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 #
5P50CA101942-09
Application #
8381282
Study Section
Special Emphasis Panel (ZCA1-RPRB-7)
Project Start
Project End
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
9
Fiscal Year
2012
Total Cost
$274,039
Indirect Cost
$61,762
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
De Velasco, Guillermo; Je, Youjin; Bossé, Dominick et al. (2017) Comprehensive Meta-analysis of Key Immune-Related Adverse Events from CTLA-4 and PD-1/PD-L1 Inhibitors in Cancer Patients. Cancer Immunol Res 5:312-318
Carey, Christopher D; Gusenleitner, Daniel; Lipschitz, Mikel et al. (2017) Topological analysis reveals a PD-L1-associated microenvironmental niche for Reed-Sternberg cells in Hodgkin lymphoma. Blood 130:2420-2430
Kansy, Benjamin A; Concha-Benavente, Fernando; Srivastava, Raghvendra M et al. (2017) PD-1 Status in CD8+ T Cells Associates with Survival and Anti-PD-1 Therapeutic Outcomes in Head and Neck Cancer. Cancer Res 77:6353-6364
Juneja, Vikram R; McGuire, Kathleen A; Manguso, Robert T et al. (2017) PD-L1 on tumor cells is sufficient for immune evasion in immunogenic tumors and inhibits CD8 T cell cytotoxicity. J Exp Med 214:895-904
Ott, Patrick A; Hu, Zhuting; Keskin, Derin B et al. (2017) An immunogenic personal neoantigen vaccine for patients with melanoma. Nature 547:217-221
Zhang, Ying; Kurupati, Raj; Liu, Ling et al. (2017) Enhancing CD8+ T Cell Fatty Acid Catabolism within a Metabolically Challenging Tumor Microenvironment Increases the Efficacy of Melanoma Immunotherapy. Cancer Cell 32:377-391.e9
Abelin, Jennifer G; Keskin, Derin B; Sarkizova, Siranush et al. (2017) Mass Spectrometry Profiling of HLA-Associated Peptidomes in Mono-allelic Cells Enables More Accurate Epitope Prediction. Immunity 46:315-326
Zhang, Yiqun; Kwok-Shing Ng, Patrick; Kucherlapati, Melanie et al. (2017) A Pan-Cancer Proteogenomic Atlas of PI3K/AKT/mTOR Pathway Alterations. Cancer Cell 31:820-832.e3
Zhou, Jun; Mahoney, Kathleen M; Giobbie-Hurder, Anita et al. (2017) Soluble PD-L1 as a Biomarker in Malignant Melanoma Treated with Checkpoint Blockade. Cancer Immunol Res 5:480-492
Akbay, Esra A; Koyama, Shohei; Liu, Yan et al. (2017) Interleukin-17A Promotes Lung Tumor Progression through Neutrophil Attraction to Tumor Sites and Mediating Resistance to PD-1 Blockade. J Thorac Oncol 12:1268-1279

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