OPPC targeting to improve pancreatic cancer treatment

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DESCRIPTION (provided by applicant): Therapeutic strategies to attack common metabolic aberrations in cancer are appealing because of their potentially broad applications. It is widely appreciated that glycolysis is activated in cancer, but it is much less known that the same is true for the oxidative pentose phosphate cycle (OPPC), a fork in the glycolysis pathway downstream of hexokinase. OPPC is responsible for generating much of the NADPH reducing activity for which cancer cells have an especially acute need, relative to normal cells. At the level of NADPH generation, there has been considerable cell biochemical research into its role in glutathione reduction where some experimental therapeutic investigations have been focused. However, there has been little study of the effects of selectively reducing NADPH actions themselves in cancer cells for therapeutic benefit. In part, this gap reflects the lack of a cancer selective probe that can achieve this end, which we address in this pilot project. All cancers including pancreatic cancers have an acute need for NADPH to sustain unregulated growth and survival in the highly oxidative stressed microenvironments found in solid tumors. However, in vivo studies have been relatively lacking, including to develop a usable chemical probe or to evaluate direct or cooperative antitumor effects of NADPH depletion. These questions define both a key gap in knowledge of cancer cell metabolism and a novel therapeutic opportunity: hypoxic, glucose starved regions of tumors are well known to be resistant to cytotoxic therapy, where selective attenuation of NADPH seems likely to kill. In this pilot project, we will evaluate novel chemical probe, Hypoxin, which has drug-like properties suitable for in vivo evaluation. NADPH is crucial to sustain glutathione levels required for cellular thiol homeostasis and cell survival. Hypoxin is a disulfide compound comprised of a dimeric form of the existing generic drug Tiopronin, which is presently approved to treat cystinuria in clinic. While simple, this compound is a novel structure of matter that represents patentable intellectual property. Under normal glucose and normoxidative conditions (i.e., normal tissue microenvironment), Hypoxin is metabolized to Tiopronin, the clinical pharmacological properties of which are well known and benign. Under hypoxic, low glucose conditions (i.e. hypoxic tumor microenvironment), Hypoxin is predicted to elicit cell death by competing for an NADPH-driven network of adaptive mechanisms needed for the survival of metabolically stressed cancer cells. The prediction that the cytotoxicity of Hypoxin relies on a glucose-deficient state will be tested in vitro and in vivoin pancreatic cancer cell lines and established human xenograft models of pancreatic cancer. This tightly focused project offers a high degree of innovation and clinical impact. Pilot studies will focus on a simple but innovative patent-protected drug candidate in Hypoxin that can selectively interfere with NADPH levels in pancreatic tumors that are typically resistant to chemotherapy. The work offers a low-risk/high-payoff prospect in terms of the opportunity it offers to advance basic knowledge of pancreatic cancer pathophysiology in the timely and rapidly emerging area of cancer metabolism, but also the potential to exploit this knowledge by clinical translation of a unique drug-like probe or derivative thereof. Therapeutic evaluation of the candidate drug in patients is a realistic possibility in a short time-frame, given intellectual property protection, ow cost of goods, and low-risk pharmacological and toxicological profiles expected based on compound engineering. In summary, this pilot project offers a high-innovation, high-impact opportunity to advance studies of a drug-like probe that could not only significantly affect fundamental knowledge of pancreatic tumor metabolism but also permit its rapid exploitation to improve therapy of this deadly disease in patients.