The major disease focus of my research is understanding how cancer cells respond to chemotherapy and understanding the pathways that are critical for maintaining drug sensitivity. The development of drug resistance is a major clinical limitation. The projects in the lab all relate to translational approaches for drug discovery that would enhance chemotherapeutic efficacy and overcome drug resistance in a variety of cancers. The specific areas of interest include: 1) Elucidating mechanisms of drug resistance in specific cancers with DNA repair defects 2) Targeting DNA repair pathways to enhance platinum based chemotherapy 3) Elucidating the role of the bystander effect in platinum resistance and how DNA damage and the DNA damage response pathway mediates the bystander effect 4) Elucidating the mechanism of how chromatin remodelers mediate cisplatin DNA repair and drug sensitivity. The lab is currently developing exciting new drugs that are entirely based on mechanistic rationales from earlier studies with goals of reaching clinical trials to combat refractory cancers. From our initial drug library screen, we have identified two candidate drugs that we are further developing that enhance platinum efficacy.
The platinum based drugs account for over $3 billion in the chemotherapy industry per year. Even though they are widely used, the limitations of these drugs are that they are used for specific cancers and that typically following treatment, cancers develop drug resistance. In recent years, we have identified a protein target, ERCC1-XPF, that when inhibited enhances the efficacy of platinum based drugs in a variety of cancer cell lines including ovarian, lung and breast cancers. Most importantly, when targeting this protein complex in cisplatin resistant cancer cells, we can reverse the resistant phenotype back to parental sensitive levels. We are currently developing two candidate drugs that inhibit ERCC1-XPF activity in the low nanomolar range and in cell culture models, enhance platinum based effects in the low micromolar range. My lab will continue with the development of drugs that inhibit the ERCC1-XPF complex as well as continue to pursue other pathways that can be targeted to enhance platinum chemotherapy and overcome drug resistance in many cancer types. Refractory cancers remain a major obstacle in the treatment of many adult and childhood cancers and thus, the identification of new targets and the development of new drugs that overcome this critical problem will make a significant contribution to the treatment of these cancers.