Contributing Physician:

Jason A. Chesney, M.D., Ph.D.
Associate Professor of Medicine, and Pharmacology & Toxicology and Biochemistry & Molecular Biology; Associate Director, Translational Research, James Graham Brown Cancer Center; Medical Director, Clinical Trials Office, James Graham Brown Cancer Center

Contact Information:
James Graham Brown Cancer Center
529 South Jackson Street
Louisville, Kentucky 40202
Phone: Appointments: (502) 589-4856

Clinical Expertise: Medical Oncology
Skin Cancer/Melanoma

Multidisciplinary Clinic: Skin/Melanoma

Research Program: Molecular Targets

Research Interests:

Translational Research Summary:

Dr. Chesney conducted his graduate studies at the Picower Institute for Medical Research where he identified a novel isozyme of 6-phosphofructo-2-kinase (PFKFB3) that is essential for cancer cell growth. Dr. Chesney's laboratory examines the metabolic properties of transformed cells and neoplastic tissues in order to identify key regulatory enzymes involved in neoplastic metabolism. His research group has established that several enzymes are essential for neoplastic metabolism, including transaldolase, transketolase, PFKFB3, lactate dehydrogenase, glutamate dehydrogenase and cytochrome c oxidase. Their approach is to suppress the activity of these metabolic regulators using a combination of siRNA silencing and genomic deletion and then to examine the effects on the metabolism, growth and survival of primary and transformed cells. Once regulatory enzymes have been validated as being selectively required for neoplastic cell growth or survival, then competitive inhibitors of the substrate-binding domains of these enzymes are identified via a combination of computational modeling and virtual screening. Candidate compounds are screened for competitive inhibitory properties against the targeted enzymes and then for cytostatic and cytotoxic effects on transformed cells grown in athymic mice. Using this approach, several PFKFB3 inhibitors have been identified that exhibit selective cytotoxic and cytostatic properties against tumors grown in mice. Pre-clinical studies are now underway to facilitate the initiation of phase I clinical trials examining this new class of chemotherapeutic agents in patients with leukemias and metastatic solid malignancies.

Clinical Specialties:
Metastatic Melanoma, Refractory Solid Tumors, Clinical Trial Testing of Immunotherapeutics, Development of Anti-Metabolites as Targeted Chemotherapies

Education:

B.A., University of Minnesota, Minneapolis, Anthropology, 1991
Ph.D., University of Minnesota, Minneapolis, and the Picower Institue for Medical Research, Manhasset, New York, Biomedical Sciences, 1997
M.D., University of Minnesota Medical School, Minneapolis, Medicine, 1998

Research and Professional Experience:

1993-1997 Research Fellow, The Picower Institute for Medical Research, Department of Medical Biochemistry, Manhasset, New York

1998-2001
Intern and Assistant Physician, New York -Presbyterian Hospital, Cornell University Medical College, New York, New York

1998-2001
Intern and Resident, Memorial Sloan-Kettering Cancer Center, New York, New York

2000-2001
Senior Scientist, The Picower Institute for Medical Research, Department of Medical Biochemistry, Manhasset, New York

2001-2002
Clinical Fellow, Division of Immunology, Cornell University Medical College, New York, New York

2002-present
Member, James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky

2003-present
Assistant Professor, Department of Medicine, Division of Medical Oncology, University of Louisville, Louisville, Kentucky

2003-present
Assistant Professor Secondary Appointments, Department of Pharmacology & Toxicology and Biochemistry & Molecular Biology, University of Louisville, Louisville, Kentucky

2005-present
Associate Director, Translational Research Program, James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky

2006-present
Medical Director, Clinical Trials Office, James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky

2008-present
Associate Professor, Department of Medicine, Division of Medical Oncology, University of Louisville, Louisville, Kentucky

2008-present
Associate Professor Secondary Appointments, Department of Pharmacology & Toxicology and Biochemistry & Molecular Biology, University of Louisville, Louisville, Kentucky

Selected Awards and Professional Honors:

1990
Undergraduate Research Opportunities Award, University of Minnesota

1990
Phi Kappa Phi

1991
Summa cum laude, Anthropology, University of Minnesota

1991-1998
National Institutes of Health Medical Scientist Training Program Scholarship

1993
Phi Beta Kappa

1995-2001
Ad Hoc Reviewer, Molecular Medicine

1997
Livermore Award in Hematology, Minnesota Medical Foundation

2001
Advisory Committee, 1st International Conference on Tumor Cell Metabolism

2003
Co-Organizer, 2nd International Conference on Tumor Cell Metabolism

2005
Co-Organizer, 3rd International Conference on Tumor Cell Metabolism

2005
Young Faculty Award, American Federation for Medical Research

2005-present
US Department of Defense Breast Cancer Research Programs

2005-present
Reviewer, Medical Research Council (United Kingdom)

2006
Organizer, 4th International Conference on Tumor Cell Metabolism

2006
Judge, Southern Society for Clinical Investiagtion Oncology Forum

Publications:
Chesney J, Mahoney JR, Eaton JW. A spectrophotometric assay for chlorine-containing compounds. Analyt Biochem 196:262-6, 1991

Bucala R, Spiegel LA, Chesney J, Hogan M, Cerami A. Circulating fibrocytes define a new leukocyte subpopulation that mediates tissue repair. Molecular Medicine 1:71-81, 1994

Chesney J, Kondoh T, Conrad JA, Low WC. Collagenase-induced intrastriatal hemorrhage in rats results in long-term locomotor deficits. Stroke 26:312-7, 1995

Chesney J, Eaton JW, Mahoney JR. Bacterial glutathione: A sacrificial defense against chlorine compounds. J Bacteriol 178:2131-5, 1996

Bacher M, Metz C, Calandra T, Mayer K, Chesney J, Lohoff M, Gemsa D, Donnelly T, Bucala R. An essential regulatory role for MIF in T cell activation. Proc Natl Acad Sci USA 93:7849-54, 1996

Bianchi M, Bloom O, Raabe T, Cohen PS, Chesney J, Sherry B, Schmidtmayrova H, Calandra T, Zhang X, Bukrinsky M, Ulrich P, Cerami A, Tracey KJ. Suppression of proinflammatory cytokines in monocytes by a tetravalent guanylhydrazone. J Exp Med 183:927-36, 1996

Chesney J, Bacher M, Bender A, Bucala R. The peripheral blood fibrocyte is a potent antigen presenting cell capable of priming naïve T cells in situ. Proc Natl Acad Sci USA 94:6307-12. 1997

Chesney J, Bucala R. Peripheral blood fibrocytes: novel fibroblast-like cells that present antigen and mediate tissue repair. Biochem Soc Trans 25:520-3, 1997.

Bacher M, Meinhardt A, Lan HY, Mu W, Chesney J, Metz CN, Gemsa D, Donnelly T, Atkins RC, Bucala R. MIF expression in experimentally-induced endotoxemia. Am J Path 150:235-46, 1997

Bacher M, Meinhardt A, Lan HY, Dhabar F, Wu M, Metz CN, Chesney J, Gemsa D, Donnelly T, Atkins RC, Bucala R. MIF Expression in the rat brain: Implications for neuronal function. Molecular Medicine 4:217-30, 1998

Chesney J, Metz C, Stavitsky A, Bacher M, Bucala R. Regulated production of Type I collagen and inflammatory cytokines by peripheral blood fibrocytes. J Immunol 160:419-25, 1998

Grab DJ, Lanners NH, Martin LN, Chesney J, Cai C, Adkisson HD, Bucala R. Interaction of Borrelia burgdorferi with peripheral blood fibrocytes, antigen-presenting cells with the potential for connective tissue targeting. Molecular Medicine 5:44-52, 1999

Chesney J, Metz CN, Bacher M, Peng T, Meinhardt A, Bucala R. An essential role for macrophage migration inhibitory factor (MIF) in angiogenesis and the growth of a murine lymphoma. Molecular Medicine 5:181-91, 1999

Chesney J, Mitchell R, Benigni F, Bacher M, Spiegel L, Al-Abed Y, Han JH, Metz C, Bucala R. An inducible gene for 6-phosphofructo-2-kinase with an AU-rich mRNA instability element: Role in tumor cell glycolysis and the Warburg Effect. Proc Natl Acad Sci USA 96:3047-52, 1999

Chesney J, Bucala R. Peripheral blood fibrocytes: Mesenchymal precursor cells and the pathogenesis of fibrosis. Current Rheumatology Reports 2(6):501-5, 2000.

Senter PD, Al-Abed Y, Metz CN, Benigni F, Mitchell RA, Chesney J, Han J, Nelson SD, Todaro GJ, Bucala R. Irreversible inhibition of macrophage migration inhibitory factor tautomerase and biological activities by acetominophen metabolites. Proc Natl Acad Sci USA 99(1):144-9, 2002

Mitchell R, Liao H, Chesney J, Bucala R. Macrophage migration inhibitory factor sustains macrophage proinflammatory function by inhibiting p53: Regulatory role in the innate immune response. Proc Natl Acad Sci USA 99(1):345-50, 2002

[Atsumi T* Chesney J*] *authors contributed equally, Metz C, Leng L, Donnelly S, Makita Z, Mitchell R, Bucala R. High expression of inducible 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (iPFK-2; PFKFB3) in human cancers. Cancer Res 62(20):5881-7, 2002

Grab DJ, Salem ML, Chesney J, Bucala R, Lanners NH. A role for peripheral blood fibrocytes in Lyme Disease. Medical Hypothesis, 59(1):1, 2002

Mahlknecht U, Chesney J, Hoelzer D, Bucala R. Cloning and chromosomal characterization of the 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 gene (PFKFB3, iPFK2). Int J Oncol 23(4):883-91, 2003

Chesney J, Telang S, Yalcin T, Clem A, Wallis N, Bucala R. Targeted disruption of inducible 6-phosphofructo-2-kinase results in embryonic lethality. Biochem Biophys Res Commun 331(1):139-46, 2005

Chesney J. 6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase and tumor cell glycolysis. Curr Opin Clin Nutr Metab Care. 9(51):535-9, 2006

Telang S, Yalcin A, Clem AL, Bucala R, Lane AN, Eaton JW, Chesney J. Ras transformation requires metabolic control by 6-phosphofructo-2-kinase. Oncogene 25(55):7225-34. 2006

Chesney J. Fibrocytes: Immunologic feathers. In: Fibrocytes: New Insights Into Tissue Repair and Systemic Fibroses, World Scientific Publishing, Singapore, 2006

Telang S, Clem AL, Eaton JW, Chesney J. Depletion of ascorbic acid restricts angiogenesis and retards tumor growth in a mouse model. Neoplasia 9(1):47-56, 2007

Clem AL, Sims J, Telang S, Eaton JW, Chesney J. Virus detection and identification using random multiplex (RT)-PCR with 3'-locked random primers. Virol J 4:65, 2007

Telang S, Lane AN, Nelson KK, Arumugam S, Chesney J. The oncoprotein H-RasV12 increases mitochondrial metabolism. Mol Cancer 6:77, 2007

Clem B, Telang S, Clem A, Yalcin A, Meier J, Simmons A, Rasku MA, Arumugam S, Dean WL, Eaton J, Lane A, Trent JO, Chesney J. Small-molecule inhibition of 6-phosphofructo-2-kinase activity suppresses glycolytic flux and tumor growth. Mol Cancer Ther 7(1):110-20, 2008

Liu Y, El-Naggar S, Clem B, Chesney J, Dean DC. The Rb/E2F pathway and Ras activation regulate RecQ helicase gene expression. Biochem J 412(2):299-306, 2008

Rasku MA, Clem AL, Telang S, Taft B, Gettings K, Gragg H, Cramer D, Lear SC, McMasters KM, Miller DM, Chesney J. Transient T cell depletion causes regression of melanoma metastases. J Transl Med 6:12, 2008

Thornburg J, Nelson K, Clem BF, Lane A, Arumugam S, Simmons A, Eaton JW, Telang S, Chesney J. Targeting aspartate aminotransferase in greast cancer. Breast Cancer Res 10:R84, 2008; PMC2614520

Liu Y, Clem B, Zuba-Surma EK, El-Naggar S, Telang S, Jenson AB, Wang Y, Shao H, Ratajczak MZ, Chesney J, Dean DC. Mouse fibroblasts lacking RB1 function form spheres and undergo reprogramming to a cancer stem cell phenotype. Cell Stem Cell 4(4):336-47, 2009

Gajewski TF, Chesney J, Curriel TJ. Emerging strategies in regulatory T-cell immunotherapies. Clin Adv Hematol Oncol 7(1):1-10, 2009; quiz 11-2. Review.

Khan MI, Chesney JA, Laber DA, Miller DM. Digitalis, a targeted therapy for cancer? Am J Med Sci 337(5):355-9, 2009

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