This K07 grant application is a request to provide Dr. Madhuri Kakarala MD, PhD with advanced didactic and practical training in 1) advanced cell biology techniques, 2) advanced analytical skills, 3) clinical trials design and interpretation, 4) enhancing publication record and securing independent federal funding, 5) the responsible conduct of research. The goal of this application is to prepare her to become a leader in translational cancer risk reduction research. Her plan is supported by a team of internationally known mentors in cancer risk reduction, breast biology, nutritional analytics and biostatistics and commitments from University of Michigan Cancer Center. Curcumin, a potent cancer preventive polyphenol, prevents cellular carcinogenesis progression via a diverse set of antioxidant and carcinogenesis mechanisms. Its efficacy in cancer risk reductive (chemoprevention) studies has been limited by poor bioavailability. I propose to enhance curcumin bioavailability by using piperine to modulate P glycoprotein, CYP 3A4 and phase II conjugation enzymes. Piperine may also have synergistic cancer preventive effect alone. This application addresses the hypothesis that curcumin, in combination with piperine, can effectively prevent breast cancer through reduction in breast stem cell numbers and changes critical stem cell associated pathways that leadto both ER positive and ER negative breast cancer. To evaluate this hypothesis, I propose in Aim 1 to determine the concentration of curcumin, piperine and curcumin + piperine in-vitro that downregulates normal human breast stem cell self renewal and signaling.
In Aim 2, I will identify the curcumin and piperine doses that produce bioactive concentrations in human plasma in a Phase I trlal.
In Aim 3, I will implement a Phase IIa translational randomized trial of oral curcumin + piperine for 28 days in women with BRCA mutations prior to prophylactic mastectomy. I will assay breast tissue and plasma for concentrations of curcumin and piperine. I will isolate and quantify breast stem cell sphere formation to assess self renewal and will compare Wnt/? catenin and Notch signaling intermediates from stem cells derived from BRCA and healthy patients. This work has broad potential future application to many cancer risk reductive interventions and solid organ malignancies. The work will link bioavailability with efficacy in preventing carcinogenic stem cell changes in-vitro, demonstrate systemic delivery of cancer risk reductives to target tissue, and test breast stem cell changes as biomarkers for future large cancer preventive trials.
Significance These proposed studies will: 1) develop an in-vitro model for screening any potential cancer preventive agents for efficacy to decrease stem cell carcinogenic changes;2) test the efficacy of curcumin and piperine to target breast stem cells;3) document the pharmacokinetics and bioavailability of curcumin and piperine in humans;and 4) test efficacy of curcumin and piperine to decrease breast stem cell number and signaling within breast stem cells in humans at risk of breast cancer.
|Hursting, Stephen D; Digiovanni, John; Dannenberg, Andrew J et al. (2012) Obesity, energy balance, and cancer: new opportunities for prevention. Cancer Prev Res (Phila) 5:1260-72|
|Carroll, Robert E; Benya, Richard V; Turgeon, Danielle Kim et al. (2011) Phase IIa clinical trial of curcumin for the prevention of colorectal neoplasia. Cancer Prev Res (Phila) 4:354-64|
|Kakarala, Madhuri; Dubey, Shiv Kumar; Tarnowski, Malloree et al. (2010) Ultra-low flow liquid chromatography assay with ultraviolet (UV) detection for piperine quantitation in human plasma. J Agric Food Chem 58:6594-9|