Research Project
6879258
DESCRIPTION (provided by applicant): One in every four deaths in the US is due to cancer. The overall cancer drug market exceeds $2 billion in the USA. There is significant need to identify novel and selective small molecule-based cancer therapies. This proposal seeks to undertake preclinical evaluation of a novel clinical candidate that targets the thioredoxin reductase enzyme, for the eventual use of this agent as a therapy against solid tumor cancers. ProIX Pharmaceuticals has demonstrated there is strong evidence for the following: 1) The redox protein thioredoxin-1 (Trx-1) is necessary for the hypoxia-induced increase in HIF-1 alpha, a critical regulator of increased angiogenesis and decreased apoptosis in solid tumors. 2) Trx-1 causes an increase in HIF-1 alpha transactivating activity and expression of VEGF as well as HIF-1 alpha staining and angiogenesis in experimental tumors in vivo. 3) The expression of Trx-1 is increased in many human primary tumors where it is associated with aggressive tumor growth and decreased patient survival. 4) Trx-1 is reduced by NADPH in the presence of the flavoprotein thioredoxin reductase (TR). 5) The fungal metabolite pleurotin is a potent inhibitor of TR and also inhibits the hypoxia induced increase of HIF-1 alpha in cancer of cell lines and xenografts. Preliminary results show that pleurotin has anti-tumor activity in spontaneous and tumor xenograft models. The objectives of this Phase I study to be conducted by ProIX Pharmaceuticals are: 1) to determine whether inhibition of TR translates to provide anti-tumor activity in vivo; 2) to determine whether the anti-tumor activity is accompanied by decreased HIF-1 alpha and VEGF production in vivo; 3) to identify the optimal dosing and scheduling of pleurotin and determine the pharmacokinetic profile of the agent. The results of this application are anticipated to lead to a Phase II application that will undertake the pre-clinical toxicological and pharmaceutical development of pluerotin as a TR inhibitor and anti-cancer drug. ProIX has the exclusive license to develop this agent as an anti-cancer drug.
