Santhi Konduri, Ph.D.

Santhi Konduri, PhD Assistant Professor Oncology Senior Research Scientist Principal Investigator Drug Discovery and Development Laboratory Lab Members Kiran Vidrevu, PhD       Postdoctoral Scientist Sheila Jeudy, BS.       Senior Lab Technician

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Biography

Dr. Konduri graduated from Andhra University, India, and later trained at the Indian Institute of Science in Bangalore. She worked on human genetic diseases and the identification of molecular mutations in inborn errors of metabolic diseases. She came to the United States in 1998 and joined the Department of Neurosurgery at MD Anderson Cancer Center in Houston, Texas, as a post-doctoral fellow. While there, she worked on brain cancer, in particular, glioblastoma multiforme, gaining significant experience in cell biology, cancer biology, molecular biology, and gene transcription. In 2002 she joined the Department of Pharmacology and Therapeutics of the Roswell Park Cancer Institute as a Research Affiliate. Here, she worked on protein-protein interactions and protein-DNA interactions in breast cancer progression. In 2006 she was recruited to MD Anderson Cancer Center Orlando as Assistant Professor. She currently works on the role of O6 methyl guanine-DNA methyl transferase (MGMT) in brain, breast and pancreatic cancers, and its implications on chemoresistance.

Research Summary

We are interested in identifying and characterizing the genes that cause cancer and drug resistance and the application of this knowledge to the management of patients. Research in our laboratory is focused on several areas:

1. Identify the genes that cause drug resistance.
2. Identify drugs that reduce resistance and enhance the chemotherapeutic drug effect without causing unwanted side effects.
3. Identify combination therapy to personalize medicine to different patient groups.
4. Investigate how cancer cells within a primary tumor acquire the ability to invade and metastasize.
5. Identify drugs that inhibit tumor invasion and metastasis.
6. Studies on angiogenesis and drugs that inhibit tumor angiogenesis.

Our major focus is on cancers of the brain, breast and pancreas. The goal of our research is to develop new approaches to prevent or treat cancers through a better understanding of the genes and pathways underlying their pathogenesis. Novel therapeutic agents that target the specific defects in cancer are under development.

We developed an interest in chemotherapy-induced DNA damage and its repair, which remains the current main focus of our lab. The anticancer drug resistance focusing on the unique DNA repair protein MGMT (O6-methylguanine DNA methyltransferase) has been funded recently by Florida Department of Health. Ongoing research projects are focusing on biochemical mechanisms of anticancer drug resistance and their modulation for improved therapies, DNA repair, post-translational modifications, cell cycle checkpoints and p53 tumor suppressor, chemoprevention and exploiting the posttranslational regulation of MGMT for enhanced anticancer therapies.

Anti-estrogens, particularly tamoxifen, have proven to be effective in the treatment of breast cancer. Resistance to tamoxifen, however, is a serious obstacle in the management of breast cancer. About 40% of ER-positive tumors fail to initially respond to tamoxifen therapy, and of those breast tumors initially responding to tamoxifen many have eventually develop resistance. Thus, a better understanding of the mechanism of anti-estrogen resistance could guide and promote new therapeutic strategies for breast cancer treatment. Our laboratory is also interested in the elucidation of factors involved in resistance to anti-estrogen therapy to breast cancer patients. The primary objective of our research study is to investigate the mechanism of anti-estrogen drug resistance most often developed in breast cancer patients and ultimately modulate the resistance by developing new therapeutic strategies. The overall aim of our research is to establish a role for O6-methylguanine DNA methyl transferase (MGMT) expression in tamoxifen resistance and to explore the development of MGMT inhibitors as therapeutic options in tamoxifen-resistant breast cancer. In the end, we hope to provide novel therapeutic strategies, which will avoid and overcome drug-related resistance and most importantly, prolong the lives of breast cancer patients.

Selected Publications

Colon J, Basha MR, Madero-Visbal R, Konduri S, Baker CH, Herrera LJ, Safe S, Sheikh-Hamad D, Abudayyeh A, Alvarado B, Abdelrahim M: Tolfenamic acid decreases c-Met expression through Sp proteins degradation and inhibits lung cancer cells growth and tumor formation in orthotopic mice. Invest New Drugs 2011, 29:41-51.

Smith JS, Colon J, Madero-Visbal R, Isley B, Konduri SD, Baker CH: Blockade of MUC1 expression by glycerol guaiacolate inhibits proliferation of human breast cancer cells. Anticancer Agents Med Chem 2010, 10:644-6650.

Konduri SD, Medisetty R, Liu W, Kaipparettu BA, Srivastava P, Brauch H, Fritz P, Swetzig WM, Gardner AE, Khan SA, Das GM: Mechanisms of estrogen receptor antagonism toward p53 and its implications in breast cancer therapeutic response and stem cell regulation. Proc Natl Acad Sci U S A 2010, 107:15081-15086.

Bobustuc GC, Baker CH, Limaye A, Jenkins WD, Pearl G, Avgeropoulos NG, Konduri SD: Levetiracetam enhances p53-mediated MGMT inhibition and sensitizes glioblastoma cells to temozolomide. Neuro Oncol 2010, 12:917-927.

Abdelrahim M, Konduri S, Basha R, Philip PA, Baker CH: Angiogenesis: an update and potential drug approaches (review). Int J Oncol 2010, 36:5-18.

Konduri SD, Ticku J, Bobustuc GC, Sutphin RM, Colon J, Isley B, Bhakat KK, Srivenugopal KS, Baker CH: Blockade of MGMT expression by O6 benzyl guanine leads to inhibition of pancreatic cancer growth and induction of apoptosis. Clin Cancer Res 2009, 15:6087-6095.

Konduri S, Colon J, Baker CH, Safe S, Abbruzzese JL, Abudayyeh A, Basha MR, Abdelrahim M: Tolfenamic acid enhances pancreatic cancer cell and tumor response to radiation therapy by inhibiting survivin protein expression. Mol Cancer Ther 2009, 8:533-542.

Kaipparettu BA, Malik S, Konduri SD, Liu W, Rokavec M, van der Kuip H, Hoppe R, Hammerich-Hille S, Fritz P, Schroth W, et al: Estrogen-mediated downregulation of CD24 in breast cancer cells. Int J Cancer 2008, 123:66-72.

Sayeed A, Konduri SD, Liu W, Bansal S, Li F, Das GM: Estrogen receptor alpha inhibits p53-mediated transcriptional repression: implications for the regulation of apoptosis. Cancer Res 2007, 67:7746-7755.

Liu W, Konduri SD, Bansal S, Nayak BK, Rajasekaran SA, Karuppayil SM, Rajasekaran AK, Das GM: Estrogen receptor-alpha binds p53 tumor suppressor protein directly and represses its function. J Biol Chem 2006, 281:9837-9840.

Yanamandra N, Berhow MA, Konduri S, Dinh DH, Olivero WC, Nicolson GL, Rao JS: Triterpenoids from Glycine max decrease invasiveness and induce caspase-mediated cell death in human SNB19 glioma cells. Clin Exp Metastasis 2003, 20:375-383.

Konduri SD, Yanamandra N, Dinh DH, Olivero WC, Gujrati M, Foster DC, Kisiel W, Rao JS: Physiological and chemical inducers of tissue factor pathway inhibitor-2 in human glioma cells. Int J Oncol 2003, 22:1277-1283.

Konduri SD, Srivenugopal KS, Yanamandra N, Dinh DH, Olivero WC, Gujrati M, Foster DC, Kisiel W, Ali-Osman F, Kondraganti S, et al: Promoter methylation and silencing of the tissue factor pathway inhibitor-2 (TFPI-2), a gene encoding an inhibitor of matrix metalloproteinases in human glioma cells. Oncogene 2003, 22:4509-4516.

Konduri SD, Yanamandra N, Siddique K, Joseph A, Dinh DH, Olivero WC, Gujrati M, Kouraklis G, Swaroop A, Kyritsis AP, Rao JS: Modulation of cystatin C expression impairs the invasive and tumorigenic potential of human glioblastoma cells. Oncogene 2002, 21:8705-8712.

Konduri SD, Osman FA, Rao CN, Srinivas H, Yanamandra N, Tasiou A, Dinh DH, Olivero WC, Gujrati M, Foster DC, et al: Minimal and inducible regulation of tissue factor pathway inhibitor-2 in human gliomas. Oncogene 2002, 21:921-928.

Tasiou A, Konduri SD, Yanamandra N, Dinh DH, Olivero WC, Gujrati M, Obeyesekere M, Rao JS: A novel role of tissue factor pathway inhibitor-2 in apoptosis of malignant human gliomas. Int J Oncol 2001, 19:591-597.

Rao CN, Lakka SS, Kin Y, Konduri SD, Fuller GN, Mohanam S, Rao JS: Expression of tissue factor pathway inhibitor 2 inversely correlates during the progression of human gliomas. Clin Cancer Res 2001, 7:570-576.

Konduri SD, Tasiou A, Chandrasekar N, Rao JS: Overexpression of tissue factor pathway inhibitor-2 (TFPI-2), decreases the invasiveness of prostate cancer cells in vitro. Int J Oncol 2001, 18:127-131.

Konduri SD, Rao CN, Chandrasekar N, Tasiou A, Mohanam S, Kin Y, Lakka SS, Dinh D, Olivero WC, Gujrati M, et al: A novel function of tissue factor pathway inhibitor-2 (TFPI-2) in human glioma invasion. Oncogene 2001, 20:6938-6945.

Konduri S, Lakka SS, Tasiou A, Yanamandra N, Gondi CS, Dinh DH, Olivero WC, Gujrati M, Rao JS: Elevated levels of cathepsin B in human glioblastoma cell lines. Int J Oncol 2001, 19:519-524.

Yanamandra N, Konduri SD, Mohanam S, Dinh DH, Olivero WC, Gujrati M, Nicolson GL, Obeyeseke M, Rao JS: Downregulation of urokinase-type plasminogen activator receptor (uPAR) induces caspase-mediated cell death in human glioblastoma cells. Clin Exp Metastasis 2000, 18:611-615.

Nirmala C, Jasti SL, Sawaya R, Kyritsis AP, Konduri SD, Ali-Osman F, Rao JS, Mohanam S: Effects of radiation on the levels of MMP-2, MMP-9 and TIMP-1 during morphogenic glial-endothelial cell interactions. Int J Cancer 2000, 88:766-771.

Lakka SS, Konduri SD, Mohanam S, Nicolson GL, Rao JS: In vitro modulation of human lung cancer cell line invasiveness by antisense cDNA of tissue factor pathway inhibitor-2. Clin Exp Metastasis 2000, 18:239-244.

Konduri SD, Tasiou A, Chandrasekar N, Nicolson GL, Rao JS: Role of tissue factor pathway inhibitor-2 (TFPI-2) in amelanotic melanoma (C-32) invasion. Clin Exp Metastasis 2000, 18:303-308.