A combination of cytotoxic chemotherapeutic drugs, such as gemcitabine and cisplatin (GC), is part of the standard of care for advanced bladder cancer. Neoadjuvant GC treatment can induce complete remission (no evidence of viable cancer cells), but less than 40% of patients respond and the regimen is toxic. Thus, there remains an unmet medical need to develop less toxic and more effective chemotherapy options for bladder cancer. We are developing an orally bioavailable drug candidate called PTUPB which has such properties. The compound has anti-inflammatory and anti-angiogenic mechanisms of action as demonstrated in several rodent models of metabolic syndrome and cancer. PTUPB potentiates cisplatin and GC efficacy in a bladder cancer mouse PDX models. We 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 xenograft (PDX) mouse model of bladder cancer. Progression free and overall survival will be assessed along with pharmacokinetic profiling, blood panels and histology assessment of selected tissues.
Public Health Relevance Statement: Project Narrative The gemcitabine and cisplatin (GC) regimen is a commonly used first line treatment for advanced bladder cancer that can induce a complete pathological response in some patients. However, less than half of patients respond and toxicity, such as renal damage, is problematic. We are developing a potential new drug, called PTUPB, which is part of a new class of molecules that inhibits two inflammation-related pathways to result in substantial antitumor activity while being organ protective. We propose to demonstrate the feasibility of treating bladder cancer with PTUPB, either as a single agent or in combination with GC therapy using mouse models of human bladder cancer.
Project Terms: angiogenesis; Angiogenesis Inhibition; Animal Model; Anti-inflammatory; Arachidonic Acids; Bilirubin; Bioavailable; Biochemistry; Bladder; Bladder Neoplasm; Blood; Blood Cell Count; cancer cell; Cancer Patient; cell type; Chemosensitization; chemotherapy; Chemotherapy-Oncologic Procedure; Chronic; Cisplatin; Clinical; Combined Modality Therapy; Complex; Control Groups; Creatinine; cyclooxygenase 2; Cytochrome P450; cytotoxic; Cytotoxic Chemotherapy; Data; Disease remission; DNA Modification Process; Dose; drug candidate; drug development; Drug Kinetics; drug metabolism; Enzymes; Epoxide hydrolase; gemcitabine; Goals; Growth; Hepatotoxicity; Histology; Human; human model; in vivo; Inflammation; Lead; Liver Microsomes; Malignant neoplasm of urinary bladder; Malignant Neoplasms; Measures; Medical; Metabolic syndrome; Metabolism; mouse model; Mus; Neoadjuvant Therapy; Neoplasm Metastasis; nephrotoxicity; novel therapeutics; Oral; Oral Administration; Organ; pain reduction; Pathologic; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phosphotransferases; Plasma; Play; pre-clinical; preclinical safety; preclinical toxicity; Property; Proto-Oncogene Proteins c-akt; PTGS2 gene; Regimen; renal damage; response; Rodent Model; Role; Signal Pathway; Signal Transduction; Small Business Innovation Research Grant; Solid Neoplasm; standard of care; Testing; Tissues; Toxic effect; treatment group; Treatment-related toxicity; tumor; tumor growth; tumor xenograft; Tumor-Derived; Vascular Endothelial Growth Factors; Work; Xenograft Model; Xenograft procedure
