Our research has 2 goals. First, to design, synthesize, and develop new agents for the treatment of human cancer. Second, to determine the differences in signaling processes between cancer cells and normal cells and exploit these differences in cancer prognosis, diagnosis, or treatment.

Biography

James Darnowski, PhD

My formal graduate and post-doctoral training was in biochemical and molecular pharmacology. My research interests are focused to identify differences between normal and neoplastic cells in their response to pharmacological agents and exploit these differences for therapeutic advantage.

Institutions

Rih

Research Description

Our research focuses on two key areas in cancer research. First, a major goal of our program is the design, synthesis, and evaluation of novel agents for the treatment of cancer. Historically, these agents have fallen into 3 broad categories; pyrimidine analogues, camptothecin analogues, and taurolidine and its analogues. Regarding pyrimidine analogues, we have been involved in the development of uracil acyclic nucleosides that have utility in the reduction in host tissue toxicity associated with the administration of selected fluoropyrimidines. Additionally, we have developed thymidine analogues with substituted deoxyribose structures for use in both cancer and AIDS. In our camptothecin program, we have been in the forefront of studies to generate and evaluate analogues possessing stable lactone ring systems. These analogues possess relatively long bio-activity and reduced systemic toxicity. Finally, taurolidine was originally developed nearly 20 years ago as a peritoneal antibiotic. We have observed that this agent also possesses remarkable antineoplastic activity in selected models of metastatic colon and ovarian cancer. Studies are proceeding in the clinical development of this agent and our laboratory is engaged in the design, synthesis, and evaluation of stable metabolic analogues of taurolidine for future use in cancer therapy.

The second major research goal in our group is to identify exploitable differences that exist between normal and neoplastic cells in selected key molecular events that govern cell survival and death in response to both normal and therapeutic cues. In this regard, we have made the novel observation that STAT molecules, specifically Stat3, undergo post-translational proteolysis. This leads to (a) reductions in full-length STAT expression and (b) the generation of STAT cleavage products. Since Stat3 is an oncogene whose expression is associated with the progression from normal to neoplastic phenotypes, our studies to determine the impact of STAT fragment expression on neoplastic cell survival and proliferation hold significant promise in the diagnosis, prognosis, and treatment of a variety of human cancers.

Awards

1988 Sigma Iota Chi (National Honor Society)

Affiliations

1985 - Present New York Academy of Sciences

1986 - Present American Association for Cancer Research

1988 - Present Ad Hoc reviewer for the following peer reviewed journals:
--Cancer Research
--Cancer
--Biochemical Pharmacology, Molecular
--Pharmacology
--Oncology Research
--Journal of the National Cancer Institute and Journal of Clinical Oncology

1992 Ad Hoc reviewer for experimental therapy grants submitted to the Canadian National Cancer Institute.

1999 State (RI) Chair for National Funding Issues, American Association for Cancer Research

1999 – 2001 CET-3 Study Section, US Army Department of Defense (DOD) Breast Cancer Program.

2001 Study Section for Transition Support Grants, Rhode Island Cancer Council

2006 - Present Editorial Board Member, Anticancer Drugs

2006 Con-CET-3 Study Section, US Army (DOD) Breast Cancer Program.

2006 CET/Prostate Cancer Study Section, US Army (DOD) Prostate Cancer Program

Funded Research

CURRENT SUPPORT

American Cancer Society (ACS) grant DPH 68213 (awarded 1990)
"AZT + FUra: Biochemical, preclinical and clinical evaluation for colon cancer"
PI James Darnowski, Ph.D., total direct award $230,000.

National Cancer Institute (NCI) grant CA 55358 (awarded 1991)
"Utilization of AZT to improve colon cancer therapy"
PI James Darnowski, Ph.D., total direct award $208,000.

Rhode Island Hospital (RIH) grant (awarded 1996)
"Modulation of AZT cytotoxcity with IFN-a"
PI James Darnowski, Ph.D., total direct award
$20,005.

T.J. Martell Foundation Grant (awarded yearly from 1996-2005)
"Development of novel therapies to treat prostate cancer."
PI James Darnowski, Ph.D., total direct award
$2,325,000.

Carter-Wallace Inc. (awarded 1999)
"Assessment and development of Taurolidine as an antineoplastic agent"
PI Paul Calabresi and James Darnowski
$2,500,000.

PENDING SUPPORT

Submitted 10/1/05 to the National Cancer Institute "Caspase-mediated STAT cleavage: cellular
and functional analysis"
PI James Darnowski, Ph.D.
Total requested award: $1,500,000

Submitted 2/1/06 to the National Institute of Allergy and Infectious Diseases "Stat3 proteoyltic
processing and CD95-DISC function"
PI James Darnowski, Ph.D.
Total requested award: $375,000

Teaching Experience

James W. Darnowski, PhD

UNIVERSITY TEACHING ROLES

1990 - 1995. Mentor, Bio 195
Brown University, Providence, RI
(1990-1991, Eric Kim)
(1991-1992, Ted Bang)
(1992-1993, Mark Poulos)
(1993-1994, Derek Brown)
(1994-1995, Elijah Murphy)
1994 Lecturer, Bio 128, Pharmacology
Brown University, Providence, RI
1994 - 2003. Mentor, Master of Medical Science Program
Brown University, Providence, RI
(1994-2003 Arshad Ahsanuddin)
2001-2004, Mentor, Post-doctoral Research Scientist
(Leslie P. Cousens, PhD)


HOSPITAL TEACHING ROLES

1988 - 1995. Mentor, Oncology Research Fellowship Program
Roger Williams Hospotal, Providence, RI
(1988-1990, Isa Brunnetti, Alfredo Falcone)
(1990-1992, Patriza Tosi)
(1992-1994, Julie Beitz)
(1994-1996, Howard Fellows)

1995 - Pres. Mentor, Fellowship Program
Rhode Island Hospital, Providence, RI
(1996-1997, Iole Ribizzi, MD)
(1998-1999, Giacomo Alegrini, MD)
(2000-2001, Roberta Sarmiento, MD)
(2001-2003, Andrea Sartore-Bianchi, MD)

2001-Pres. Mentor, Summer Intern Program
Rhode Island Hospital, Providence, RI
(2001, Elin Simms)
(2002, Elin Simms)
(2003, Thomas Earl)
(2005, Edward Richards)

Courses Taught

• General Pharmacology (Bio 128)

View My Full Publication List in pdf format

Selected Publications

• 14. Darnowski, J. W., Goulette, F.A., Guan, Y-j, Chatterjee, D., Yang, Z-F., Cousens, L.P. and and Chin, Y.E. Stat3 cleavage by caspases: impact on full-length Stat3 expression, fragment formation and transcriptional activity. J. Biol. Chem., 2006.(2006)
• 13. Cousens, L.P., Goulette, F.A., Calabresi, P. and Darnowski, J.W. IFNa-mediated signaling inhibits Fas Ligand-induced apoptosis independent of de novo protein synthesis. J. Immunol., 174: 320-327, 2005.(2005)
• 12. Chaterjee, D., Roy, R., Braastad, C., Mott, S., Sun, Y., Mukhopadhay, A., Aggarwal, B., Darnowski, J., Wyche, J.H., Pantazis, P., Wyche, J.H., Sedivy, J.M. and Yeung, K. RKIP sensitizes prostate and breast cancer cells to drug-induced apoptosis. J. Biol. Chem., 279: 17515-17523, 2004(2004)
• 11. Han, Z., Wei, W., Dunaway, S., Darnowski, J.W., Calabresi, P., Sedivy, J., Hendrickson, E.A., Balan, K.V., Pantazis, P. and Wyche, J.H. Role of p21 in apoptosis and senescence of human colon cancer cells treated with camptothecin. J. Biol. Chem., 277: 17154-17160, 2002.(2002)
• 10. Calabresi, P., Goulette, F.A. and Darnowski, J.W. Taurolidine: Cytotoxic and mechanistic evaluation of a novel antineoplastic agent. Cancer Res., 61:6816-6821, 2001.(2001)
• 9. Pizzorno, G, Yee, L, Burtness, BA, Marsh, JC, Darnowski, JW, Chu, MYW, Chu, SH, Chu, E, Leffert, JJ, Handschumacher, RE and Calabresi, P. Phase I clinical and pharmacological studies of benzylacyclouridine (BAU), a uridine phosphorylase inhibitor. Clinical Cancer Res.,4:1165-1175, 1998.(1998)
• 8. Darnowski, JW, Davol, PA and Goulette, FA. Human recombinant interferon alpha-2a plus 3'-azido-3'-deoxythymidine. Synergistic growth inhibition with evidence of impaired DNA repair in human colon adenocarcinoma cells. Biochem. Pharmacol., 53:571-580, 1997.(1997)
• 7. Davol, PA, Goulette, FA, Frackelton, ARJr and Darnowski, JW. Modulation of p53 expression by human recombinant interferon alpha-2a correlates with abrogation of cisplatin resistance in a human melanoma cell line. Cancer Res., 56:2522-2526, 1996.(1996)
• 6. Posner, MR, Darnowski, JW, Weitberg, AB, Corvese, D, Cummings, FJ, Clark, J, Murry, C, Goulette, F, Clendenin, N, Bigley, J, and Calabresi, P. A phase I clinical and pharmacokinetic study of high dose intravenous zidovudine with 5-fluorouracil and leucovorin. Cancer, 70:2929-2934, 1992.(1992)
• 5. Tosi, P, Calabresi, P, Goulette, F, Renaud, C and Darnowski, JW. 3'-Azido-3'-deoxythymidine antineoplastic activity is enhanced by methotrexate in vitro and in vivo. Cancer Res., 52:4069-4073, 1992.(1992)
• 4. Posner MR, Darnowski JW, Calabresi P, Brunetti I, Corvese D, Curt G, Cummings FJ, Clark J, Browne MJ, Beitz J, Weitberg AB. Oral Azidothymidine, continuous infusion 5-fluorouracil and oral leucovorin: A Phase I Study. J Natl Cancer Inst, 82:1710-1714,1990.(1990)
• 3. Falcone A, Darnowski JW, Chu SH, Brunetti I, Ruprecht RM and Calabresi P. Azidothymidine antiretroviral efficacy in mice is modulated by the concomitant administration of benzylacyclouridine or uridine. Blood,76:2216-2221, 1990.(1990)
• 2. Brunetti I, Falcone A, Calabresi P, Goulette FA and Darnowski JW. 5-Fluorouracil enhances azidothymidine cytotoxicity. In vitro, in vivo and biochemical studies. Cancer Res 50:4026-4031, 1990.(1990)
• 1. Darnowski JW, Holdridge C and Handschumacher RE. Concentrative uridine transport by murine splenocytes: Kinetics, substrate specificity and sodium dependency. Cancer Res 47:2614-2619, 1987.(1987)
• Selected Publications
• James William Darnowski, Ph.D.