George C. Prendergast, PhD

Email:  Prendergast@limr.org Phone: 484.476.8144 Fax: 484.476.8533 Office: L48 Department: Administration Association: Resident Faculty Other Appointment:Professor

Education BA, Biochemistry, University of Pennsylvania, 1983 MS, Molecular Biophysics, Yale University, 1984 PhD, Molecular Biology, Princeton University, 1989 Appointments 2004 - Professor, President & CEO, Lankenau Institute for Medical Research 2006 - Professor, Dept. of Pathology, Anatomy & Cell Biology, Jefferson Medical School, Thomas Jefferson University 2006 - Co-Director, Program in Cell Biology & Signaling, Kimmel Cancer Center, Thomas Jefferson University 2007 - CEO, LIMR Development, Inc. 2007 - CEO, LIMR Chemical Genomics Center, Inc. 2010 - Editor-in-Chief, Cancer Research Research Interests Cancer suppression genes, cancer immunology, molecular therapeutics Google Scholar page Lab Personnel James DuHadaway, Research Lab Associate Minzhou Huang, PhD, Research Assistant Professor Sunil Thomas, PhD, Research Assistant Professor U. Margaretha Wallon, PhD, Research Assistant Professor Selected Awards and Honors 1995 - American Cancer Society Junior Faculty Award 1995 - Pew Scholar in the Biomedical Sciences Award 2000 - Who's Who in America 2003 - Highlighted Project, 2003 DoD Prostate Cancer Research Program Report 2008 - Special Achievement Award, Chinese Society for Clinical Oncology 2008 - Designated One of the 250 Historically Most Influential Alumni of Princeton University 2011 - Translational Medicine Award, Shanghai Translational Medicine Forum, Shanghai China 2011 - Highlighted ‘In the Pipeline’ Project, DoD Breast Cancer Research Program Annual Report 2012 - Inventor of the Year, Jefferson Kimmel Cancer Center

Lay Description

By studying disease modifier genes we seek to develop new principles to treat cancer, diabetes, autoimmune disorders and cardiovascular disease. Currently most biomedical research focuses on understanding disease pathways. We seek to understand general disease modifier pathways that determine disease severity, an understudied area from which many useful drugs such as NSAIDs and statins are based. A major thrust of our present work focuses on modifiers of inflammatory processes which contribute significantly to the severity of many age-associated diseases. In our main project, we have developed a new class of drugs that recruit the immune system to eradicate a broad spectrum of advanced cancers, including breast, lung, skin, and pancreas tumors that are often refractory to chemotherapy. These drugs, called IDO inhibitors, are presently in Phase II clinical trials. In other projects, with our Lankenau colleagues we are developing new agents to treat autoimmune disorders, reduce risks of cardiovascular disease, and ameliorate diabetes.

Scientific Description

Our laboratory is interested primarily in cancer genes, cancer immunology and molecular therapeutics. We use transgenic mouse models and preclinical drug strategies to learn new ways to suppress cancer, focusing on long-term goals of improving strategies for cancer prognosis and treatment.

Localized tumors are often curable if they are detected before progression to invasive status, but many patients diagnosed with cancer already have invasive disease. What factors dictate malignant progression and how might they be therapeutically exploited? Molecular therapeutics that target key oncogene and tumor suppressor pathways show some clinical promise, but they have shown limited efficacy to date. Cancer modifier pathways that influence the immune microenvironment of tumor cells may strongly influence clinical course. Accordingly, new therapies we are developing are based on blocking enzymes that limit the ability of immune cells to destroy cancer cells or drive disease.

RhoB studies derive from our long-standing research on this member of the Ras/Rho superfamily in cancer cell signaling. Recent work in collaboration with Drs. Lisa Laury-Kleintop and Laura Mandik-Nayak at Lankenau has opened exciting new directions in studies of the role of RhoB in autoimmune and cardiovascular disease. A start-up company has been created to fund and advance the preclinical and clinical work needed to explore a provocative new therapy emerging from these novel directions, which in principle may be useful to treat one or more diseases in important areas of medicine.

Bin1 studies originating in cancer cell studies led us to discover that it regulates the immune modulatory enzyme indoleamine 2,3-dioxygenase (IDO). Bin1 modifies inflammation in a variety of settings including cancer. Recently, in preclinical studies we found that its genetic blockade can limit the development of inflammatory bowel disease (colitis). Based on this finding, we are now investigating the use of Bin1 antibodies we have developed to treat this disorder.

IDO is a tryptophan catabolic enzyme that blocks T cell activation in physiological settings such as pregnancy and in many pathophysiological settings like cancer. IDO is very widely activated as a mechanism of immune escape by cancer cells. Genetic studies reveal that IDO is essential for inflammation-driven cancers, not only supporting immune escape but also angiogenesis and metastasis. We pioneered preclinical studies of IDO inhibitory drugs that can arrest tumor growth and enhance chemotherapeutic efficacy. Mechanistic studies of one clinical lead inhibitor, D-1MT (indoximod), will greatly assist ongoing Phase II studies of this drug. Translational studies including on an IDO-related gene called IDO2 discovered at Lankenau are currently a major focus of the laboratory.

Dr. Prendergast's Google Scholar page

Selected Publications

(from 145 peer-reviewed papers and 75 books, book chapters, or reviews):

1. IDO inhibits a tryptophan sufficiency signal needed to stimulate mTOR: a novel IDO effector pathway targeted by 1-methyl-D-tryptophan. Metz R, Rust S, DuHadaway JB, Mautino MR, Munn DH, Vahanian NN, Link CJ and Prendergast GC. OncoImmunology 2012 Dec;1(9) [Epub ahead of print].
2. Immunological thought in the mainstream of cancer research: past divorce, recent remarriage and elective affinities of the future. Prendergast GC. OncoImmunology 2012 Sept;1(6) [Epub ahead of print].
3. A perspective on new immune adjuvant principles: reprogramming inflammatory states to permit clearance of cancer and other age-associated pathologies. Metz R and Prendergast GC. OncoImmunology 2012 Sept;1(6) [Epub ahead of print].
4. A bioactive probe of the oxidative pentose phosphate cycle: Novel strategy to reverse radioresistance in glucose deprived human colon cancer cells. Li J, Ward KM, Zhang D, Dayanandam E, Denittis AS, Prendergast GC, Ayene IS. Toxicol In Vitro. 2012 Aug 16 [Epub ahead of print].
5. IDO Is a Nodal Pathogenic Driver of Lung Cancer and Metastasis Development. Smith C, Chang MY, Parker KH, Beury DW, Duhadaway JB, Flick HE, Boulden J, Sutanto-Ward E, Soler AP, Laury-Kleintop LD, Mandik-Nayak L, Metz R, Ostrand-Rosenberg S, Prendergast GC, Muller AJ. Cancer Discov. 2012 Aug;2(8):722-35. Epub 2012 Jul 19.
6. Role of RhoB in the regulation of pulmonary endothelial and smooth muscle cell responses to hypoxia. Wojciak-Stothard B, Zhao L, Oliver E, Dubois O, Wu Y, Kardassis D, Vasilaki E, Huang M, Mitchell JA, Louise H, Prendergast GC, Wilkins MR. Circ Res. 2012 May 25;110(11):1423-34. Epub 2012 Apr 26.
7. Bin1 attenuation suppresses experimental colitis by enforcing intestinal barrier function. Chang MY, Boulden J, Valenzano MC, Soler AP, Muller AJ, Mullin JM, Prendergast GC. Dig Dis Sci. 2012 Jul;57(7):1813-21. Epub 2012 Apr 18.
8. Hydroxyethyl disulfide as an efficient metabolic assay for cell viability in vitro. Li J, Zhang D, Ward KM, Prendergast GC, Ayene IS. Toxicol In Vitro. 2012 Jun;26(4):603-12. Epub 2012 Jan 31.
9. Cardiac and gastrointestinal liabilities caused by deficiency in the immune modulatory enzyme indoleamine 2,3-dioxygenase. Chang M-Y, Smith C, DuHadaway JB, Pyle JR, Boulden J, Peralta-Soler A, Muller AM, Laury-Kleintop LM and Prendergast GC. (2011). Cancer Biol. Ther., Dec 15;12, 1050-8.
10. Altered apoptotic responses in neurons lacking RhoB GTPase. Barberan S, McNair K, Iqbal K, Smith N, Prendergast GC, Stone TW, Cobb SR, and Morris BJ. (2011). Eur. J. Neurosci., 34, 1737-46.
11. Lactoferrin-endothelin 1 axis contributes to the development and invasiveness of triple-negative breast cancer phenotypes. Ha, N.-H., Vasudha, N., Reddy, D.N.S., Mudvari, P., Ohshiro, K., Ghanta, K.S., Pakala, S.B., Li, D.-Q., Costa, L., Lipton, A., Badwe, R.A., Fuqua, S., Wallon, U.M., Prendergast, G.C. and Kumar, R. (2011). Cancer Res., 71, 7259-69.
12. Why tumours eat tryptophan. Prendergast GC. (2011). Nature 478, 192-194.
13. Opposing biological functions of tryptophan catabolizing enzymes during intracellular infection. Divanovic, S., Sawtell, N.M., Trompette, A., Warning, J.I., Dias, A., Cooper, A.M., Yap, G.S., Arditi, M., Shimada, K., DuHadaway, J.B., Prendergast, G.C., Basaraba, R.J., Mellor, A.L., Munn, D.H., Aliberti, J. and Karp, C.L. (2012). J. Infect. Dis. 205, 152-61.
14. RhoB links PDGF signaling to cell migration by coordinating activation and localization of Cdc42 and Rac. Huang, M., Satchell, L., DuHadaway, J.B., Prendergast, G.C. and Laury-Kleintop, L.D. (2011). J. Cell. Biochem. 112, 1572–1584.
15. Indoleamine 2,3-dioxygenase as a modifier of pathogenic inflammation in cancer and other inflammation-associated diseases. Prendergast, G.C., Chang, M.-Y., Mandik-Nayak, L., Metz, R., and Muller, A.J. (2011). Curr. Med. Chem. 18, 2257-2262.
16. From the Editor's Chair: Perspectives on emerging trends in cancer research. Prendergast, G.C. (2011). Cancer Res. 71, 2027-2028.
17. RhoB loss prevents streptozotocin-induced diabetes and ameliorates diabetic complications in mice. Bravo-Nuevo, A., Sugimoto, H., Iyer, S., Fallon, Z., Lucas, J.M., Kazerounian, S., Prendergast, G.C., Kalluri, R., Shapiro, N.I. and Benjamin, L.E. (2011). Amer. J. Pathol. 178, 245-252.
18. Immunotherapeutic suppression of IDO and tumor growth with ethyl pyruvate. Muller, A.J., DuHadaway, J.B., Jaller, D., Curtis, P., Metz, R. and Prendergast, G.C. (2010). Cancer Res. 70, 1845-1853.
19. Towards a genetic definition of 'cancer-associated' inflammation: role of the IDO pathway. Prendergast, G.C., Metz, R. and Muller A.J. (2010). Am. J. Pathol. 176, 2082-2087.
20. Zinc protoporphyrin-IX stimulates tumor immunity by disrupting the activity of immunosuppressive enzyme indoleamine 2,3-dioxygenase. Metz, R., DuHadaway, J.B., Rust, S., Munn, D.H., Muller, A.J., Mautino, M., and Prendergast, G.C. (2010). Molec. Cancer Ther. 9, 1864-1871.
21. Beyond immunosuppression: reconsidering IDO as a pathogenic element of chronic inflammation. Muller, A.J., Mandik-Nayak, L., and Prendergast, G.C. (2010). Immunotherapy 2, 293-297.
22. Non-hematopoietic expression of IDO is integrally required for inflammatory tumor promotion. Cancer Immunol. Muller, A.J., DuHadaway, J.B., Chang, M.Y., Ramalingam, A., Sutanto-Ward, E., Boulden, J., Mandik-Nayak, L., Gilmour, S.K. and Prendergast, G.C. (2010). Immunother. 59, 1655-1663.
23. Tissue inhibitor of metalloproteinase-4 (TIMP-4) is elevated in early-stage breast cancers with accelerated progression and poor clinical course. Liss, M., Sreedhar, N., Keshgegian, A.A., Sauter, G., Chernick, M.R., Prendergast, G.C. and Wallon, U.M. (2009). Amer. J. Pathol. 175, 940-946.
24. Chronic inflammation that facilitates tumor progression creates local immune suppression by inducing indoleamine 2,3-dioxygenase. Muller, A.J., Sharma, M.D., Chandler, P.R., DuHadaway, J.B., Everhart, M., Johnson, B.A., Dahler, D.J., Pihkala, J., Soler, A.P., Munn, D.H., Prendergast, G.C. and Mellor, A.L. (2008). Proc. Natl. Acad. Sci. USA 105, 17073-17078.
25. Indoleamine 2,3-dioxygenase is the anticancer target for a novel series of potent naphthoquinone-based inhibitors. Kumar, S., Malachowski, W.P., DuHadaway, J.B., LaLonde, J.M., Carroll, P.J., Jaller, D., Metz, R., Prendergast, G.C., and Muller, A.J. (2008). J. Med. Chem. 51, 1706-1718.
26. Antitumor properties of chemopreventive natural product brassinin are based upon inhibition of indoleamine 2,3-dioxygenase (IDO). Banerjee, T., DuHadaway, J.B., Gaspari, P., Sutanto-Ward, E., Munn, D.H., Mellor, A.L., Malachowski, W.P., Prendergast, G.C. and Muller, A.J. (2008). Oncogene 27, 2851-2857.
27. Bin1 ablation increases cancer susceptibility during aging, particularly lung cancer. Chang, M.Y., Boulden, J., Sutanto-Ward E., DuHadaway, J.B., Katz, J.B., Wang, L., Meyer, T.B., Soler, A.P., Muller, A.J., and Prendergast, G.C. (2007). Cancer Res. 67, 7605-7612.
28. Bin1 attenuation in breast cancer is correlated to nodal metastasis and reduced survival. Ghaneie, A., Zemba-Palko, V., Ito, H., Ito, K., Sakamuro, D., Nakamura. S., Soler. A.P., and Prendergast, G.C. (2007). Cancer Biol. Ther. 6, 192-194
29. Bin1 ablation in mammary gland delays tissue remodeling and drives cancer progression. Chang, M.Y., Boulden, J., Sutanto-Ward E., DuHadaway, J.B., Soler, A.P., Muller, A.J., and Prendergast, G.C. (2007). Cancer Res. 67, 100-107
30. Inhibition of IDO in dendritic cells by stereoisomers of 1-methyl-tryptophan correlates with anti-tumor responses. Hou, D.-Y., Muller, A.J., Sharma, M., DuHadaway, J., Banerjee, T., Johnson, M., Mellor, A.L., Prendergast, G.C., and Munn, D.H. (2007). Cancer Res. 67, 792-801.
31. Structure-activity study of brassinin derivatives as indoleamine 2,3-dioxygenase inhibitors. Gaspari, P., Banerjee, T., Malachowski, W.P. Muller, A.J., Prendergast, G.C., DuHadaway, J., Bennett, S. and Donovan, A.M. (2006). J. Med. Chem. 49, 684-692.
32. Inhibition of indoleamine 2,3-dioxygenase, a target of the cancer suppression gene Bin1, potentiates cancer chemotherapy. Muller, A.J., DuHadaway, J.B., Donover, P.S., Sutanto-Ward, E., and Prendergast, G.C. (2005). Nature Med. 11, 312-319.
33. Cyclin B1 is a critical target of RhoB in the cell suicide program triggered by farnesyl transferase inhibition. Kamasani, U., Huang, M., DuHadaway, J., Prochownik, E.V., Donover, P.S. and Prendergast, G.C. (2004). Cancer Res. 64, 8389-8396.
34. Transformation selective apoptotic program triggered by farnesyltransferase inhibitors requires Bin1. DuHadaway, J.B., Du, W., Liu, A.-X., Baker, J., Donover, P.S., Sharp, D.M., Muller, A.J., and Prendergast, G.C. (2003). Oncogene 22, 3578-3588.
35. RhoB controls Akt trafficking and stage-specific survival of endothelial cells in vascular development. Adini, I., Rabinovitz, I., Sun, J.F., Prendergast, G.C., and Benjamin, L.E. (2003). Genes Dev. 17, 2721-2732.