Steve A. Maxwell, PhD

Education and Training

• Abilene Christian University, BA, BS, 1980
• University of Texas Graduate School, PhD, 1985

Research Interests

• Primary interests include cancer; oncogenes; tumor suppressor; genes programmed cell death (apoptosis); chemoresistance, and angiogenesis My laboratory studies mechanisms of evolution of chemoresistance in diffuse large B-cell lymphoma (DLBCL). The CHOPS drug regimen (doxorubicin/ cyclophosphamide/vincrinstine/prednisone) is currently the most effective treatment for DLBCL patients. Unfortunately, about one-half of DLBCL patients develop drug resistance leading to high mortality. As a model system, we generated CHOP-resistant DLBCL cell lines through repeated selections in the presence of CHOP. We have been using proteomics to investigate differences in protein expression between the CHOP-sensitive and -resistant DLBCL cells. One target of interest has been identified as the 14-3-3zeta protein, a known prosurvival gene product. CHOP-resistant cells overexpressed the 14-3-3zeta protein leading us to hypothesize that it might provide DLBCL cells with the selective advantage to survive CHOP treatment. We tested this hypothesis and showed that modulation of 14-3-3zeta, indeed, played a role in chemoresistance of DLBCL cells. In collaboration with Dr. James Sacchettini at Texas A&M University, we utilized my chemoresistant cell lines in high-throughput screening and identified a member of the rifamycin family as a non-toxic compound that could restore chemosensitivity in lymphoma, breast, prostate, glioma, and pancreatic cancer cells. Medicinal chemistry in Sacchettini's laboratory led to rifabutin derivatives that were ten-times more potent in chemosensitizing activity. Our lead compound, RTI-79, has been patented. One mode of action of RTI-79 is the induction of reactive oxygen species in cancer cells. Our working model hypothesizes that acquired drug resistance in cancer involves the upregulation of anti-oxidant pathways like Nrf-2 that result in low oxidative stress. RTI-79 induces chemosensitization by upregulating both reactive oxygen species and downregulating anti-oxidant Nrf2 pathways. This two-pronged action results in a pronounced oxidative stress that re-sensitizes a broad range of cancer cells to chemotherapeutics. In support of our model, we have shown that RTI-79 not only induces superoxide, but downregulates the anti-oxidant Nrf-2 pathway and drug efflux. Current studies in my lab are focused on identifying the primary target of RTI-79 and conducting mechanistic studies into its mode of action. One current primary objective is to conduct a Phase I study that (1) confirms RTI-79 safety in platinum-resistant/refractory ovarian cancer patients, and (2) demonstrates signals of efficacy in humans (ex: time-to-disease progression and changes in CA125 biomarker). A second objective is to better define the RTI-79 mechanism of action ("MOA") by (1) determining how RTI-79 causes a rapid burst in superoxides, and (2) elucidating the basis of Nrf-2 pathway downregulation.