The AACR Judah Folkman Career Development Award for Anti-Angiogenesis Research is open to junior faculty who completed postdoctoral studies or clinical fellowships no more than three years prior to the start of the grant term; who are in their first full-time, faculty appointment and hold the title of instructor, research assistant professor, assistant professor or an equivalent full-time faculty appointment; and who are at an academic, medical or research Institution. Research projects are restricted to basic, clinical, translational or epidemiological projects that substantially advance the field of anti-angiogenesis research in cancer.
Richard W. Joseph, M.D.
Senior Associate Consultant, Mayo Clinic, Jacksonville, FL
The Relationship of Angiogenesis and Immune Evasion in Renal Cell Carcinoma
"One of the primary mechanisms by which clear cell renal cell carcinoma (ccRCC) metastasize and proliferate is through increased angiogenesis through the loss of function of the tumor suppressor protein, Von Hippel Lindau (VHL), which in turns leads to upregulation of hypoxia induced factor 1 alpha (HIF1?) and activation of the vascular endothelial growth factor (VEGF) pathway. While the majority (~80 percent) of patients with ccRCC have loss of VHL and activated VEGF pathways, anti-VEGF therapies are marginally effective producing responses in only ~30-40 percent of patients and even in those that do respond, resistance invariably develops. The lack of consistent benefit to anti-VEGF therapies implies that ccRCC is molecularly heterogeneous and that additional pathways must be targeted. A second pathway by which ccRCC metastasize and proliferate is through tumor induced immune evasion. A prominent mechanism by which ccRCC evade immune surveillance is through tumor expression of programmed death ligand one (PDL1) present on ~65 percent of ccRCC. When bound to PD1 present on activated T cells, PDL1 inactivates and causes apoptosis of the T cells. A new class of targeted immunotherapy inhibiting the PDL1/PD1 interaction has demonstrated marked clinical activity with responses appearing to be related to tumor PDL1 expression. While much is known individually about angiogenesis and immune evasion in ccRCC, there is a lack of information on how these two pathways interact with each other. Our preliminary data in ccRCC patient samples demonstrates an inverse relationship between VEGF receptors (VEGFR) and PDL1 expression suggesting that least two phenotypes of ccRCC may exist: immune evasive and angiogenic. Our goal in this project is to further explore the relationship between the VEGF pathway and PDL1 expression in primary and metastatic ccRCC tissue with downstream goals to use these phenotypes to design trials for patients with ccRCC in the adjuvant and metastatic setting."
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