Controlled Inhibition of the Glycolytic Pathway for Lung Cancer-Targeted Therapy

Lung tumors take up 10-fold more glucose than adjacent normal tissues in vivo and oncogenic proteins converge on glycolysis by activating the 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatases (PFKFB) to produce fructose-2,6-bisphosphate, an allosteric activator of 6-phosphofructo-1-kinase (PFK1). Although there are four PFKFB family members, PFKFB3 is activated in human lung cancer cell lines and required for the growth of lung xenograft tumors in mice. We recently reported the computational identification of a small molecule antagonist of PFKFB3, 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO), which suppresses glycolysis, is selectively cytostatic to lung cancer cells relative to normal epithelial cells, and reduces the growth of established lung tumors in vivo. Although these data support the development of optimized derivatives and formulations of 3PO as chemotherapeutic agents, 3PO has limited bioavailability, including poor water-solubility and short plasma retention time. Our initial exploration has proven that block copolymer micelles (BCM) may be a drug nanocarrier platform «100 nm) suitable for the delivery of 3PO. In preliminary studies, we demonstrate that block copolymer micelles (BCM) with poly(ethylene glycol)-poly(amino acids) possessing either methyl sulfoxide moieties or butyric acid linkers markedly improved the solubility of 3PO in aqueous solutions and decreased the anchorage-independent growth of lung cancer cells as soft agar colonies. We have previously demonstrated that BCMs can achieve prolonged plasma retention time, tumorspecific accumulation, in vivo stimuli-responsive release, reduced systemic toxicity, and enhanced therapeutic efficacy of other cytotoxic agents. We now propose to test the hypothesis that the BCM formulations of 3PO will significantly improve bioavailability and reduce toxicity while causing regressions of lung adenocarcinomas in vivo. We anticipate that the results to be generated in this proposed project should facilitate dosage formulation design, GMP/NSF production, and pre-clinical pharmacokinetic and toxicity studies needed for an INO application and phase I clinical trial of BCM formulated 3PO in advanced lung cancer patients.