- University of Pennsylvania
- Yale University
- Princeton University
Awards & 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 (#30 under Science & Mathematics)
- 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
- 2017 – The Havens Chair for Biomedical Research
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 III clinical trials as the final step toward FDA approval. In other projects with our Lankenau collaborators, we are developing new agents to treat autoimmune disorders, reduce risks of cardiovascular disease, and ameliorate diabetes.
Our laboratory is interested primarily in cancer genes, cancer immunology and molecular therapeutics. We use transgenic mouse models and preclinical drug approaches 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.
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. In particular, a new therapeutic antibody has been developed to target RhoB, which may be useful to treat a variety of inflammation-related diseases in medicine, including autoimmune disorders, atherosclerosis, diabetes, kidney disease and ocular disorders.
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.
- James DuHadaway, research lab associate
- Sunil Thomas, PhD, research assistant professor
- Diaryl hydroxylamines as pan or dual inhibitors of IDO1, IDO2 and tryptophan dioxygenase. Winters M, DuHadaway JB, Pham KN, Lewis-Ballester A, Badir S, Wai J, Sheikh E, Yeh SR, Prendergast GC, Muller AJ, Malachowski WP. Eur J Med Chem. 2018 Nov 14;162:455-64.
- Host IDO2 gene status influences tumor progression and radiotherapy response in KRAS-driven sporadic pancreatic cancers. Nevler A, Muller AJ, Sutanto-Ward E, DuHadaway JB, Nagatomo K, … Mandik-Nayak L, Winter JM, Yeo CJ, Prendergast GC, Brody JR. Clin Cancer Res. 2018 Sep 28. doi: 10.1158/1078-0432.CCR-18-0814.
- Indoximod: An Immunometabolic Adjuvant That Empowers T Cell Activity in Cancer. Fox E, Oliver T, Rowe M, Thomas S, Zakharia Y, Gilman PB, Muller AJ, Prendergast GC. Front Oncol. 2018 Sep 11;8:370.
- Inhibiting IDO pathways to treat cancer: lessons from the ECHO-301 trial and beyond. Muller AJ, Manfredi MG, Zakharia Y, Prendergast GC. Semin Immunopathol. 2018 Sep 10.
- A Sub-Type of Familial Pancreatic Cancer: Evidence and Implications of Loss-of-Function Polymorphisms in Indoleamine-2,3-Dioxygenase-2. Nevler A, Muller AJ, Cozzitorto JA, Goetz A, Winter JM, Yeo TP, Lavu H, Yeo CJ, Prendergast GC, Brody JR. J Am Coll Surg. 2018 Feb 7. doi.org/10.1016/j.jamcollsurg.2017.12.052.
- Indoleamine 2,3-Dioxygenase and Its Therapeutic Inhibition in Cancer. Prendergast GC, Malachowski WJ, Mondal A, Scherle P, Muller AJ. Int Rev Cell Mol Biol. 2018;336:175-203.
- CCR5 governs DNA damage and breast cancer stem cell expansion. Jiao X, Velasco-Velázquez MA, Wang M, Li Z, Rui H, Peck AR, Korkola JE, Chen X, Xu S, DuHadaway JB, Guerrero-Rodriguez S, Addya S, Sicoli D, Mu Z, Zhang G, Stucky A, Zhang X, Cristofanilli M, Fatatis A, Gray JW, Zhong JF, Prendergast GC, Pestell RG. Cancer Res. 2018 Jan 22. doi: 10.1158/0008-5472.CAN-17-0915.
- Inflammatory Reprogramming with IDO1 Inhibitors: Turning Immunologically Unresponsive 'Cold' Tumors 'Hot'. Prendergast GC, Mondal A, Dey S, Laury-Kleintop LD, Muller AJ. Trends Cancer. 2018 Jan;4(1):38-58.
- Discovery of IDO1 Inhibitors: From Bench to Bedside. Prendergast GC, Malachowski WP, DuHadaway JB, Muller AJ. Cancer Res. 2017 Dec 15;77(24):6795-6811.
- Investigation of the Tissue Distribution and Physiological Roles of Indoleamine 2,3-Dioxygenase-2. Jusof FF, Bakmiwewa SM, Weiser S, Too LK, Metz R, Prendergast GC, Fraser ST, Hunt NH, Ball HJ. 2017 Int J Tryptophan Res. 2017 Oct 9;10.
- RhoB blockade selectively inhibits autoantibody production in autoimmune models of rheumatoid arthritis and lupus. Mandik-Nayak L, DuHadaway JB, Mulgrew J, Pigott E, Manley K, Sedano S, Prendergast GC, Laury-Kleintop LD. Dis Model Mech. 2017 Sep 7.
- The Host Microbiome Regulates and Maintains Human Health: A Primer and Perspective for Non-Microbiologists. Thomas S, Izard J, Walsh E, Batich K, Chongsathidkiet P, Clarke G, Sela DA, Muller AJ, Mullin JM, Albert K, Gilligan JP, DiGuilio K, Dilbarova R, Alexander W, Prendergast GC. Cancer Res. 2017 Mar 14.
- Therapeutic antibody targeting of indoleamine-2,3-dioxygenase (IDO2) inhibits autoimmune arthritis. Merlo LM, Grabler S, DuHadaway JB, Pigott E, Manley K, Prendergast GC, Laury-Kleintop LD, Mandik-Nayak L. Clin Immunol. 2017 Feb 20;179:8-16.
- IDO1 is an Integral Mediator of Inflammatory Neovascularization. Mondal A, Smith C, DuHadaway JB, Sutanto-Ward E, Prendergast GC, Bravo-Nuevo A, Muller AJ. EBioMedicine. 2016 Dec;14:74-82.
- A Milestone Review on How Macrophages Affect Tumor Growth. Caux C, Ramos RN, Prendergast GC, Bendriss-Vermare N, Menetrier-Caux C. Cancer Res. 2016 Nov 15;76(22):6439-6442.
- Preliminary evaluation of a predictive blood assay to identify patients at high risk of chemotherapy-induced nausea. Kutner T, Kunkel E, Wang Y, George K, Zeger EL, Ali ZA, Prendergast GC, Gilman PB, Wallon UM. Support Care Cancer. 2016 Oct 12.
- IDO2 Modulates T Cell-Dependent Autoimmune Responses through a B Cell-Intrinsic Mechanism. Merlo LM, DuHadaway JB, Grabler S, Prendergast GC, Muller AJ, Mandik-Nayak L. J Immunol. 2016 Jun 1;196(11):4487-97.
- Hum Mol Genet.BIN1 regulates BACE1 intracellular trafficking and amyloid & beta production. Miyagawa T, Ebinuma I, Morohashi Y, ... Prendergast GC, Tomita T. 2016 May 14. [Epub ahead of print]
- BIN1 regulates BACE1 intracellular trafficking and amyloid & beta; production. Miyagawa T, Ebinuma I, Morohashi Y, ... Prendergast GC. Hum Mol Genet. 2016 May 14.
- Antimetabolite TTL-315 selectively kills glucose-deprived cancer cells and enhances responses to cytotoxic chemotherapy in preclinical models of cancer. DuHadaway J, Prendergast GC. Oncotarget. 2016 Feb 16;7(7):7372-80.
- O-alkylhydroxylamines as rationally-designed mechanism-based inhibitors of indoleamine 2,3-dioxygenase-1. Malachowski WP, Winters M, DuHadaway JB, ... Prendergast GC, Muller AJ. Eur J Med Chem. 2016 Jan 27;108:564-76.
- Accumulation of an endogenous tryptophan-derived metabolite in colorectal and breast cancers. Puccetti, P., Fallarino, F., Italiano, A., ... Prendergast, G.C., et al. 2015. PLoS ONE 10, e0122046.
- Indoleamine 2,3-dioxygenase pathways in pathogenic inflammation and immune escape in cancer. Prendergast, G.C., Smith, C., Thomas, S., Mandik-Nayak, L., Laury-Kleintop, L.D., Metz, R. and Muller, A.J. 2014.Cancer Immunol. Immunother. 63, 721-735. Cover article
- IDO is a nodal pathogenic driver of lung cancer development and metastasis. 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. Cancer Discov. 2, 722-735. *Co-senior authors.
- 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, J.B., Mautino, M.R., Munn, D.H., Vahanian, N.N., Link, C.J. and Prendergast, G.C. 2012. OncoImmunology 1, 1460-1468.
- Why tumours eat tryptophan. Prendergast, G.C. 2011. Nature 478, 192-194.
- 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.
- Non-hematopoietic expression of IDO is critical for inflammatory tumor promotion. 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. Cancer Immunol. Immunother. 59, 1655-1663.
- Genotyping and expression analysis of IDO2 in human pancreatic cancer: a novel, active target. Witkiewicz, A.K., Costantino, C.L., Metz, R., Muller, A.J., Prendergast, G.C., Yeo, C.J., and Brody, J.R. 2009. J. Amer. Coll. Surg. 2008, 781-787.
- 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., ... Prendergast, G.C.* and Mellor, A.L.* 2008. Proc. Natl. Acad. Sci. USA 105, 17073-17078. *Co-senior authors
- Indoleamine 2,3-dioxygenase in T cell tolerance and tumoral immune escape. Katz, J.B., Muller, A.J., and Prendergast, G.C. 2008. Immunol. Rev. 222, 206-221.
- 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.
- 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.
- Immune escape as a fundamental trait of cancer: focus on IDO. Prendergast, G.C. 2008. Oncogene 27, 3889-3900.
- 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.
- Novel tryptophan catabolic enzyme IDO2 is the preferred biochemical target of the antitumor IDO inhibitory compound D-1MT. Metz, R., DuHadaway, J.B., Kamasani, U., Laury-Kleintop, L., Muller, A.J., and Prendergast, G.C. 2007.Cancer Res. 67, 7082-7087.
- 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.
- Structure based development of phenylimidazole-derived inhibitors of indoleamine 2,3-dioxygenase. Kumar, S., Jaller, D., Patel, B., LaLonde, J.M., DuHadaway, J.B., Malachowski, W.P., Prendergast, G.C. and Muller, A.J. 2008. J. Med. Chem. 51, 4968-4977.
- 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, GC 2005. Nature Med. 11, 312-319.
- Marrying immunotherapy with chemotherapy: why say IDO? Muller, A.J. and Prendergast, G.C. 2005. Cancer Res. 65, 8065-8068.
- RhoB antibody alters retinal vascularization in models of murine retinopathy. Almonte-Baldonado R, Bravo-Nuevo A, Gerald D, Benjamin LE, Prendergast GC, Laury-Kleintop LD. J Cell Biochem. 2018 Dec 9. doi: 10.1002/jcb.28213.
- Intestinal barrier tightening by a cell-penetrating antibody to Bin1, a candidate target for immunotherapy of ulcerative colitis. Thomas S, Hoxha K, Alexander W, Gilligan J, Dilbarova R, Whittaker K, Kossenkov A, Prendergast, GC Mullin JM. J Cell Biochem. 2018 Sep 30. doi: 10.1002/jcb.27716.
- Novel colitis immunotherapy targets Bin1 to improve colon cell barrier function. Thomas S, Mercado JM, DuHadaway J, DiGuilio K, Mullin JM and Prendergast GC Dig Dis Sci. 2016 Feb;61(2):423-32.
- From the Editor’s Chair: A perspective on cancer as an abortive autoimmune response to altered-self. Prendergast GC. 2015. Cancer Res. 75, 3-4.
- IDO2 in immunomodulation and autoimmune disease. Prendergast GC, Metz, R., Muller, A.J., Merlo, L.M.F. and Mandik-Nayak, L. 2014.Front Immunol. 5, 585-590.
- IDO2 is critical for IDO1-mediated T cell regulation and exerts a non-redundant function in inflammation. 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. Int. Immunol. 26, 357-367.
- IDO2 is a critical mediator of autoantibody production and inflammatory pathogenesis in a mouse model of autoimmune arthritis. Merlo, L.M.F., Pigott, E., DuHadaway, J.B., Grabler, S., Metz, R., Prendergast, G.C. and Mandik-Nayak, L. 2014. J. Immunol. 192, 2082-2090. Cover article
- Inhibition of the IDO pathway with 1-methyl-tryptophan synergizes with methotrexate to alleviate arthritis in the K/BxN mouse model of arthritis. Pigott, E., DuHadaway, J.B., Muller, A.J., Gilmour, S.K., Prendergast, G.C. and Mandik-Nayak, L. 2014. Autoimmunity 47, 409-418.
- Aryl hydrocarbon receptor control of a disease tolerance defense pathway. Bessede, A., Gargaro, M., Pallotta, T., ... DuHadaway, J.B., Prendergast GC, et al. 2014. Nature 511, 184-190.
- Bin1 attenuation suppresses inflammatory colitis by enforcing intestinal barrier function. Chang, M.-Y., Boulden, J., Valenzano, M.C., Soler, A.P., Muller, A.J., Mullin, J.M. and Prendergast, G.C. 2012. Digest. Dis. Sci. 57, 1813-1821.
- The immunoregulatory enzyme IDO paradoxically drives B cell-mediated autoimmunity. Scott, G.N., DuHadaway, J., Pigott, E., Ridge, N., Prendergast, G.C., Muller, A.J., and Mandik-Nayak, L. 2009. J. Immunol. 182, 7509-7517.