Inhibition of Tumor Growth in an Orthotopic Model of Invasive Pancreatic Cancer: A Novel Molecular Pathway Inhibitor

Abstract

In the United States, pancreatic cancer is the fourth leading cause of cancer‐related fatalities and is predicted to increase to number two by 2030. Despite the prevalence, therapeutic options for pancreatic cancer are still limited to surgery and/or combinations of chemotherapy and radiotherapy. Pancreatic ductal adenocarcinoma (PDAC) tumors are the most common and aggressive form of pancreatic cancer and comprise >90% of all pancreatic cancer. The standard systemic chemotherapy for PDAC is gemcitabine with other cytotoxic agents (i.e., paclitaxel), but this treatment only marginally extends a patient's survival rate for < 1 year and has proven to be ineffective. The development of new therapeutic approaches for PDAC is urgently needed. The goal of our work is to characterize a small molecule that suppresses pancreatic cancer progression and develop a drug candidate for pancreatic cancer. Herein, we report a novel small molecule that potently inhibits PDAC tumor growth based on the results from in vitro molecular target and mechanism validation, pharmaceutical characterization and in vivo xenograft studies. Compound 1 very potently induced apoptosis and suppressed PDAC cell proliferation in a variety of PDAC cell types (i.e., LM‐P (a murine PDAC cell line developed by Dr. Andy Lowy at UCSD), MIA PaCa‐2, BxPC‐3) and patient‐derived PDAC cells. In the mechanism of action, lead compound 1 functioned by selectively destabilizing microtubule polymerization as well as activating DNA damage and multiple apoptotic pathways. Moreover, in the presence of lead compound 1, gemcitabine and/or paclitaxel showed enhanced potency to inhibit cellular proliferation of several typical PDAC cells (i.e., LM‐P, MIA PaCa‐2, BxPC‐3). Lead compound 1 is a non‐toxic, pharmaceutically suitable, drug‐like compound with excellent physiochemical properties. Acute administration of compound 1 to mice (1000 mg/kg, 24 h end point) or chronic administration (20 mg/kg/day, 28 days) did not show any abnormal serum clinical chemical values or abnormal pathology. Pharmacokinetic studies showed that compound 1 possessed acceptable bioavailability. An in vivo orthotopic mouse xenograft study using invasive murine PDAC cells (LM‐P) showed that lead compound 1 (20 mg/kg/day, 28 days, i.p.) inhibited pancreatic tumor growth 60% compared to vehicle‐treated mice (at day 29) without any apparent acute or chronic toxicity. Lead compound 1 represents a novel, non‐toxic agent that uses a distinct mechanism of action to treat PDAC. Use of 1 in PDAC therapy is an innovative strategy that will mitigate against unwanted toxic effects otherwise encountered by pancreatic cancer chemotherapeutics.