Bladder cancer chemotherapy potentiation with a multiprong arachidonic acid pathway modulator

Abstract A combination of cytotoxic chemotherapeutic drugssuch as gemcitabine and cisplatinGCis part of the standard of care for advanced bladder cancerNeoadjuvant GC treatment can induce complete remissionno evidence of viable cancer cellsbut less thanof patients respond and the regimen is toxicThusthere remains an unmet medical need to develop less toxic and more effective chemotherapy options for bladder cancerWe are developing an orally bioavailable drug candidate called PTUPB which has such propertiesThe compound has anti inflammatory and anti angiogenic mechanisms of action as demonstrated in several rodent models of metabolic syndrome and cancerPTUPB potentiates cisplatin and GC efficacy in a bladder cancer mouse PDX modelsWe propose to extend this work to include determination of dose dependent PK and anti tumor activity and preliminary toxicity assessment for PTUPB as a single agent and in combination with GC therapy in an established patient derived xenograftPDXmouse model of bladder cancerProgression free and overall survival will be assessed along with pharmacokinetic profilingblood panels and histology assessment of selected tissues Project Narrative The gemcitabine and cisplatinGCregimen is a commonly used first line treatment for advanced bladder cancer that can induce a complete pathological response in some patientsHoweverless than half of patients respond and toxicitysuch as renal damageis problematicWe are developing a potential new drugcalled PTUPBwhich is part of a new class of molecules that inhibits two inflammation related pathways to result in substantial antitumor activity while being organ protectiveWe propose to demonstrate the feasibility of treating bladder cancer with PTUPBeither as a single agent or in combination with GC therapy using mouse models of human bladder cancer