GMaP Region 3

Highlight on Diversity Supplement Awardees!

GMaP Region 3 Mentors and Mentees…

Project Number: 3R01CA195708-04S1 (NCI Research Supplements to Promote Diversity in Health-Related Research)

Abstract: 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.

rajeshagarwal

Rajesh Agarwal, Ph.D.

Rajesh Agarwal, Ph.D.

Professor and Vice Chairman, Department of Pharmaceutical Sciences
Co-Leader, Cancer Prevention and Control Program
University of Colorado Cancer Center
University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences
12850 E. Montview Blvd, C238, Room V20-2118
Aurora, CO 80045
Phone: 303-724-4055
Fax: 303-724-7266
Email: Rajesh.Agarwal@UCDenver.edu

Prof. Rajesh Agarwal, a Cancer Pharmacologist, graduated from the chemistry department, Lucknow University, India in 1981 with Ph.D. degree. He worked in India for some years as an Assistant Professor (Chemistry), and then moved to USA in 1988, as a Research Associate in Case Western Reserve University, Cleveland, OH, USA, where he grew to the Position of Assistant Professor in Dermatology Department in 1992. Beginning 1998, he moved to Colorado as an Associate Professor at AMC Cancer Research Center and grew to a full Professor position in 2000. In early 2001, he moved to University of Colorado School of Pharmacy as a full Professor followed by tenure and is in the current position since then. He also serves as the Vice-Chair of the Department of Pharmaceutical sciences, School of Pharmacy and as Co-Program Leader, Cancer Prevention & Control Program at the University of Colorado Cancer Center. He has over 360 peer-reviewed publications and written several book chapters and several of his work have been featured as “cover articles”. He has been an invited speaker across the globe, has over three hundred presentations in national and international scientific meetings, is an active member of several National Institutes of Health, USA grant review committee, and is an editorial board member of several lead cancer journals. He has trained graduate students (8 all together), and post-doctoral fellows, research faculty and entry level physicians (>50 all together) in the last 25 years; he is also part of the Department’ mentoring program for junior faculty. He is an elected fellow of the American Association for the Advancement of Science (AAAS) in Pharmaceutical Sciences since 2009; recipient of outstanding achievement award from Society of American Asian Scientists in Cancer Research in 2009, and several other national and international awards. He has a broad background in cancer research in different epithelial cancer models, including skin, prostate, lung, colon, pancreas, and has made significant contributions in establishing the efficacy of natural, non-toxic agents for effective cancer chemoprevention, as well as discerning the molecular mechanisms involved in the agents’ anti-cancer efficacy. Using cutting edge technologies, his recent translational research focus has been to examine the effect of natural agents on cancer stem cell population, its self-renewal and metabolism and associated inflammatory tumor microenvironment components including the microbiome which influence epithelial cancer initiation, promotion and progression, under chronic disease conditions. His other translational research focus has been to bridge the bench to bedside gap via initiating clinical trials of these identified natural agents, with collaborating clinicians. Notably, the relentless efforts of this principal investigator over the years on the natural agent silymarin and its components, have reached at a point where its patented novel formulation against skin toxicity has been marketed recently.

Dominique Z. Reed, Ph.D.

Post-doctoral Fellow, Department of Pharmaceutical Sciences
University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences

Reed Dominique

Dominique Z. Reed, Ph.D.

Dominique Z. Reed (Jones) is a 1st year post-doctoral fellow in the laboratory of Dr. Rajesh Agarwal in the Department of Pharmaceutical Sciences and Skaggs School of Pharmacy and Pharmaceutical Sciences. She received her Ph.D. in fields of Pharmacology and Toxicology from the University of Louisville in Louisville, Kentucky in May 2016. Dominique has first authored and co-authored several peer-reviewed publications and has been the recipient of several awards including the American Association for Cancer Research Minorities In Cancer Research travel award and Southern Regional Education Board (SREB) Doctoral fellowship for her work in the areas of cancer epidemiology and non-coding RNAs in prostate cancer. As a post-doctoral fellow, Dominique has transitioned from cancer epidemiology and molecular biology to cancer chemoprevention research in pancreatic cancer. She also has passion for cancer health disparity work demonstrated by her graduate work. Outside of the lab, Dominique has served as President of the Black Biomedical Graduate Student Organization (BBGSO), and Vice-President of the Minority Association of Graduate Students (MAGS) while at the University of Louisville. In service to the profession, she has served as a graduate student representative on the University of Louisville School of Medicine Diversity and American Society for Pharmacology and Experimental Therapeutics (ASPET) Mentoring and Career Development Committees. For the past 2 years, she has also participated in mentoring and educational programming as a member of the ASPET Young Scientist Committee. Currently, Dominique is an active member of the Post-Doctoral Association (PDA) serving as a co-chair for the Travel Awards and Seminar Series Committees at the University of Colorado Anschutz Medical Campus.

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From the NCI

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