Steve A. Maxwell

Biography

Dr. Steve Maxwell received his BA in chemistry and BS in biology in 1980 from Abilene Christian University. In 1985 he received a PhD in molecular virology from the University of Texas Graduate School of Biomedical Sciences where he worked with Dr. Ralph Arlinghaus. His postdoctoral training was in the Department of Molecular Virology at Baylor College of Medicine. Maxwell joined the faculty at Texas A&M in 1995. He is the coordinator for the Medical Sciences 602 Graduate course and has taught several medical pathology courses.

Research Interest

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. Graduate training is available through the Medical Science PhD program (College of Medicine), through the MD/PhD program (College of Medicine) and other programs that our faculty are affiliated with joint research.