Steve A. Maxwell, PhD

Associate Professor
Contact
Molecular & Cellular Medicine
4418 Medical Research Education Building II
Bryan
, TX
77807
s-maxwell@tamu.edu
Phone: 979.436.0804
Fax: 979.436.9293
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.
Representative Publications
- Dave, JM, Kang, H, Abbey, CA, Maxwell, SA, and Bayless, KJ (2013) Proteomic profiling of endothelial invasion revealed receptor for activated C kinase 1 (RACK1) complexed with vimentin to regulate focal adhesion kinase (FAK). J. Biol Chem. 288(42):30720-33. PMID: 24005669. http://www.ncbi.nlm.nih.gov/pubmed/24005669
- Maxwell, SA and Mousavi-Fard, S (2013) Non-Hodgkin's B-cell lymphoma: advances in molecular strategies targeting drug resistance. Exp. Biol. Med. 238(9):971-90. PMID: 23986223. http://www.ncbi.nlm.nih.gov/pubmed/23986223
- Kwak, HI, Kang, H, Dave, JM, Mendoza, EA, Su, SC, Maxwell, SA, and Bayless KJ. (2012) Calpain-mediated vimentin cleavage occurs upstream of MT1-MMP membrane translocation to facilitate endothelial sprout initiation. Angiogenesis 15(2):287-303. PMID. 22407449. http://www.ncbi.nlm.nih.gov/pubmed/22407449
- Maxwell, SA, Cherry, E, and Bayless, KJ (2011) Akt, 14-3-3z, and Vimentin Mediate a Drug-Resistant Invasive Phenotype in Diffuse Large B-Cell Lymphoma. Leuk. Lymphoma, 52(5):849-864. PMID: 21323512. http://www.ncbi.nlm.nih.gov/pubmed/21323512
- Su, SC, Maxwell, SA, and Bayless, KJ. (2010) Annexin 2 regulates endothelial morphogenesis by controlling AKT activation and junctional integrity. J Biol Chem. 285(52):40624-40634. PMID: 20947498. http://www.ncbi.nlm.nih.gov/pubmed/20947498
- Maxwell, SA, Li, Z, Jaya, D, Ballard, S, Ferrell, J, and Fu, H. (2009) 14-3-3zeta mediates resistance of diffuse large B cell lymphoma to an anthracycline-based chemotherapeutic regimen. J. Biol. Chem. 284(33):22379-22389. PMID: 19525224. http://www.ncbi.nlm.nih.gov/pubmed/19525224
- Maxwell, SA, and Kochevar, GJ (2008) Identification of a p53-response element in the promoter of the proline oxidase gene. Biochem. Biophys. Res. Commun. 369(2): 308-813. PMID: 18279664. http://www.ncbi.nlm.nih.gov/pubmed/18279664
- Rivera A, Mavila A, Bayless KJ, Davis GE and Maxwell SA (2006) Cyclin A1 is a p53-Induced Gene That Mediates Apoptosis, G2/M Arrest, and Mitotic Catastrophe in Renal, Ovarian, and Lung Carcinoma Cells. Cell Mol. Life Sci. 63, 1425-1439. PMID: 16799873. http://www.ncbi.nlm.nih.gov/pubmed/16799873
- Rivera, A and Maxwell, SA (2005) The p53-induced gene-6 (proline oxidase) mediates apoptosis through a calcineurin-dependent pathway. J. Biol. Chem. 280, 29345-29354. PMID: 15914462. http://www.ncbi.nlm.nih.gov/pubmed/15914462
- Maxwell, SA and Davis, GE (2004) Gene expression profiling of p53-sensitive and-resistant tumor cells using DNA microarray. Apoptosis. 9, 171-179. PMID: 15004514. http://www.ncbi.nlm.nih.gov/pubmed/15004514
- Maxwell, SA and Rivera, A (2003) Proline oxidase induces apoptosis in tumor cells, and its expression is frequently absent or reduced in renal carcinomas. J. Biol. Chem. 278, 9784-9789. PMID: 12514185. http://www.ncbi.nlm.nih.gov/pubmed/12514185
- Bell, SE, Mavila, A, Salazar, R, Bayless, KJ, Kanagala, S, Maxwell, SA, and Davis GE. (2001) Differential gene expression during capillary morphogenesis in 3D collagen matrices: regulated expression of genes involved in basement membrane matrix assembly, cell cycle progression, cellular differentiation and G-protein signaling. J Cell Sci. 114(Pt 15):2755-73. PMID: 11683410.http://www.ncbi.nlm.nih.gov/pubmed/11683410
- Nelson, V, Davis, GE, and Maxwell SA. (2001) A putative protein inhibitor of activated STAT (PIASy) interacts with p53 and inhibits p53-mediated transactivation but not apoptosis. Apoptosis 6(3):221-34. PMID: 11388671.http://www.ncbi.nlm.nih.gov/pubmed/11388671
- Maxwell, SA and Davis GE. (2000) Biological and molecular characterization of an ECV-304-derived cell line resistant to p53-mediated apoptosis. Apoptosis 5(3):277-90. PMID: 11225849.http://www.ncbi.nlm.nih.gov/pubmed/11225849
- Davis, GE, Pintar, Allen, KA, Salazar, R, and Maxwell, SA (2001) Matrix metalloproteinase-1 and -9 activation by plasmin regulates a novel endothelial cell-mediated mechanism of collagen gel contraction and capillary tube regression in three-dimensional collagen matrices. .J Cell Sci. 114(Pt 5):917-30. PMID: 11181175. http://www.ncbi.nlm.nih.gov/pubmed/11181175
- Maxwell, SA and Davis, GE (2000) Differential gene expression in p53-mediated apoptosis-resistant vs. apoptosis-sensitive tumor cell lines. Proc. Natl. Acad. Sci. USA 97(24):13009-14. PMID: 11069295. http://www.ncbi.nlm.nih.gov/pubmed/11069295
Lab Members
Graduate Research Assistant
- Seyed Hossein Mousavi-Fard