Research Summary

Our laboratory is interested in genes that suppress cancer and the in the discovery and development of new molecular therapeutics to treat cancer.

We use transgenic mouse models to study cancer suppression by members of the Rho GTPase and BAR adapter families, with a focus on the modifier genes RhoB and Bin1. Our long-term goal is to gain new insights into how to improve 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 are very expensive and have shown limited efficacy to date. We hypothesize that cancer modifier genes might offer better targets for drug development, given emerging evidence that such genes dictate later clinical course. Accordingly, a new therapy we are developing is based on targeting a Bin1-regulated enzyme that modifies the reaction of T immune cells to cancer cells.

RhoB studies are derived from our work on farnesyl transferase inhibitors (FTIs), perhaps the first class of signal transduction inhibitors to be developed for clinic. Our work has stimulated new ideas about how to apply FTIs not only for cancer but also for macular degeneration, atherosclerosis, and diabetes based on knowledge of their mechanism of action involving RhoB.

Bin1 studies have led us to develop a radically new strategy to treat cancer, using small molecule inhibitors of the Bin1-regulated immunomodulatory enzyme indoleamine 2,3-dioxygenase (IDO) which mediates immune escape. This exciting line of work is being translated rapidly to clinical trials in 2007, through partnership with a biotechnology company, NewLink Genetics Corporation.

I. RhoB in cancer suppression and therapy

RhoB is a member of the Rho family of small GTPases that modulates cell survival, adhesion, invasion, and metastasis by regulating the actin cytoskeleton. RhoB has a unique function in trafficking through its ability to regulate the movement of membraneous vesicles in cells. RhoB is a critical mediator of the antineoplastic and apoptotic effects of FTIs, a class of experimental drugs originally strategized to block the Ras oncoprotein. Additionally, RhoB is also a critical mediator of the apoptotic response of cancer cells to DNA damaging agents and taxanes that are used to treat cancer in clinic. RhoB is non-essential for normal cell physiology but it has a modifier function in cancer: after an oncogenic lesion mice lacking RhoB are more prone to developing cancer. However, due to a positive role for RhoB in the blood vasculature these cancers progress poorly as they can not gain an effective blood supply. Evidence suggests that RhoB modulates cancer by affecting the activities of cyclin B1, Akt, and Myc.

II. BAR adapter proteins: Bin1 in cancer suppression and immune escape.

A long-standing interest in c-Myc function led us to identify a Bin1 adapter protein as a c-Myc binding factor. The Bin1 gene encodes at least 10 alternately spliced adapter proteins that localize to different compartments of the cell. Only Bin1 isoforms that can localize to the nucleus have cancer suppression properties, and in many human tumors, Bin1 is shut off or misspliced in a way that abolishes its nuclear localization and anticancer activity. Bin1 has a common signature domain that we named the BAR domain (found in the Bin/Amphiphysin/RVS proteins), the canonical function of which is in curved membrane binding and vesicle trafficking. Evidence also suggests a distinct nuclear function for certain BAR adapter proteins including Bin1. Two BAR adapter genes are conserved throughout evolution to yeast, the second we discovered called Bin3.

Genetic analysis of Bin1 and Bin3 in mouse and fission yeast "gene knockout" models suggest that these genes function in stress processes. Mice lacking Bin1 die at birth due to cardiac hypertrophy, highighting a key role in cardiac muscle cells. Fission yeast studies show that Bin1 and Bin3 homologs are important for cell cycle arrest and repair responses that follow starvation or genotoxic stress. Genetic studies of Bin1 in the mouse suggest that Bin1 can facilitate certain apoptotic signals in cancer cells and also strongly limit their escape from immune control. Deficiencies in Bin1 cause lung and liver cancer and in other tissues can accelerate malignant progression. Mechanistic investigations of how Bin1 supports immune control led us to identify the immunomodulatory enzyme indoleamine 2,3-dioxygenase (IDO) as a crucial genetic target of Bin1 (collaboration with Dr. A. Muller at LIMR).

III. Preclinical and clinical translational research of IDO inhibitors for cancer therapy.

IDO suppresses T cell activation and it is widely activated in cancer cells as a strategy for immune escape. Preclinical studies in mouse models of breast cancer show that small molecular inhibitors of IDO, including several discovered at LIMR, can greatly enhance the efficacy of cancer chemotherapy. One major implication is that cancer treatment may be enhanced by combining immunotherapy and chemotherapy.Recently we have discovered a second IDO gene called IDO2 that may be similarly important in immune control in cancer and other diseases. Clinical trials of a 'lead' IDO inhibitor are starting in 2007. Bin-IDO genetics and the study and development of IDO inhibitors is emerging as a major focus of the laboratory.

Selected Research Reports

1. Liu AX, Du W, Liu JP, Jessell TM and Prendergast GC. (2000). RhoB alteration is necessary for apoptotic and antineoplastic responses to farnesyltransferase inhibitors. Mol. Cell. Biol. 20, 6105.
2. Liu AX, Cerniglia GJ, Bernhard EJ and Prendergast GC. (2001). RhoB is required for the apoptotic response of neoplastically transformed cells to DNA damage. PNAS 98, 6192.
3. Muller AJ, DuHadaway JB, Donover PS, Sutanto-Ward E and Prendergast GC. (2005). Inhibition of indoleamine 2,3-dioxygenase, a target of the cancer suppression gene Bin1, potentiates cancer chemotherapy. Nature Medicine 11, 312.
4. Huang M, Kamasani U and Prendergast GC. (2006). RhoB facilitates c-Myc turnover by supporting efficient nuclear accumulation of GSK3. Oncogene 25, 1281.
5. Chang MY, Boulden J, Sutanto-Ward E, DuHadaway JB, Soler AP, Muller AJ and Prendergast GC. (2007). Bin1 ablation in mammary gland delays tissue remodeling and drives cancer progression. Cancer Res. 67, 100.
   
6. Chang MY, Boulden J, Sutanto-Ward E, DuHadaway JB, Katz JB, Wang L, Meyer TB, Soler AP, Muller AJ and Prendergast GC. (2007). Bin1 ablation increases cancer susceptibility during aging, particularly lung cancer. Cancer Res. 67, 7605.
7. Ramalingam A and Prendergast GC. (2007). Bin1 homolog Hob1 supports a Rad6-Set1 pathway of transcriptional repression in fission yeast. Cell Cycle 6, 1655-1662.
8. Metz R, DuHadaway JB, Kamasani U, Muller AJ and Prendergast GC. (2007). Novel tryptophan catabolic enzyme IDO2 is the preferred biochemical target of the antitumor IDO inhibitory compound D-1MT. Cancer Res. 67, 7082.

Selected Reviews and Books 

1. Prendergast GC. (2001). Actin' up: RhoB in cancer and apoptosis. Nature Rev. Canc. 1, 162.
2. Prendergast GC. (2004). Molecular Cancer Therapeutics: Strategies for Drug Discovery and Development (Book Editor). New York: John Wiley & Sons. 351 pg.
   • review in the New England Journal of Medicine
   
3. Muller AJ, Malachowski WB and Prendergast GC. (2005). IDO in cancer: targeting pathological immune tolerance with small molecule inhibitors. Exp. Opin. Ther. Targets 9, 831.
4. Muller AJ and Prendergast GC. (2005). Marrying immunotherapy with chemotherapy: why say IDO? Cancer Res. 65, 8065.
5. Prendergast GC and Jaffee EM. (2007). Cancer Immunotherapy: Immune Suppression and Tumor Growth (Book Editors). New York: Academic Press. 428 pg.

Education

• B.A., 1983, Biochemistry, 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 the Biomedical Sciences Award
• 2003 Senior Editor, Cancer Research
• 2005- Deputy Editor, Cancer Research
• 2006- Member, NIH DMP Study Section
  (Drug Discovery and Molecular Pharmacology)
  
• 2006- Leadership Council, President's Circle American Association for Cancer Research