the University of California Office of the President’s Tobacco-Related Disease Research Program.
Diana Hargreaves, Ph.D. is currently a postdoctoral scholar in the laboratory of Gerald Crabtree at Stanford University. She is investigating the function of a protein, ARID1A, which has recently been shown to be frequently mutated in clear-cell and endometrioid ovarian cancer. ARID1A is a member of a complex of proteins, the BAF complex, which utilizes energy derived from ATP to alter DNA structure. Using a combination of biochemistry and mouse genetics, she hopes to uncover how ARID1A functions within this complex to protect cells from becoming oncogenic. Diana received her Ph.D. from the Department of Immunology at Yale University under the guidance of Dr. Ruslan Medzhitov and her B.S. from Haverford College. Diana was awarded the NSF Graduate Research Fellowship as a graduate student and is currently sponsored by a fellowship from the Helen Hay Whitney Foundation.