Jason Chesney, M.D., Ph.D.

Education:

B.A., Anthropology, Summa Cum Laude, University of Minnnesota, 1987-1991
Ph.D., Biomedical Sciences, University of Minnesota Graduate School, 1993-1997
M.D., University of Minnesota Medical School, 1991-1998
Internship and Residency, Cornell University Medical College, 1998-2001
Residency, Memorial Sloan Kettering Cancer Center, 1998-2001
Board Certified, American Board of Internal Medicine, 2001-2011
Clinical Fellowship, Immunology, Cornell University Medical College, 2001-2002
Post-Graduate Clinical Training, Medical Oncology/Hematology, University of Louisville, 2003-2005

Curriculum Vitae

Current Positions:


Deputy Director
, J. Graham Brown Cancer Center, University of Louisville
Endowed Chair Professor, Depts. of Medicine (Hematology/Oncology), Biochemistry/Molecular Biology and Pharmacology/Toxicology
Director, J. Graham Brown Cancer Center Clinical Research Program and Biorepository
Chairman, Medical Oncology and Hematology Data and Safety Monitoring Committee

Contact Information:


brooke.degroote@louisville.edu

502-852-3679

Research Description:


Dr. Chesney's laboratory discovered that a regulator of glucose metabolism, 6-phosphofructo-2-kinase (PFKFB3), is over-expressed in leukemia and adenocarcinoma cells (1), required for de novo nucleic acid synthesis (1), increased in human solid tumors relative to adjacent normal tissues (2), and essential for Ras transformation and tumor growth in vivo (3), the activation of cyclin-dependent kinases (4, 5) and the estrogen-mediated survival of ER+ breast cancer cells (6). Working with Peter Carmeliet at the Katholieke Universiteit, his group recently observed that PFKFB3 also is required for angiogenesis and vessel sprouting (7, 8).  In 2008, Dr. Chesney reported with Dr. John Trent the discovery of the first PFKFB3 small molecule antagonist, 3PO – they found that this compound acutely suppressed the glucose metabolism of cancer cells but not normal epithelial cells and suppressed tumor growth in mice (9). Based on these studies, they developed a collaboration with an industry partner, Advanced Cancer Therapeutics, to screen synthetic derivatives of the parent compound (10). This effort led to the identification of a synthetic derivative of 3PO termed PFK158 that is currently undergoing evaluation by Dr. Rebecca Redman in a phase I trial (Phase 1 Safety Study of ACT-PFK-158, 2HCl in Patients With Advanced Solid Malignancies, clinicaltrials.gov #NCT02044861).  They are now testing the ability of PFK-158 to overcome the intrinsic and acquired resistance of cancer cells to multiple targeted, immunotherapeutic and radiation therapies including BRAF inhibitors for melanoma patients (vemurafenib), EGFR inhibitors for lung cancer patients (erlotinib), anti-estrogen agents for breast cancer patients (fulvestrant) and anti-CTLA4 antibodies for all types of cancer (ipilimumab).

Dr. Chesney's group has expanded their original studies on PFKFB3 to additional metabolic pathways and molecular targets in cancer.  For example, their research group has established that the oncogene Ras activates glycolytic flux into the TCA cycle in immortalized bronchial epithelial cells (11) and identified additional enzymes that are regulated by oncogenes and essential for activating aberrant metabolic pathways required for transformation including aspartate aminotransferase (12), choline kinase (13) and cytochrome c oxidase (14).  Importantly, they recently synthesized a novel choline kinase inhibitor that has anti-tumor activity without significant toxicity (15) and are currently optimizing this small molecule to improve potency and pharmacokinetic properties.

Dr. Chesney is funded by the National Cancer Institute, the Congressionally Directed Medical Research Program and the National Center for Research Resources as well as multiple pharmaceutical sponsors.  He serves as a reviewer on multiple National Cancer Institute subcommittees to evaluate Specialized Programs of Research Excellence (SPOREs), Tumor Cell Biology and P30-Designated Cancer Center grants. He has been named a Top Doctor by U.S. News and World Report for Solid Tumors and Clinical Trials and is the recipient of the Kentucky Derby Julep Scientist of the Year Award.

Learn about Dr. Chesney's clinical research programs.

Literature Cited:

  1. Chesney, J., Mitchell, R., Benigni, F., Bacher, M., Spiegel, L., Al-Abed, Y., Han, J. H., Metz, C., and Bucala, R.  An inducible gene for 6-phosphofructo-2-kinase (iPFK-2) with an AU-rich mRNA instability element:  Role in tumor cell glycolysis and the Warburg Effect.  Proc. Natl. Acad. Sci. USA 96(6):3047-3052, 1999.  PMID: 10077634
  2. Atsumi, T.*, Chesney, J.*, Metz, C., Leng, L., Donnelly, S., Makita, Z., Mitchell, R. and Bucala, R.  High expression of inducible 6-phosphofructo-2-kinase (iPFK-2; PFKFB3) in human cancers. Cancer Research 62 (20):5881-5887, 2002. (*authors contributed equally)  PMID: 12384552
  3. Telang S., Yalcin A., Clem A. L., Bucala R., Lane A. N., Eaton J. W.,Chesney J.   Ras transformation requires metabolic control by 6-phosphofructo-2-kinase.  Oncogene, 25(55): 7225-34, 2006. PMID: 16715124
  4. Yalcin, A, Clem, BF, Simmons, A, Lane, A, Nelson, K, Clem, A, Brock, E, Siow, D, Wattenburg, B, Telang, S, and Chesney J.   Nuclear targeting of 6-phosphofructo-2-kinase (PFKFB3) increases proliferation via cyclin-dependent kinases.  J Biol Chem, 284(36): 24223-32, 2009. PMID: 19473963
  5. Yalcin, A., Telang, S., Clem, A., O’Neal, J., Imbert-Fernandez, Y., Klarer, A., Clem, B. F., and Chesney, J. 6-Phosphofructo-2-Kinase (PFKFB3) Promotes Cell Cycle Progression and Suppresses Apoptosis via Cdk1-Mediated Phosphorylation of p27. Cell Death and Disease (Nature), 5, e1337, 2014.  PMID: 25032860
  6. Imbert-Fernandez  Y., Spaulding R., Lanceta L., Clem B.F., O’Neal J., Clem A., Telang S. and Chesney J.  Estradiol Stimulates Glucose Metabolism via 6-Phosphofructo-2-Kinase (PFKFB3). J Biol Chem, 289(13):9440-8, 2014. PMID: 24515104
  7. De Bock, K., Georgiadou, M., Schoors, S.,  Cauwenberghs, S., Cascante, M., Telang, S., De Berardinis, R., Schoonjans, L., Vinckier, S., Chesney, J., Ghesquière, B., Gerhardt, H., Dewerchin, M. & Carmeliet, P.  Role of PFKFB3-Driven Glycolysis in Vessel Sprouting.  Cell, 154: 651–663, 2013. PMID: 23911327
  8. Schoors S, De Bock K, Cantelmo AR, Georgiadou M, Ghesquière B, Cauwenberghs S, Kuchnio A, Wong BW, Quaegebeur A, Goveia J, Bifari F, Wang X, Blanco R, Tembuyser B, Cornelissen I, Bouché A, Vinckier S, Diaz-Moralli S, Gerhardt H, Telang S, Cascante M, Chesney J, Dewerchin M, Carmeliet P.  Partial and Transient Reduction of Glycolysis by PFKFB3 Blockade Reduces Pathological Angiogenesis.   Cell Metabolism, 19(1):37-48, 2014. PMID: 24332967 65.
  9. Clem, B., Telang, S., Clem, A., Yalcin, A., Meier, J., Simmons, A., Rasku, M., Dean, W., Trent, J.O., and Chesney J. Small molecule inhibition of 6-phosphofructo-2-kinase activity suppresses established tumor growth.  Molecular Cancer Therapeutics, 7(1):110-20, 2008. PMID: 18202014
  10. Clem, B.F., O’Neal, J., Tapolsky, G., Clem, A., Imbert-Fernandez, Y., Klarer, A. C, Redman, R., Trent, J.O., Telang, S. and Chesney, J. Targeting 6-phosphofructo-2-kinase (PFKFB3) as a therapeutic strategy against cancer. Molecular Cancer Therapeutics (AACR) 12(8), 1-10, 2013.  PMID: 23674815  Article selected for cover page of August 2013 Molecular Cancer Therapeutics Issue.
  11. Telang, S., Nelson, K., Lane, A., and Chesney J. The oncoprotein H-RasV12 increases mitochondrial metabolism.  Molecular Cancer, 6(1):77-83, 2007. PMID: 17598900
  12. Thornburg, J., Nelson, K., Clem, B. F., Lane, A., Arumugam, S., Simmons, A., Eaton, J. W., Telang, S. and Chesney J.  Targeting aspartate aminotransferase in breast cancer. Breast Cancer Research, 10:R84, 2008.  PMID: 18922152
  13. Yalcin, A, Clem, BF, Makoni, S, Clem, A, Nelson, K, Thornburg, J, Siow, D, Lane, AN, Brock, SE, Goswami, U, Eaton, JW, Telang, S, and Chesney J. Selective inhibition of choline kinase simultaneously attenuates MAPK and PI3K/AKT signaling. Oncogene 29(1):139-49, 2010. PMID: 19855431
  14. Telang, S., Nelson, K. K., Siow, D.L., Yalcin, A., Thornburg, J. M., Imbert-Fernandez, Y., Klarer, A. C., Farghaly, H., Clem, B. F., Eaton, J. W., and Chesney J.  Cytochrome c oxidase is activated by the oncoprotein Ras and is required for A549 lung adenocarcinoma growth.  Molecular Cancer, 11(1):60-72, 2012. PMID: 22917272
  15. Clem, B., Clem, A., Yalcin, A., Goswami, U., Arumugam, S., Telang, S., Trent, J., and Chesney J.  A novel small molecule antagonist of choline kinase- that simultaneously suppresses MAPK and PI3K/AKT signaling.  Oncogene, 30(30):3370-80, 2011. PMID: 21423211

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