The Lankenau Institute for Medical Research
Association: Resident Faculty
Selected Awards and Honors
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.
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
(from 163 peer-reviewed research reports and 80 reviews, book chapters, or edited books):
A perspective on cancer as an abortive autoimmune response to altered-self. Prendergast GC. Cancer Res. 2015 Jan 1;75(1):3-4.
IDO2 in Immunomodulation and Autoimmune Disease. Prendergast GC, Metz R, Muller AJ, Merlo LM, Mandik-Nayak L. Front Immunol. 2014 Nov 20;5:585.
Aryl hydrocarbon receptor control of a disease tolerance defence pathway. Bessede A, Gargaro M, Pallotta MT, Matino D, Servillo G, Brunacci C, Bicciato S, Mazza EM, Macchiarulo A, Vacca C, Iannitti R, Tissi L, Volpi C, Belladonna ML, Orabona C, Bianchi R, Lanz TV, Platten M, Della Fazia MA, Piobbico D, Zelante T, Funakoshi H, Nakamura T, Gilot D, Denison MS, Guillemin GJ, DuHadaway JB, Prendergast GC, Metz R, Geffard M, Boon L, Pirro M, Iorio A, Veyret B, Romani L, Grohmann U, Fallarino F, Puccetti P. Nature. 2014 Jul 10;511(7508):184-90.
1-methyl-tryptophan synergizes with methotrexate to alleviate arthritis in a mouse model of arthritis. Pigott E, DuHadaway JB, Muller AJ, Gilmour S, Prendergast GC, Mandik-Nayak L. Autoimmunity. 2014 Sep;47(6):409-18.
Specific in situ detection of murine indoleamine 2, 3-dioxygenase. Thomas S, DuHadaway J, Prendergast GC, Laury-Kleintop L. J Cell Biochem. 2014 Feb;115(2):391-6.
Indoleamine 2,3-dioxygenase pathways of pathogenic inflammation and immune escape in cancer. Prendergast GC, Smith C, Thomas S, Mandik-Nayak L, Laury-Kleintop L, Metz R, Muller AJ. Cancer Immunol Immunother. 2014 Jul;63(7):721-35.
Meglumine exerts protective effects against features of metabolic syndrome and type II diabetes. Bravo-Nuevo A, Marcy A, Huang M, Kappler F, Mulgrew J, Laury-Kleintop L, Reichman M, Tobia A, Prendergast GC. PLoS One. 2014 Feb 27;9(2):e90031.
IDO2 is a critical mediator of autoantibody production and inflammatory pathogenesis in a mouse model of autoimmune arthritis. Merlo LM, Pigott E, DuHadaway JB, Grabler S, Metz R, Prendergast GC, Mandik-Nayak L. J Immunol. 2014 Mar 1;192(5):2082-90.
IDO2 is critical for IDO1-mediated T-cell regulation and exerts a non-redundant function in inflammation. Metz R, Smith C, DuHadaway JB, Chandler P, Baban B, Merlo LM, Pigott E, Keough MP, Rust S, Mellor AL, Mandik-Nayak L, Muller AJ, Prendergast GC. Int Immunol. 2014 Jul;26(7):357-67.
The SOCS3-independent expression of IDO2 supports the homeostatic generation of T regulatory cells by human dendritic cells. Trabanelli S, Očadlíková D, Ciciarello M, Salvestrini V, Lecciso M, Jandus C, Metz R, Evangelisti C, Laury-Kleintop L, Romero P, Prendergast GC, Curti A, Lemoli RM. J Immunol. 2014 Feb 1;192(3):1231-40.
RhoB controls coordination of adult angiogenesis and lymphangiogenesis following injury by regulating VEZF1-mediated transcription. Gerald D, Adini I, Shechter S, Perruzzi C, Varnau J, Hopkins B, Kazerounian S, Kurschat P, Blachon S, Khedkar S, Bagchi M, Sherris D, Prendergast GC, Klagsbrun M, Stuhlmann H, Rigby AC, Nagy JA, Benjamin LE. Nat Commun. 2013;4:2824.
CONCURRENT WHOLE BRAIN RADIOTHERAPY AND SHORT-COURSE CHLOROQUINE IN PATIENTS WITH BRAIN METASTASES: A PILOT TRIAL. Eldredge HB, Denittis A, Duhadaway JB, Chernick M, Metz R, Prendergast GC. J Radiat Oncol. 2013 Sep 1;2(3).
IDO inhibits a tryptophan sufficiency signal that stimulates mTOR: A novel IDO effector pathway targeted by D-1-methyl-tryptophan. Metz R, Rust S, Duhadaway JB, Mautino MR, Munn DH, Vahanian NN, Link CJ, Prendergast GC. Oncoimmunology. 2012 Dec 1;1(9):1460-1468.
Necrostatin-1 analogues: critical issues on the specificity, activity and in vivo use in experimental disease models. Takahashi N, Duprez L, Grootjans S, Cauwels A, Nerinckx W, DuHadaway JB, Goossens V, Roelandt R, Van Hauwermeiren F, Libert C, Declercq W, Callewaert N, Prendergast GC, Degterev A, Yuan J, Vandenabeele P. Cell Death Dis. 2012 Nov 29;3:e437.
A perspective on new immune adjuvant principles: Reprogramming inflammatory states to permit clearance of cancer cells and other age-associated cellular pathologies. Prendergast GC, Metz R. Oncoimmunology. 2012 Sep 1;1(6):924-929.
RhoB differentially controls Akt function in tumor cells and stromal endothelial cells during breast tumorigenesis. Kazerounian S, Gerald D, Huang M, Chin YR, Udayakumar D, Zheng N, O'Donnell RK, Perruzzi C, Mangiante L, Pourat J, Phung TL, Bravo-Nuevo A, Shechter S, McNamara S, Duhadaway JB, Kocher ON, Brown LF, Toker A, Prendergast GC, Benjamin LE. Cancer Res. 2013 Jan 1;73(1):50-61.
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. 2013 Feb;27(1):367-77.
Amino acid catabolism: a pivotal regulator of innate and adaptive immunity. McGaha TL, Huang L, Lemos H, Metz R, Mautino M, Prendergast GC, Mellor AL. Immunol Rev. 2012 Sep;249(1):135-57.
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.
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.
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.
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.
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.
Why tumours eat tryptophan. Prendergast GC. (2011). Nature 478, 192-194.
Opposing biological functions of tryptophan catabolizing enzymes during intracellular infection. Divanovic S, Sawtell NM, Trompette A, Warning JI, Dias A, Cooper AM, Yap GS, Arditi M, Shimada K, DuHadaway JB, Prendergast GC, Basaraba RJ, Mellor AL, Munn, DH, Aliberti J and Karp CL. (2012). J. Infect. Dis. 205, 152-61.
RhoB links PDGF signaling to cell migration by coordinating activation and localization of Cdc42 and Rac. Huang M, Satchell L, DuHadaway JB, Prendergast GC and Laury-Kleintop LD. (2011). J. Cell. Biochem. 112, 1572–1584.
Indoleamine 2,3-dioxygenase as a modifier of pathogenic inflammation in cancer and other inflammation-associated diseases. Prendergast GC, Chang MY, Mandik-Nayak L, Metz R and Muller AJ. (2011). Curr. Med. Chem. 18, 2257-2262.
RhoB loss prevents streptozotocin-induced diabetes and ameliorates diabetic complications in mice. Bravo-Nuevo A, Sugimoto H, Iyer S, Fallon Z, Lucas JM, Kazerounian S, Prendergast GC, Kalluri R, Shapiro NI and Benjamin LE. (2011). Amer. J. Pathol. 178, 245-252.
Immunotherapeutic suppression of IDO and tumor growth with ethyl pyruvate. Muller AJ, DuHadaway JB, Jaller D, Curtis P, Metz R and Prendergast GC. (2010). Cancer Res. 70, 1845-1853.
Towards a genetic definition of 'cancer-associated' inflammation: role of the IDO pathway. Prendergast GC, Metz R and Muller AJ. (2010). Am. J. Pathol. 176, 2082-2087.
Zinc protoporphyrin-IX stimulates tumor immunity by disrupting the activity of immunosuppressive enzyme indoleamine 2,3-dioxygenase. Metz R, DuHadaway JB, Rust S, Munn DH, Muller AJ, Mautino M, and Prendergast GC. (2010). Molec. Cancer Ther. 9, 1864-1871.
Non-hematopoietic expression of IDO is integrally required for inflammatory tumor promotion. Muller AJ, DuHadaway JB, Chang MY, Ramalingam A, Sutanto-Ward E, Boulden J, Mandik-Nayak L, Gilmour SK and Prendergast GC. (2010). Cancer Immunol. Immunother. 59, 1655-1663.
Chronic inflammation that facilitates tumor progression creates local immune suppression by inducing indoleamine 2,3-dioxygenase. Muller AJ, Sharma MD, Chandler PR, DuHadaway JB, Everhart M, Johnson BA, Dahler DJ, Pihkala J, Soler AP, Munn DH, Prendergast GC and Mellor AL. (2008). Proc. Natl. Acad. Sci. USA 105, 17073-17078.
Indoleamine 2,3-dioxygenase is the anticancer target for a novel series of potent naphthoquinone-based inhibitors. Kumar S, Malachowski WP, DuHadaway JB, LaLonde JM, Carroll PJ, Jaller D, Metz R, Prendergast GC and Muller AJ. (2008). J. Med. Chem. 51, 1706-1718.
Antitumor properties of chemopreventive natural product brassinin are based upon inhibition of indoleamine 2,3-dioxygenase (IDO). Banerjee T, DuHadaway JB, Gaspari P, Sutanto-Ward E, Munn DH, Mellor AL, Malachowski WP, Prendergast GC and Muller AJ (2008). Oncogene 27, 2851-2857.
Bin1 ablation increases cancer susceptibility during aging, particularly lung cancer. Chang MY, Boulden J, Sutanto-Ward E, DuHadaway JB, Katz JB, Wang L, Meyer TB, Soler AP, Muller AJ and Prendergast GC. (2007). Cancer Res. 67, 7605-7612.
Bin1 ablation in mammary gland delays tissue remodeling and drives cancer progression. Chang MY, Boulden J, Sutanto-Ward E, DuHadaway JB, Soler AP, Muller AJ and Prendergast GC. (2007). Cancer Res. 67, 100-107
Inhibition of IDO in dendritic cells by stereoisomers of 1-methyl-tryptophan correlates with anti-tumor responses. Hou DY, Muller AJ, Sharma M, DuHadaway J, Banerjee T, Johnson M, Mellor AL, Prendergast GC and Munn DH. (2007). Cancer Res. 67, 792-801.
Structure-activity study of brassinin derivatives as indoleamine 2,3-dioxygenase inhibitors. Gaspari P, Banerjee T, Malachowski WP Muller AJ, Prendergast GC, DuHadaway J, Bennett S and Donovan AM. (2006). J. Med. Chem. 49, 684-692.
Inhibition of indoleamine 2,3-dioxygenase, a target of the cancer suppression gene Bin1, potentiates cancer chemotherapy. Muller AJ, DuHadaway JB, Donover PS, Sutanto-Ward E and Prendergast GC. (2005). Nature Med. 11, 312-319.
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 EV, Donover PS and Prendergast GC. (2004). Cancer Res. 64, 8389-8396.
RhoB controls Akt trafficking and stage-specific survival of endothelial cells in vascular development. Adini I, Rabinovitz I, Sun JF, Prendergast GC and Benjamin LE. (2003). Genes Dev. 17, 2721-2732.