Abstract 277: Gaining insights into pancreatic cancer intervention with bitter melon, a natural agent, in combination with gemcitabine using patient derived xenografts
Authors: Dhar Deepanshi , Kumar Dileep , Bagby Stacey , Pitts Todd M. , Messersmith Wells A. , Raina Komal , Agarwal Rajesh 
Published: August 2018

Pancreatic cancer (PanC) remains the 4th leading cause of cancer related-deaths in U.S. resulting in a dismal survival rate of &lt;5%. This generates a critical need for identifying novel non-toxic agents aimed at effective PanC management with minimal patient distress. Bitter melon (Momordica charantia), a dietary agent, is actively being examined for its anti-cancer efficacy against a panel of malignancies. Recent data from our group highlights the anti-PanC potential of bitter melon juice (BMJ); its role in PanC-cancer stem cell (CSC) self-renewal/ kinetics and gemcitabine (GEM) resistance in PanC cells. GEM is the standard of care drug used in PanC therapeutics but there has been a continual increase in GEM resistant PanC patients lately. In our current study, we determined the nature of combinations for BMJ (0.5- 2% v/v) and GEM (2- 25 μM) in vitro using 3 human PanC cell lines. Combination indices (CI) determined using Chou-Talalay method for BMJ and GEM were: PANC1 (no observed interaction), AsPC1 (CI=0.5-1, leaning towards synergism) and BxPC3 (CI=0.1-0.8, synergistic). Patient-derived xenografts (PDX) are gaining importance as representatives of the genomic complexities and interactions with tumor microenvironment like primary patient tumors, thereby contributing to accelerated therapeutic approaches. Subsequently, we focused on assessing the efficacy of BMJ alone, or in addition to GEM using the PanC-PDX mouse model. Treatment regimen had 4 cohorts: Controls (untreated); BMJ alone- 200mg/Kg; GEM alone- 50mg/Kg; and Combo (BMJ+GEM). BMJ efficacy was examined in 3 human PanC-PDX explants in nude mice, denoted by PanC-PDX 272, 266 and 271, alongside GEM, and Combo. Tumor volumes recorded post first part of study (~day 35; first sacrifice time-point) showed significant tumor growth inhibition in all treated groups. GEM and Combo displayed comparable efficacies by decrease in tumor volume (~70-80% decrease), followed by BMJ (~50-60% decrease). Interestingly, tumor regrowth determination with subsequent treatment washout period (~30 days), showed maximum tumor regrowth in GEM-treated mice, nearing the untreated controls. BMJ consistently showed a prolonged effect by containment of tumors until the study end (~day 64; second sacrifice time-point). Combo tumors remained close to BMJ, suggesting no apparent antagonistic interference. Notably, at study completion (day 64), BMJ or Combo displayed the most significant and sustained effect on tumor volumes (~60-80% decrease for BMJ, 80-90% decrease for Combo) compared to GEM (~40-50% decrease), after treatments were stopped. Together, these results point to the chemopreventive efficacy of BMJ as a monotherapeutic as well a perfect combinatorial candidate in studies with chemotherapeutic agents like GEM aimed at PanC management utilizing the resourceful PanC-PDX mouse model.

Citation Format: Deepanshi Dhar, Dileep Kumar, Stacey Bagby, Todd M. Pitts, Wells A. Messersmith, Komal Raina, Rajesh Agarwal. Gaining insights into pancreatic cancer intervention with bitter melon, a natural agent, in combination with gemcitabine using patient derived xenografts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 277.