Research Summary

Our laboratory is interested in cancer suppression genes and molecular cancer therapeutics.

We use transgenic mouse models to study cancer suppression, focusing on the long-term goal 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. We hypothesize that cancer modifier genes might offer better targets for drug development based on the idea that they may dictate clinical course. Accordingly, a new therapy we are developing is based on targeting a enzyme regulated by the Bin1 tumor suppressor gene we have studied, called IDO, that improves the reaction of T immune cells to cancer.

RhoB studies derive from our previous work on the cellular targets of farnesyl transferase inhibitors (FTIs), an early class of signal transduction inhibitors to enter clinical development. While FTIs have not been widely useful against cancer, our work on RhoB and how it is affected by FTIs has stimulated new ideas on treatment of athersclerosis and other vascular diseases.

Bin1 studies have led us to develop a radically new strategy to treat cancer using small molecule inhibitors of the enzyme indoleamine 2,3-dioxygenase (IDO), and a newly discovered enzyme called IDO2 which modulate immune control. This exciting line of work has translated rapidly to clinical trials with the help of a biopharmaceutical company that acquired our start-up company begun to develop this technology.

I. Genetics: cancer suppression and immune escape

Bin1 is the prototypical member of the BAR adapter gene family that includes the amphiphysin-like genes. Like other members of this family, Bin1 functions in actin-membrane dynamics but it also has unique functions in the nucleus and in cell polarity signaling. Bin1 isoforms that can localize to the nucleus exert anti-cancer effects. In many human tumors, Bin1 is attenuated or misspliced in a way that abolishes nuclear localization.

Genetic analysis in mouse and fission yeast establish that Bin1 has essential conserved functions in stress response and cancer suppression. Fission yeast studies indicate support for transcriptional repression and cell division cycle control after starvation or genotoxic stress. Mice lacking Bin1 develop cardiac hypertrophy, identifying an essential role in heart function. Studies in tissue-specific and mosaic knockout models establish that Bin1 restricts cancer to a large degree by limiting escape from immune control.

Mechanistic investigations of how Bin1 mediates immune control led us to identify the immunomodulatory enzyme indoleamine 2,3-dioxygenase (IDO) as a crucial regulatory target. More recently, we have discovered the iDO-related gene IDO2, which encodes a novel tryptophan catabolic enzyme that may also function in immune regulation and cancer.

II. Therapeutics: IDO inhibitor development

IDO is a tryptophan catabolic enzyme that blocks T cell activation in physiolgical settings such as pregnancy and in pathophysiological settings including cancer. Notably, IDO is widely activated in cancer as a mechanism of immune escape. Genetic studies reveal that IDO is essential for inflammation-driven cancer. In mouse models of breast cancer, drug-like inhibitors of IDO arrest tumor growth and enhance chemotherapeutic efficacy. The action of a clinical lead inhibitor, D-1MT, is genetically reliant on IDO but appears to preferentailly target IDO2, suggesting a possible IDO>IDO2 pathway. Clinical translation of IDO inhibitors and studies of their mechanism of action is presently emerging as a major focus of the laboratory.

Selected Research Reports

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 Medicine 11, 312.
2. 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.
3. 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.
4. Metz, R., DuHadaway, J.B., Kamasani, U., 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. 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.

Selected Reviews and Books 

1. Prendergast, G.C. (2001). Actin' up: RhoB in cancer and apoptosis. Nature Rev. Cancer 1, 162.
2. Prendergast, G.C. (2004). Molecular Cancer Therapeutics: Strategies for Drug Discovery and Development. New York: John Wiley & Sons.
   • review in the New England Journal of Medicine
   
3. Muller, A.J. and Prendergast, G.C. (2005). Marrying immunotherapy with chemotherapy: why say IDO? Cancer Res. 65, 8065.
4. Prendergast, G.C. and Jaffee, E.M. (2007). Cancer immunologists and cancer biologists: why we didn’t talk then but need to now. Cancer Res 67, 3500-3505.
5. Prendergast, G.C. and Jaffee, E.M. (2007). Cancer Immunotherapy: Immune Suppression and Tumor Growth. New York: Academic Press.
   • review in the New England Journal of Medicine
6. Prendergast, G.C. (2008). Immune escape as a fundamental trait of cancer: focus on IDO. Oncogene 27, 3889-3900.
7. Prendergast, G.C., Muller, A.J., Ramalingam, A., and Chang, M.Y. (2009). BAR the door: cancer suppression by amphiphysin-like genes. BBA Rev. Cancer 1795: 25-36.

Education

• B.A., 1983, Biochemistry, magna cum laude, University of Pennsylvania
• M.S., 1984, Molecular Biophysics and Biochemistry, Yale University
• Ph.D., 1989, Molecular Biology, Princeton University

Previous Appointments

• 1989-1991   ACS Postdoctoral Fellow,
  Howard Hughes Medical Institute and
  Department of Biochemistry
  New York University Medical Cancer
• 1991-1993  Senior Research Biochemist
  Merck Research Laboratories
• 1993-2001 Assistant and Associate Professor
  The Wistar Institute, Philadelphia PA
• 1999-2001  Senior Director, Cancer Research Group
  DuPont Pharmaceuticals Company

Selected Awards and Appointments

• 1980-1983  Benjamin Franklin Scholar (top 5% undergraduates), University of Pennsylvania
• 1984  IBM University Prize Fellowship
• 1989 American Cancer Society Postdoctoral Award
• 1995 American Cancer Society Jr Faculty Award
• 1995 Pew Scholar in Biomedical Sciences Award
• 1997  Pfizer Traveling Fellow
• 2003-2005  Senior Editor, Cancer Research
• 2005-2009 Deputy Editor, Cancer Research
• 2006-current Member, NIH DMP Study Section
  (Drug Discovery and Molecular Pharmacology)
  
• 2006-current Leadership Council, President's Circle American Association for Cancer Research
• 2008 Special Achievement Award in Cancer Research, Chinese Society for Clinical Oncology
• 2010- Editor-in-Chief (elect), Cancer Research