Dr. Ratner's Lab
The current research of our laboratory is focused on 1) disruption of the homologous recombination (HR) repair pathway as concurrent therapy to sensitize chemoresistant and sporadic ovarian cancer; 2) inhibition of the AKT/mTOR pathway to synergize with platinum and PARP inhibitor therapy in BRCA- associated ovarian cancer; 3) gene expression profiling to identify molecular targets for synthetic lethal approaches in chemoresistant and sporadic ovarian cancer; 4) blockade of the p53 pathway as therapeutic strategy for chemo-sensitizing p53-wild type ovarian cancer and ovarian cancer stem cells.
Poly(ADP-ribose) polymerase (PARP) inhibitors belong to a new class of cancer drugs that exploit synthetic lethality to target hereditary ovarian cancer with BRCA mutations or deficiency in HR repair. In clinical trials, ovarian cancer patients with BRCA mutations exhibit favorable responses to the PARP inhibitor olaparib compared to patients without BRCA mutations. Despite that the effectiveness of PARP inhibitors is limited to a small subset of ovarian cancer patients, the hypersensitivity of BRCA-associated ovarian cancer to PARP inhibitors provides a “proof-of-concept” strategy to rationalize that the HR repair pathway can be targeted to circumvent chemoresistant phenotypes with conventional chemotherapy and new-generation anticancer therapy. To this end, the laboratory is currently partaking target identification and drug discovery by 1) characterizing known small-molecule inhibitors that disrupt the HR repair pathway; 2) developing drug combinations using mechanism-based and synthetic lethal approaches; 3) identifying novel small-molecule inhibitors using high-throughput screening of compound libraries against molecular interactions critical for DNA repair pathways; 4) conducting siRNA screening and phenotypic/gene expression profiling to discover cellular targets responsible for chemoresistant phenotypes in ovarian cancer.
Our research interests include ovarian cancer, chemotherapeutic resistance, synthetic lethality, DNA repair, BRCA genes, combination therapy, drug discovery, gene expression profiling and study of microRNA