DEPARTMENT OF PATHOLOGY

David Cheresh, Ph.D.

David Cheresh, Ph.D.

  • Distinguished Professor
  • Vice-Chair for Research and Development, Department of Pathology
  • Associate Director, Institute of Engineering in Medicine (IEM)
  • Associate Director for Innovation and Industry Alliances, Moores Cancer Center
  • Ph.D. - University of Miami, 1982

Research Interests

A major goal of Dr. Cheresh’s research is to understand the molecular mechanisms promoting angiogenesis as well as tumor progression, and metastasis in order to develop novel therapeutics for cancer. His laboratory efforts have led to the understanding of how growth factors, growth factor receptors, and integrins drive signaling pathways leading to tumor cell invasion, migration, proliferation, and survival. Dr. Cheresh has helped to delineate how these processes are regulated at the molecular level, and we have identified downstream signaling events that play a critical role. These studies have led to the development of integrin antagonists as novel therapeutics for cancer treatment that function to suppress the growth of angiogenic blood vessels (1). Two drugs that have developed from his work include Vitaxin (Abegrin), a humanized monoclonal antibody that targets αvβ3, and Cilengitide, a cyclic peptide antagonist of integrins αvβ3 and αvβ5 (2).  Both of these drugs have shown clinical activity in cancer patients in Phase II trials. David Cheresh was the scientific founder of TargeGen Inc. which has developed a selective JAK2 inhibitor recently shown to have met its primary endpoint in a Phase III registration trial for patient with myeloproliferative disease.  Most recently, the Cheresh laboratory identified a pathway of drug resistance leading to the development of cancer stem cells.  Integrin αvβ3 was identified as a marker and driver of both resistance and stemness based on its ability to potentiate KRAS activation of NFκB (3). These drug resistant tumor stem cells are highly metastatic but can be treated by targeting the NFκB with existing drugs such as Velcade or Revlimid.  Clinical trials will soon get underway to investigate whether targeting the NFκB pathway in drug resistant cancer patients can reverse drug resistance, stemness and thereby suppress the metastatic properties of these tumors. Early in his career working closely with Dr. Ralph Reisfeld, Dr. Cheresh developed antibodies to tumor antigens and used these as both research tools and potential therapeutics.  Among the antibodies he developed was one specific for the oligosaccharide portion of the GD2 ganglioside, expressed on tumors of neuroectoderm origin (4).  This antibody was later humanized (named Unituxin) and tested clinically for its activity in patients with advanced neuroblastoma.  Unituxin produced a significant survival benefit in a phase III registration trial and in March of 2015 was approved by the FDA as a front line therapy for patients with advanced neuroblastoma. 

Representative Publications

  1. Hood, JD, Bednarski, M, Frausto, R, Guccione, S, Reisfeld, RA, Xiang, R. & Cheresh DA.  Tumor regression by targeted gene delivery to the neovasculature.  Science 296:2404-7, 2002
  2. Alavi, A, Hood, JD, Frausto, R, Stupack, DG. & Cheresh DA. Role of Raf in vascular protection from distinct apoptotic stimuli.  Science 301:94-6, 2003
  3. Weis, SM. & Cheresh DA.  Pathophysiological consequences of VEGF-induced vascular permeability. Nature 437:497-504, 2005
  4. Stupack, DG, Teitz, T, Potter, M, Mikolon, D, Kidd, VJ, Lahti, JM. & Cheresh DA.  Potentiation of neuroblastoma metastasis by loss of caspase 8. Nature 439:95-9, 2006 
  5. Stockmann, C, Doedens, A, Weidemann, A, Zhang, N, Takeda, N, Greenberg, JI, Cheresh DA. & Johnson, RS. Deletion of vascular endothelial growth factor in myeloid cells accelerates tumorigenesis.  Nature 456: 814-9, PMC3103772, 2008
  6. Greenberg, JI, Shields, DJ, Barillas, SG, Acevedo, LM, Murphy, E, Huang, J, Scheppke, E, Stockmann, C, Johnson, RS, Angle, N. & Cheresh DA. A role for VEGF as a negative regulator of pericyte function and vessel maturation. Nature 456: 809-13, PMC2605188, 2008
  7. Desgrosellier, JS, Barnes, LA, Shields, DJ, Huang, M, Lau, SK, Prévost, N, Tarin, D, Shattil, SJ. & Cheresh DA. Integrin αvβ3/c-src “Oncogenic Unit” Promotes Anchorage-independence and Tumor Progression. Nature Medicine 15:1163-1169, PMC2759406, 2009
  8. Anand, S, Majeti, BK, Acevedo, LM, Murphy, EA, Mukthavaram, R, Scheppke, L, Huang, M, Shields, DJ, Lindquist, JN, Lapinski, PE, King, PD, Weis, SM. & Cheresh, D A.  MicroRNA-132 mediated loss of p120RasGAP activates endothelium to facilitate pathological angiogenesis. Nature Medicine 6:909-14, PMC3094020, 2010
  9. Mielgo, A, Seguin, L, Huang, M, Camargo, MF, Anand, S, Franovic, A, Weis, SM, Advani, SJ, Murphy, E. and Cheresh, DA. A MEK-independent role for CRAF in mitosis and tumor progression. Nature Medicine 17(12): 1641-1645, PMC3233644, 2011
  10. Seguin, L, Kato, S, Franovic, A, Camargo, MF, Lesperance, J, Elliott, K, Yebra, M, Mielgo, A, Lowy, AM, Husain, H, Cascone, T, Diao, L, Wang, J, Wistuba, I, Heymach, JV, Lippman, SM, Desgrosellier, JS, Anand, S, Weis, SM. & Cheresh, DA. A β3 integrin-KRAS-RalB complex drives tumor stemness and resistance to EGFR inhibition. Nat Cell Biol 16, 457-468, 2014
  11. Desgrosellier, JS, Lesperance, J, Seguin, L, Gozo, M, Kato, S, Franovic, A, Yebra, M, Shattil, SJ and Cheresh, DA. Integrin αvβ3 drives slug activation and stemness in the pregnant and neoplastic mammary gland. Developmental Cell 30:3, 295-308, PMC4147869, 2014
  12. Advani, SJ, Camargo, MF, Seguin, L, Mielgo, A, Anand, S, Hicks, A.M, Aguilera, J, Franovic, A,  Weis, SM, and Cheresh DA. Kinase-independent role for CRAF drives tumor radioresistance via CHK2. Nat Commun 6:8154, PMC4559870, 2015

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Biography

Dr. Cheresh is Professor and Vice Chairman of Pathology at Moores UCSD Cancer Center, University of California, San Diego. Prior to relocating his laboratory in 2005, Dr. Cheresh was a professor in the Departments of Immunology and Vascular Biology at The Scripps Research Institute, focusing on the role of adhesion receptors and growth factors in the angiogenesis of tumors.

Dr. Cheresh received his doctorate in Immunology from the University of Miami in Florida. In 1982 he joined The Scripps Research Institute as a postdoctoral fellow in the Department of Immunology. He was promoted to Assistant Professor in 1985 and to Professor in the Departments of Immunology and Vascular Biology in 1996. Dr. Cheresh is the recipient of several awards including the 15th Hans Linder Memorial Lecture from the Weizmann Institute of Science in Rehovot, Israel, the XXIII Annual Myron Karon Memorial Lectureship from the University of Southern California, the Robert Flynn Professorship Award from Tufts University School of Medicine, and he was a recipient of The American Cancer Society Faculty Research Award and a Merit Award from the National Institutes of Health. He currently serves as Associate Editor for several major scientific journals and is on the advisory board of several others. He has been a member of the Pathobiochemistry Study Section of NIH, and currently is Chairman on the Scientific Advisory Board for the Keystone Symposia.

Dr. Cheresh continues to be a prolific researcher and scientist in the fields of cancer, vascular biology and angiogenesis. Dr. Cheresh also works with a number of firms developing angiogenesis-related drug therapies.

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