George C. Prendergast, PhD

Photo of George Prendergast

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.
  • 2010 – Editor-in-Chief, Cancer Research

Research Interests

Lab Personnel

  • James DuHadaway, Research Lab Associate
  • 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, 2014 – Highlighted ‘In the Pipeline’ Project, DoD Breast Cancer Research Program Annual Report
  • 2011 – European Academy of Tumor Immunology
  • 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

'Immune Checkpoint’ Pathways in Cancer: IDO inhibitors

  1. Muller, A.J., DuHadaway, J.B., Donover, P.S., Sutanto-Ward, E., and Prendergast, G.C. (2005). Inhibition of indoleamine 2,3-dioxygenase, a target of the cancer suppression gene Bin1, potentiates cancer chemotherapy. Nature Med. 11, 312-319.
  2. Muller, A.J. and Prendergast, G.C. (2005). Marrying immunotherapy with chemotherapy: why say IDO? Cancer Res. 65, 8065-8068.
  3. 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). Inhibition of IDO in dendritic cells by stereoisomers of 1-methyl-tryptophan correlates with anti-tumor responses. Cancer Res. 67, 792-801.
  4. Metz, R., DuHadaway, J.B., Kamasani, U., Laury-Kleintop, L., Muller, A.J., and Prendergast, G.C. (2007). Novel tryptophan catabolic enzyme IDO2 is the preferred biochemical target of the antitumor IDO inhibitory compound D-1MT. Cancer Res. 67, 7082-7087.
  5. 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). Bin1 ablation increases cancer susceptibility during aging, particularly lung cancer. Cancer Res. 67, 7605-7612.
  6. Kumar, S., Jaller, D., Patel, B., LaLonde, J.M., DuHadaway, J.B., Malachowski, W.P., Prendergast, G.C. and Muller, A.J. (2008). Structure based development of phenylimidazole-derived inhibitors of indoleamine 2,3-dioxygenase. J. Med. Chem. 51, 4968-4977.
  7. 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). Chronic inflammation that facilitates tumor progression creates local immune suppression by inducing indoleamine 2,3-dioxygenase. Proc. Natl. Acad. Sci. USA 105, 17073-17078. *Co-senior authors
  8. Katz, J.B., Muller, A.J., and Prendergast, G.C. (2008). Indoleamine 2,3-dioxygenase in T cell tolerance and tumoral immune escape. Immunol. Rev. 222, 206-221.
  9. 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). Antitumor properties of chemopreventive natural product brassinin are based upon inhibition of indoleamine 2,3-dioxygenase (IDO). Oncogene 27, 2851-2857.
  10. 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). Indoleamine 2,3-dioxygenase is the anticancer target for a novel series of potent naphthoquinone-based inhibitors. J. Med. Chem. 51, 1706-1718.
  11. Prendergast, G.C. (2008). Immune escape as a fundamental trait of cancer: focus on IDO. Oncogene 27, 3889-3900.
  12. Witkiewicz, A.K., Costantino, C.L., Metz, R., Muller, A.J., Prendergast, G.C., Yeo, C.J., and Brody, J.R. (2009). Genotyping and expression analysis of IDO2 in human pancreatic cancer: a novel, active target. J. Amer. Coll. Surg. 208, 781-787.
  13. Muller, A.J., DuHadaway, J.B., Jaller, D., Curtis, P., Metz, R. and Prendergast, G.C. (2010). Immunotherapeutic suppression of IDO and tumor growth with ethyl pyruvate. Cancer Res. 70, 1845-1853.
  14. 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). Non-hematopoietic expression of IDO is critical for inflammatory tumor promotion. Cancer Immunol. Immunother. 59, 1655-1663.
  15. Prendergast, G.C. (2011). Why tumours eat tryptophan. Nature 478, 192-194.
  16. Smith, C., Chang, M.-Y., Parker, K., Beury, D., DuHadaway, J., Flick, H., Boulden, J., Sutanto-Ward, E., Soler, A.P., Laury-Kleintop, L., Mandik-Nayak, L., Metz, R., Ostrand-Rosenberg, S., Prendergast, G.C.* and Muller, A.J.* (2012). IDO is a nodal pathogenic driver of lung cancer development and metastasis. Cancer Discov. 2, 722-735. *Co-senior authors.
  17. Metz, R., Rust, S., DuHadaway, J.B., Mautino, M.R., Munn, D.H., Vahanian, N.N., Link, C.J. and Prendergast, G.C. (2012). IDO inhibits a tryptophan sufficiency signal needed to stimulate mTOR: a novel IDO effector pathway targeted by 1-methyl-D-tryptophan. OncoImmunology 1, 1460-1468.
  18. Prendergast, G.C., Smith, C., Thomas, S., Mandik-Nayak, L., Laury-Kleintop, L.D., Metz, R. and Muller, A.J. (2014). Indoleamine 2,3-dioxygenase pathways in pathogenic inflammation and immune escape in cancer. Cancer Immunol. Immunother. 63, 721-735. Cover article
  19. Puccetti, P., Fallarino, F., Italiano, A., Soubeyran, I., MacGrogan, G., Debled, M., Velasco, V., Bodet, D., Eimer, S., Veldhoen, M., Prendergast, G.C., Platten, M., Bessede, A. and Guillemin, G.J. (2015). Accumulation of an endogenous tryptophan-derived metabolite in colorectal and breast cancers. PLoS ONE 10, e0122046.
  20. O-alkylhydroxylamines as rationally-designed mechanism-based inhibitors of indoleamine 2,3-dioxygenase-1.Malachowski WP, Winters M, DuHadaway JB, Lewis-Ballester A, Badir S, Wai J, Rahman M, Sheikh E, LaLonde JM, Yeh SR, Prendergast GC, Muller AJ.Eur J Med Chem. 2016 Jan 27;108:564-76. d

“Anti-Immune Checkpoint” Pathways in Inflammation and Autoimmunity

  1. Scott, G.N., DuHadaway, J., Pigott, E., Ridge, N., Prendergast, G.C., Muller, A.J., and Mandik-Nayak, L. (2009). The immunoregulatory enzyme IDO paradoxically drives B cell-mediated autoimmunity. J. Immunol. 182, 7509-7517.
  2. Prendergast, G.C., Metz, R. and Muller, A.J. (2010). Towards a genetic definition of ‘cancer-associated’ inflammation: role of the IDO pathway. Am. J. Pathol. 176, 2082-2087.
  3. Ciorba, M.A., Bettonville, E.E., McDonald, K.G., Metz, R., Prendergast, G.C., Newberry, R.D. and Stenson, W.F. (2010). Induction of IDO-1 by immunostimulatory DNA limits severity of experimental colitis. J. Immunol. 184, 3907-3916.
  4. 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). RhoB loss prevents streptozotocin-induced diabetes and ameliorates diabetic complications in mice. Amer. J. Pathol. 178, 245-252.
  5. Chang, M.-Y., Boulden, J., Valenzano, M.C., Soler, A.P., Muller, A.J., Mullin, J.M. and Prendergast, G.C. (2012). Bin1 attenuation suppresses inflammatory colitis by enforcing intestinal barrier function. Digest. Dis. Sci. 57, 1813-1821.
  6. Metz, R., Smith, C., DuHadaway, J.B., Chandler, P., Baban, B., Merlo, L.M.F., Pigott, E., Keough, M.P., Rust, S., Mellor, A.L., Mandik-Nayak, L., Muller, A.J. and Prendergast, G.C. (2014). IDO2 is critical for IDO1-mediated T cell regulation and exerts a non-redundant function in inflammation. Int. Immunol. 26, 357-367.
  7. Merlo, L.M.F., Pigott, E., DuHadaway, J.B., Grabler, S., Metz, R., Prendergast, G.C. and Mandik-Nayak, L. (2014). IDO2 is a critical mediator of autoantibody production and inflammatory pathogenesis in a mouse model of autoimmune arthritis. J. Immunol. 192, 2082-2090. Cover article
  8. Pigott, E., DuHadaway, J.B., Muller, A.J., Gilmour, S.K., Prendergast, G.C. and Mandik-Nayak, L. (2014). Inhibition of the IDO pathway with 1-methyl-tryptophan synergizes with methotrexate to alleviate arthritis in the K/BxN mouse model of arthritis. Autoimmunity 47, 409-418.
  9. Bessede, A., Gargaro, M., Pallotta, T., Matino, D., Servillo, G., Brunacci, C., Bicciato, B., Mazza, E.M.C., Macchiarulo, A., Vacca, C. Iannitti, R., Tissi, L., Volpi, C., Belladonna, M.L., Orabona, C., Bianchi, R., Lanz, T., Platten, M., Della Fazia, M.A., Piobbico, D., Zelante, T., Funakoshi, H., Nakamura, T., Gilot, D., Denison, M.S., Guillemin, G.J., DuHadaway, J.B., Prendergast, G.C., Metz, R., Geffard, M., Boon, L., Pirro, M., Iorio, A., Veyret, B., Romani, L., Grohmann, U., Fallarino, F. and Puccetti, P. (2014). Aryl hydrocarbon receptor control of a disease tolerance defense pathway. Nature 511, 184-190.
  10. Prendergast, G.C., Metz, R., Muller, A.J., Merlo, L.M.F. and Mandik-Nayak, L. (2014). IDO2 in immunomodulation and autoimmune disease. Front Immunol. 5, 585-590.
  11. Prendergast, G.C. (2015). From the Editor’s Chair: A perspective on cancer as an abortive autoimmune response to altered-self. Cancer Res. 75, 3-4.
  12. Thomas, S., Mercado, J.M., DuHadaway, J., DiGuilio, K., Mullin, J.M. and Prendergast, G.C. (2015). Novel colitis immunotherapy targets Bin1 to improve colon cell barrier function. Dig. Dis. Sci., in press. PMID: 26195312.
  13. Merlo LM, DuHadaway JB, Grabler S, Prendergast G.C., Muller AJ, Mandik-Nayak L. IDO2 Modulates T Cell-Dependent Autoimmune Responses through a B Cell-Intrinsic Mechanism. J Immunol. 2016 Jun 1;196(11):4487-97.
  14. Miyagawa T, Ebinuma I, Morohashi Y, Hori Y, Chang MY, Hattori H, Maehara T, Yokoshima S, Fukuyama T, Tsuji S, Iwatsubo T, Prendergast G.C., Tomita T. Hum Mol Genet.BIN1 regulates BACE1 intracellular trafficking and amyloid-β production. 2016 May 14. [Epub ahead of print]
  15. DuHadaway J, Prendergast G.C. Antimetabolite TTL-315 selectively kills glucose-deprived cancer cells and enhances responses to cytotoxic chemotherapy in preclinical models of cancer. Oncotarget. 2016 Feb 16;7(7):7372-80.
  16. BIN1 regulates BACE1 intracellular trafficking and amyloid-β production. Miyagawa T, Ebinuma I, Morohashi Y, Hori Y, Young Chang M, Hattori H, Maehara T, Yokoshima S, Fukuyama T, Tsuji S, Iwatsubo T, Prendergast GC, Tomita T. Hum Mol Genet. 2016 May 14.
 
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