Cancer arises from progressive acquisition of alterations in DNA of cells. Knowledge of these alterations has led to groundbreaking discoveries in targeted therapies for some cancers such as Herceptin which targets over-produced HER2 proteins in HER2-positive breast cancer. However, identifying targeted therapeutic approaches for treating ovarian cancer remains in its infancy. One challenge is that tumors from ovarian cancer patients contain thousands of DNA alterations, making it difficult to identify causal genes critical for cancer development and progression. This proposal has applied a high-throughput screening approach to analyze gene function in cancer genomes, aiming to identify cancer-causing genes with therapeutic potential in ovarian cancer.
Preliminary studies revealed 17 candidate genes that were able to transform non-cancer cells into cancerous cells and often over-produced in primary ovarian tumors. Furthermore, we confirmed the top candidate GAB2 signaling protein to be over-produced in at least 44% of primary ovarian tumors. Patients whose tumors are GAB2-positive showed poor prognosis. This proposal will investigate the cancer-causing ability and therapeutic potential of these 17 genes in ovarian cancer. This proposal will also test hypotheses that over-produced GAB2 proteins promote the aggressive growth of ovarian tumors, and in response to chemotherapy, enable tumor cells to survive and re-grow rapidly as resistant tumors.