Pancreatic cancer (PanC) is an aggressive disease; median life of PanC patients post-diagnosis is <6 months and overall 5-year survival rate is 3-5%. Gemcitabine is the frontline chemotherapy for PanC that effectively eliminates bulk PanC cells; however spares cancer stem cell (CSC) population which causes cancer relapse as well as aggressiveness. Together, it is clear that additional strategies are urgently warranted to effectively lower PanC incidence, target CSC to control PanC relapse, and associated mortality. Noteworthy, PanC is a complex disease with multiple combinations of mutations, and therefore it is necessary to identify the agents with multiple targets to control both PanC growth and CSC-associated PanC relapse. Our published and preliminary studies show that bitter melon (Momordica charantia) juice (BMJ) significantly decreases the viability and induces strong apoptotic death of human PanC cell lines, which was associated with a robust AMPK activation, as both AMPK inhibitor and siRNA reversed BMJ-caused apoptosis. Furthermore, BMJ inhibited glycolysis and oxidative phosphorylation rate in PanC cells. Together these results suggested a 'metabolic shift' by BMJ in PanC cells. BMJ also strongly inhibited the sphere formation by PanC CSCs suggesting that it also targets CSC for its anti-PanC efficacy. Most notably, BMJ feeding by oral gavage at only 5mg dose/mouse/day resulted in 60% inhibition in MIA PaCa-2 xenograft growth in nude mice without any noticeable side effects or toxicity. Immunohistochemical analysis of xenografts showed that BMJ also inhibits proliferation and CSC biomarkers, induces apoptosis, and activates AMPK in vivo. Together, based on these and other findings, we hypothesize that BMJ causes metabolic shift in PanC cells through nutrient stress, AMPK activation and inhibiting signaling molecules related to metabolism and proliferation, which leads to strong growth inhibition and apoptosis specifically in PanC cells. Additionally, BMJ targets Notch/ Hedgehog signaling to effectively eliminate PanC CSC population; resulting in strong activity against PanC. The specific aims proposed are: I) To further define the mechanisms by which BMJ targets metabolism and affects AMPK-mediated growth inhibition and apoptosis in PanC cells; II) To further define the mechanisms by which BMJ targets Notch and Hedgehog pathways and effectively inhibits CSC population in PanC; and III) To further establish BMJ molecular mechanisms defined in specific aims I and II in PDX1-Cre; LSL-KRASG12D transgenic mouse model. It is important to highlight here that bitter melon is widely consumed as vegetable as well as juice especially in Asian countries; and has been attributed with multiple health beneficial properties such as anti-diabetic, anti-inflammatory, etc. Most notably, bitter melon has been tested in several clinical trials for its anti-diabetic effects and has plenty of human safety data. We, therefore, anticipate that the positive outcomes from the proposed studies will provide compelling rationale for initiating clinical trials to establish BMJ activity against human pancreatic cancer.