Development of an inhibitor of VEGF expression

DESCRIPTION (provided by applicant): Up-regulation of vascular endothelial growth factor (VEGF), a key factor for angiogenesis, is an important contributor to the pathogenesis of cancer. The abundance of VEGF is in large part controlled at the posttranscriptional levels by sequences in both the 5'- and 3'-untranslated regions (UTRs) of its mRNA. The 5'- UTR contains an internal ribosomal entry site (IRES) that mediates a unique, cap-independent mode of translation initiation. Under hypoxic conditions, cap-dependent translation is dramatically impaired and the translation of the VEGF mRNA occurs through its cap-independent IRES. Thus, even under severe hypoxic conditions, cells are capable of producing large amounts of VEGF resulting in angiogenesis to support further tumor growth. Using PTC's proprietary technology platforms, we have successfully identified a compound that selectively and potently inhibits the expression of VEGF post transcriptionally. In the Phase I of this grant, we proposed to (1) characterize the UTR-selectivity of these compounds, (2) perform medicinal chemistry lead optimization to improve potency, selectivity, and pharmaceutical properties, and (3) establish a pharmacodynamic assay to measure in vivo efficacy. We exceeded these goals, and have identified a compound that is potent, seletive, and orally active in vivo. Here, in Phase II, we propose the following: (1) Conduct efficacy studies in a number of tumor models to establish the spectra of tumor types, optimal dosing regimens, and combination therapies utilizing this agent. Efficacy and combination studies will focus on the following five indications: soft tissue fibrosarcom; glioblastoma; hormone sensitive breast cancer; gastric cancer; and ovarian cancer. (2) Conduct ADME studies and toxicology of the lead compound to enable and design the clinical trials. These studies will include both non-GLP as well as IND-enabling GLP studies. (3) CMC, (4) Further elucidate the mechanism of action, and (5) Preparationion and submission of IND to initiate Phase I trials establishing safety and proof-of-concept in humans.