Professor, Co-Director T32 Training Grant, Cancer Biology Graduate Program
4100 John R, HW05A-2
Detroit, MI 48201
Jacob Lindquist and Istri Ndoja
• DNA Repair pathways and understanding how they mediate cisplatin efficacy
• Assessing the role of APOBEC3 cytidine deaminases in chemotherapy response
• Targeting DNA repair to overcome chemotherapy drug resistance
• Understanding the bystander effect following cisplatin treatment
• Novel combination therapies and mechanistic understanding of drug synergism
The major disease focus of my research is understanding how cancer cells respond to chemotherapy, including the pathways that are critical for maintaining drug sensitivity. The development of drug resistance is a major clinical limitation. The platinum-based chemotherapy drugs account for over $3 billion in the medical 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. The projects in the lab all relate to translational approaches for drug discovery that would enhance platinum- based 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) assessing the role and understanding the mechanism of how APOBEC3 cytidine deaminases can influence platinum based chemotherapy response; 3) targeting DNA repair pathways to enhance platinum-based chemotherapy; 4) elucidating the role of the "bystander effect" in platinum resistance and how DNA damage and the DNA damage response pathway mediate the bystander effect; and 5) identifying novel drug combinations and mechanistic understanding of drug synergism. 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.
Kayla L. Conner*, Asra N. Shaik*, Elmira Ekinci*, Seongho Kim, Julie J. Ruterbusch, Michele L. Cote, Steve M. Patrick. HPV induction of APOBEC3 enzymes mediate overall survival and response to cisplatin in head and neck cancer. DNA Repair. 2020;87:102802.
Joshua Heyza*, Wen Lei*, Donovan Watza, Hao Zhang*, Wei Chen, Jessica B. Back, Ann G. Schwartz, Gerold Bepler and Steve M. Patrick. Identification and characterization of synthetic viability with ERCC1 deficiency in response to interstrand crosslinks in lung cancer. Clinical Cancer Research (AACR) 2019;25:2523-36.
Sanjeevani Arora*, Joshua Heyza*, Hoa Ellen Zhang*, Kayla Conner*, Wen Lei*, Ashley Floyd*, Rahul Deshmukh, Jeffrey Sarver, Christopher Trabbic, Paul Erhardt, TakHan Chan, Q. Ping Dou, Steve M. Patrick. Targeting the DNA Repair Endonuclease ERCC1-XPF with Green Tea Polyphenol Epigallocatechin-3-Gallate (EGCG) and Its Prodrug to Enhance Cisplatin Efficacy in Human Cancer Cells. Nutrients. 2018;10:E1644.
Sanjeevani Arora*, Joshua Heyza*, Elaine Chalfin*, RJ Ruch, Steve M. Patrick. Gap Junction Intercellular Communication Positively Regulates Cisplatin Toxicity by Inducing DNA Damage through Bystander Signaling. Cancers (Basel). 2018;10:E368.
Akshada Sawant*, Ashley M. Floyd*, Mohan Dangeti*, Wen Lei*, Robert W. Sobol and Steve M. Patrick. Differential Role of Base Excision Repair Proteins in Mediating Cisplatin Cytotoxicity. DNA Repair. 2017;51:46-59.
Sanjeevani Arora*, Joshua Heyza*, Hao Zhang*, Vivian Kalman-Maltese, Kristin Tillison, Ashley M. Floyd*, Elaine M. Chalfin, Gerold Bepler and Steve M. Patrick. Identification of small molecule inhibitors of ERCC1-XPF that inhibit DNA repair and potentiate cisplatin efficacy in cancer cells. Oncotarget, 2016;7:75104-17.
Akshada Sawant*, Anbarasi Kothandapani*, Anatoly Zhitkovich, Robert W. Sobol and Steve M. Patrick. Role of Mismatch Repair Proteins in the Processing of Cisplatin Interstrand Cross-Links. DNA Repair. 2015;35:126-36.
Anbarasi Kothandapani, Akshada Sawant, Venkata Srinivas Mohan Nimai Dangeti, Robert W. Sobol, and Steve M. Patrick. Epistatic role of base excision repair and mismatch repair pathways in mediating cisplatin cytotoxicity. Nucleic Acids Research. 2013;41:7332-43.
Anbarasi Kothandapani and Steve M. Patrick. Evidence For Base Excision Repair Processing of DNA Interstrand Crosslinks. Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, Invited Review Article. 2013;743-744:44-52.
Moises Serrano, Zhengke Li, Venkata Srinivas Mohan Nimai Dangeti, Phillip Musich, Steve M. Patrick, Marina Roginskaya, Brian Cartwright, and Yue Zou. DNA-PK, ATM and ATR collaboratively regulate p53-RPA interaction to facilitate homologous recombination DNA repair. Oncogene. 2013;32:2452-62.
Anbarasi Kothandapani, Kathirvel Gopalakrishnan, Bhaskar Kahali, David Reisman and Steve M. Patrick. Downregulation of SWI/SNF chromatin remodeling factor subunits modulate cisplatin cytotoxicity. Experimental Cell Research. 2012; 318:1973-86.
Anbarasi Kothandapani, Venkata Srinivas Mohan Nimai Dangeti, Ashley R. Brown, Lauren A. Banze, Xiao-Hong Wang, Robert W. Sobol and Steve M. Patrick. Novel Role of Base Excision Repair (BER) in Mediating Cisplatin Cytotoxicity. Journal of Biological Chemistry. 2011;286:14564-74.
Saravanan Kaliyaperumal, Steve M. Patrick, and Kandace J. Williams. Phosphorylated hMSH6: DNA mismatch versus DNA damage recognition. Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis. 2011;706:36-45.
Sanjeevani Arora, Anbarasi Kothandapani, Kristin Tillison Vivian Kalman-Maltese and Steve M. Patrick. Downregulation of the XPF-ERCC1 complex enhances cisplatin efficacy in cancer cells. DNA Repair. 2010;9:745-53.
Greg G. Oakley and Steve M. Patrick. Replication Protein A: Directing the traffic at the intersection of replication and repair. (Invited Review) Frontiers in Bioscience. 2010;15:883-900.
Greg G. Oakley, Kristin Tillison, Stephen A. Opiyo, Jason G. Glanzer, Jeffrey M. Horn, and Steve M. Patrick. Physical Interaction between Replication Protein A (RPA) and MRN: Involvement of RPA2 Phosphorylation and the N-Terminus of RPA1. Biochemistry. 2009;48:7473-81.
Allen G. Schroering, Anbarasi Kothandapani, Steve M. Patrick, Saravanan Kaliyaperumal and Kandace J. Williams. Prolonged cell cycle response of HeLa cells to low-level alkylation exposure. Cancer Research. 2009;69:6307-14.
B.S., 1994, Urbana University, Urbana, OH.
Ph.D., 1999, Wright State University, Dayton, OH.
Postdoctoral Fellow, 1999-2002, John J. Turchi's Lab, Wright State University, Dayton, OH.
CB7240 Principles of Cancer Therapy
CB7300 Special Topics F31 Grant Writing Course
CB7460 Mechanism of Neoplasia: Alterations to Cellular Signaling
CB7890 Seminar (Course Co-Director)