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, effective, small molecule-based cancer therapies. This proposal seeks to undertake further clinical development of a novel targeted agent, PX-12. 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 in cancer cells. Trx-q causes an increase in HIF-1 alpha transactivating activity and expression of VEGF as well as HIF-1 alpha straining and angiogenesis in experimental tumors in vivo. 2) The expression of Trx-1 is increased in many human primary tumors where it is associated with aggressive tumor growth and decreased patient survivial. 3) Pancreatic tumors are highly hypoxic and express both high levels of HIF and Trx. 4) The small molecule, PX-12 is a potent inhibitor of Trx-1 and the hypoxia induced increase of HIF-1 alpha in a solid tumors. 5) A Phase 1 clinical trial has shown that administration of PX-12 via an i.v. infusion is well tolerated by cancer patients and decreases Trx-1 up to 50-80%. 6) Efficacy, defined as tumor reduction or stable disease, was seen in 7 of 32 advanced metastatic patients treated with PX-12. 7) Trx lowering >25% over a 21 day period (1 cycle) was significantly correlated to increased patient survival. The hypothesis upon which the study is based is that PX-12 is an effective inhibitor of Trx-1, HIF-1 alpha and tumor angiogenesis, with low patient toxicities and good efficacy in Phase 1 clinical trial. Pancreatic cancer, because of its high Trx-1 and HIF-1 alpha levels and angiogenic character is an ideal tumor in which to test the disease specific activity of PX-12. The objectives of this SBIR renewal by ProIX Pharmaceuticals are to: 1) study the efficacy of PX-12 against pancreatic cancer in patients who have failed a single round of gemcitabine therapy and 2) to determine whether PX-12 inhibition of Trx translates a modification in tumor blood flow(angiogenesis). ? ?
|Ramanathan, Ramesh K; Abbruzzese, James; Dragovich, Tomislav et al. (2011) A randomized phase II study of PX-12, an inhibitor of thioredoxin in patients with advanced cancer of the pancreas following progression after a gemcitabine-containing combination. Cancer Chemother Pharmacol 67:503-9|