Inactivation of the VHL tumor suppressor gene is a common event in hereditary (VHL Disease) and non- hereditary clear cell renal carcinoma, which is the most common form of kidney cancer. The VHL gene product, pVHL, has many functions including acting as the substrate recognition component of an ubiquitin ligase complex that targets the alpha subunit of the heterodimeric transcription factor HIF for destruction. Genotype-phenotype correlations and preclinical models suggest that downregulation of HIF2a is both necessary and sufficient for pVHL to suppress renal carcinoma growth, thus validating HIF2a as a potential therapeutic target in this disease. Unfortunately, transcription factors such as HIF2a are historically difficult to inhibit with drug-like small organic molecules. As an alternative, we propose to inhibit HIF2a using siRNA. Recent studies suggest that siRNA can be effectively delivered in vivo when incorporated within nanoparticles targeted to the transferrin receptor.
In specific aims 1 and 2 we will test whether this technology can be used to downregulate HIF2a in VHL-/- renal carcinoma lines grown orthotopically in nude mice and we will attempt to develop pharmacodynamic markers suitable for preclinical and clinical studies.
In Aim 3 we will measure HIF2a and transferrin receptor levels in human kidney cancer samples to assess their relationship to each other and VHL loss, the influence of acquired resistance to VEGFR blockade on their expression, as well as their prognostic significance and ability to predict benefit to standard therapies. Finally, in Aim 4 we proposed an investigator initiated follow-on Phase lb trial to a Phase I industry sponsored "first in man" Phase I trial of HIF2a siRNA-containing nanoparticles. This Phase lb trial will be performed in a population of patients with advanced clear cell RCC selected based on tumor HIF2a expression and other factors identified in Aims 2 and 3 and will include correlative pharmacodynamic endpoints modeled after those developed in Aim 2. Taken together, this work, which clearly goes from bench-to-bedside, should establish the safety and therapeutic potential for targeting this critical etiologic factor in VHL -/- clear cell RCC using transferrin-targeted, siRNA-containing nanoparticle technology and lay the groundwork for future clinical development of this potentially exciting approach in patients with this disease. If successful, this trial would also have implications for other forms of cancer that are driven by "undruggable" oncoproteins.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA101942-10
Application #
8517016
Study Section
Special Emphasis Panel (ZCA1-RPRB-7)
Project Start
Project End
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
10
Fiscal Year
2013
Total Cost
$254,796
Indirect Cost
$57,408
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
McDermott, David F; Cheng, Su-Chun; Signoretti, Sabina et al. (2015) The high-dose aldesleukin "select" trial: a trial to prospectively validate predictive models of response to treatment in patients with metastatic renal cell carcinoma. Clin Cancer Res 21:561-8
Zerbini, Luiz Fernando; Bhasin, Manoj K; de Vasconcellos, Jaira F et al. (2014) Computational repositioning and preclinical validation of pentamidine for renal cell cancer. Mol Cancer Ther 13:1929-41
Akhavanfard, Sara; Vargas, Sara O; Han, Moonjoo et al. (2014) Inactivation of the tumor suppressor WTX in a subset of pediatric tumors. Genes Chromosomes Cancer 53:67-77
Bhatt, Rupal S; Atkins, Michael B (2014) Molecular pathways: can activin-like kinase pathway inhibition enhance the limited efficacy of VEGF inhibitors? Clin Cancer Res 20:2838-45
Choueiri, T K; Fay, A P; Gray, K P et al. (2014) PD-L1 expression in nonclear-cell renal cell carcinoma. Ann Oncol 25:2178-84
Panka, David J; Buchbinder, Elizabeth; Giobbie-Hurder, Anita et al. (2014) Clinical utility of a blood-based BRAF(V600E) mutation assay in melanoma. Mol Cancer Ther 13:3210-8
Gubin, Matthew M; Zhang, Xiuli; Schuster, Heiko et al. (2014) Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens. Nature 515:577-81
Wang, Xiaoen; Bullock, Andrea J; Zhang, Liang et al. (2014) The role of angiopoietins as potential therapeutic targets in renal cell carcinoma. Transl Oncol 7:188-95
Davis, Caleb F; Ricketts, Christopher J; Wang, Min et al. (2014) The somatic genomic landscape of chromophobe renal cell carcinoma. Cancer Cell 26:319-30
Choueiri, Toni K; Je, Youjin; Cho, Eunyoung (2014) Analgesic use and the risk of kidney cancer: a meta-analysis of epidemiologic studies. Int J Cancer 134:384-96

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