Due to their highly vascular nature and high level of vascular permeability factor or vascular endothelial growth factor (VPF/VEGF) expression, clear-cell renal cell carcinoma (RCC) patients show initial success with anti-VEGF therapy. Unfortunately, the majority of patients eventually develop a refractory response to anti-VEGF therapy over time. In this regard, we would like to develop unique treatment strategies for nonresponsive, highly aggressive tumor types to overcome the current clinical challenges. Concurrently, we would like to understand the molecular mechanism of these untreatable tumor types by utilizing patient samples and also using different genetic approaches. We postulate that the proposed experimental plan will be helpful to design new treatment options for lasting anti-angiogenic effects and better clinical management. In addition, we will work on sarcomatoid variant renal cell carcinoma (sRCC), a spindle cell phenotype with a poor prognosis due to a modest or non-response to systemic therapy. To address our objectives, we have developed the following Specific Aims.
Aim 1 will examine whether tumor cell targeted inhibition of VEGF and NRP-1 expression by using novel U1 Adaptor can block metastasis and overall tumor growth and override the anti-VEGF refractory phenotype.
Aim 2 will examine whether we can override anti-VEGF resistance by using a VEGFR3 blocking antibody in a preclinical model. We will also evaluate whether ecto-domain of PDGFRB can override vascular remodeling due to anti-angigenesis resistance and in combination with the VEGFR3 antibody will be more effective in the preclinical setting. Finally, Aim 3 will focus on developing customized therapy against sRCC by utilizing U1 Adaptor-mediated targeting agents and we will also validate some of the data using patient samples. Overall, the proposed experiments will provide new and important information on the mechanisms of carcinogenesis and suggest new targets for intervention in anti-VEGF therapy resistant cRCC and sRCC.

Public Health Relevance

Based upon our previous studies as well as that of others, therapy against the most potent angiogenesis factor, namely VEGF, is now the first line of treatment for patients afflicted with advanced vascular cancers including clear cell renal cell carcinoma (cRCC). However, the overall clinical outcome is not encouraging due to the eventual development of resistance against the anti-VEGF therapy. During this current grant cycle, we have proposed experiments to overcome this clinical problem by developing new treatment strategies. We hope the outcome of our studies will shed new light on the mechanisms of carcinogenesis, address the current clinical challenges, and increase patient survival.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA078383-21
Application #
9633921
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Alley, Michael C
Project Start
1998-08-11
Project End
2020-01-31
Budget Start
2019-02-01
Budget End
2020-01-31
Support Year
21
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Mayo Clinic Jacksonville
Department
Type
DUNS #
153223151
City
Jacksonville
State
FL
Country
United States
Zip Code
32224
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