Abstract
Targeted therapy against VEGF and mTOR pathways has been established as the standard-of-care for metastatic clear cell renal cell carcinoma (ccRCC); however, these treatments frequently fail and most patients become refractory requiring subsequent alternative therapeutic options. Therefore, development of innovative and effective treatments is imperative. About 80%-90% of ccRCC tumors express an inactive mutant form of the von Hippel-Lindau protein (pVHL), an E3 ubiquitin ligase that promotes target protein degradation. Strong genetic and experimental evidence supports the correlate that pVHL functional loss leads to the accumulation of the transcription factor hypoxia-inducible factor 2α (HIF2α) and that an overabundance of HIF2α functions as a tumorigenic driver of ccRCC. In this report, we describe an RNAi therapeutic for HIF2α that utilizes a targeting ligand that selectively binds to integrins αvβ3 and αvβ5 frequently overexpressed in ccRCC. We demonstrate that functional delivery of a HIF2α-specific RNAi trigger resulted in HIF2α gene silencing and subsequent tumor growth inhibition and degeneration in an established orthotopic ccRCC xenograft model. Mol Cancer Ther; 17(1); 140-9. ©2017 AACR.
Highlights
Promising targeted treatment options derived from better understanding of molecular characteristics of cancer biology have resulted in significant improvement in the overall survival of patients with metastatic clear cell renal cell carcinoma
The protease cleavable masking reagents were developed to provide the dynamic polyconjugates (DPC) with longer systemic circulation time compared to the pH-labile maleic anhydride (CDM) masking chemistry used in first-generation DPC [29, 37]
For targeting tissue outside of the liver, longer circulation times are necessary for targeting receptors that are likely less abundant and potentially less efficient than the Ashwell-asialoglycoprotein receptors (ASGPr) expressed on hepatocytes [30, 38]
Summary
Promising targeted treatment options derived from better understanding of molecular characteristics of cancer biology have resulted in significant improvement in the overall survival of patients with metastatic clear cell renal cell carcinoma (ccRCC). These treatments include therapies that target molecules regulating angiogenesis and proliferation pathways such as bevacizumab, an antibody against VEGF, and several multikinase inhibitors that inhibit multiple receptor tyrosine kinases including VEGFR [1,2,3].
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