Alec Kimmelman, MD, PhD
Professor and Chairman, Department of Radiation Oncology
The Kimmelman Lab
NYU Radiation Oncology
560 1st Avenue, 2nd Floor Energy Building
New York, NY 10016
Pancreatic cancers are highly resistant to currently available therapeutics which results in a 5-year survival rate of approximately 6%. We believe that this resistance points toward altered cell metabolic pathways. In this regard we have previously shown that that oncogenic Kras promotes a rewiring of pancreatic cancer metabolism allowing carbon sources to be utilized in a variety of biosynthetic pathways. Importantly, several of these metabolic pathways are critical for tumor growth and therefore represent potential therapeutic targets. Ongoing studies from our group are exploring targeting various aspects of metabolism as therapeutic approaches.
Additional studies from our group have demonstrated pancreatic cancers have elevated basal autophagy which is required for their continued growth. Importantly, inhibition of autophagy pharmacologically or genetically leads to decreased oxidative phosphorylation, a drop in ATP production, and ultimately growth inhibition. These findings have implicated autophagy as a key component of pancreatic cancer metabolism and have motivated the opening of multiple clinical trials assessing the efficacy of hydroxychloroquine as an autophagy inhibitor in pancreatic cancer. Recently, we have identified an autophagy-dependent metabolic cross-talk that exists between pancreatic tumor cells and the surrounding stroma. Ongoing work from our group seeks to understand the metabolic contributions that autophagy makes in pancreatic tumors.
·Yang, S, Wang, X, Contino, G, Liesa, M, Sahin, E, Ying, H, Bause, A, Li, Y, Stommel, JM, Dell’Antonio, G, Mautner, J, Tonon, G, Haigis, M, Shirihai, OS, Doglioni, C, Bardeesy, N, Kimmelman, AC. (2011) Pancreatic cancers require autophagy for tumor growth. Genes Dev. 25(7):717-29. PMCID:PMC3070934
·Yang A, Rajeshkumar NV, Wang X, Yabuuchi S, Alexander BM, Chu GC, Von Hoff DD, Maitra A, Kimmelman AC. (2014). Autophagy is critical for pancreatic tumor growth and progression in tumors with p53 alterations. Cancer Discov. 4(8):905-13. PMCID: PMC4125497
·Ying H, Kimmelman AC*, Lyssiotis CA, Hua S, Chu GC, Fletcher-Sananikone E, Locasale JW, Son J, Zhang H, Coloff JL, Yan H, Wang W, Chen S, Viale A, Zheng H, Paik J, Lim C, Guimaraes AR, Martin ES, Chang J, Hezel AF, Perry SR, Hu J, Gan B, Xiao Y, Asara JM, Weissleder R, Wang YA, Chin L, Cantley LC, DePinho RA*. (2012). Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism. Cell. 149(3):656-670. PMCID:PMC3472002 *co-corresponding
·Son J, Lyssiotis CA, Ying H, Wang X, Hua S, Ligorio M, Perera RM, Ferrone CR, Mullarky E, Shyh-Chang N, Kang Y, Fleming JB, Bardeesy N, Asara JM, Haigis MC, DePinho RA, Cantley LC and Kimmelman AC. (2013).Glutamine supports pancreatic cancer growth through a Kras-regulated metabolic pathway. Nature. 496(7443):101-5. PMCID:PMC3656466
·Mancias JD, Wang X, Gygi SP, Harper JW*, Kimmelman AC*. (2014). Quantitative proteomics identifies NCOA4 as the cargo receptor mediating ferritinophagy. Nature. 509 (7498):105-9. PMCID:PMC4180099.
·Sousa CM, Biancur DE, Wang X, Halbrook CJ, Sherman MH, Zhang L, Kremer D, Hwang RF, Witkiewicz AK, Ying H, Asara JM, Evans RM, Cantley LC, Lyssiotis CA, Kimmelman AC. (2016). Pancreatic stellate cells support tumour metabolism through autophagic alanine secretion. Nature. 536(7617):479-83.