Photo of Alec Kimmelman,  MD, PhD

Alec Kimmelman, MD, PhD

Dana-Farber Cancer Institute

Dana-Farber Cancer Institute


alec_kimmelman@dfci.harvard.edu

Alec Kimmelman, MD, PhD

Dana-Farber Cancer Institute

EDUCATIONAL TITLES

  • Associate Professor, Radiation Oncology, Harvard Medical School
  • Assistant Professor, Radiation Oncology, Dana-Farber Cancer Institute

DF/HCC PROGRAM AFFILIATION

Research Abstract

The majority of my research career has been on understanding the role of the Ras oncogenes in malignancy and in this regard we were able to identify a novel member of the Ras family, M-Ras (Kimmelman et al., 1997). We went on to dissect the critical signal transduction pathways that were responsible for mediating its functions of promoting cellular survival and differentiation (Kimmelman et al., 2000; Kimmelman et al., 2002). This focus on Ras continued during my most recent efforts in studying pancreatic adenocarcinoma, a cancer that is nearly universally driven by a mutation in the Kras oncogene (Hezel and Kimmelman et al., 2006). In recent work, we have identified novel oncogenes in pancreatic cancer using a combination of genomic and functional approaches and have linked these genes to the invasive phenotype of this deadly. Additionally, we have established an inducible model of pancreatic adenocarcinoma that is phenotypically identical to the human disease. This model, driven by an inducible Kras oncogene will provide a platform for pre-clinical therapeutic testing as well as for in depth interrogation of the biology of the disease. We are currently utilizing this model to understand the role of Kras in terms of tumor initiation and maintenance.

A major focus of the lab is to identify defects in mitotic checkpoints and DNA repair pathways that can be exploited for therapeutic gain. Related to this, we are actively studying pathways involved in pancreatic cancer cell survival and metabolism to identify novel vantage points of attack.

Clinically, I am also a practicing radiation oncologist with a focus on gastrointestinal malignancies (20% of my time). During this time I am involved in supervising and teaching Radiation Oncology Residents as well as medical students that rotate through our department. I am also a faculty advisor for a resident run translational science group.

 

Publications

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  • Kimmelman AC. Metabolic Dependencies in RAS-Driven Cancers. Clin Cancer Res 2015; 21:1828-34. PubMed
  • Galluzzi L, Pietrocola F, Bravo-San Pedro JM, Amaravadi RK, Baehrecke EH, Cecconi F, Codogno P, Debnath J, Gewirtz DA, Karantza V, Kimmelman A, Kumar S, Levine B, Maiuri MC, Martin SJ, Penninger J, Piacentini M, Rubinsztein DC, Simon HU, Simonsen A, Thorburn AM, Velasco G, Ryan KM, Kroemer G. Autophagy in malignant transformation and cancer progression. EMBO J 2015; 34:856-880. PubMed
  • Maiso P, Huynh D, Moschetta M, Sacco A, Aljawai Y, Mishima Y, Asara JM, Roccaro AM, Kimmelman AC, Ghobrial IM. Metabolic signature identifies novel targets for drug resistance in Multiple Myeloma. Cancer Res 2015. PubMed
  • Buescher JM, Antoniewicz MR, Boros LG, Burgess SC, Brunengraber H, Clish CB, DeBerardinis RJ, Feron O, Frezza C, Ghesquiere B, Gottlieb E, Hiller K, Jones RG, Kamphorst JJ, Kibbey RG, Kimmelman AC, Locasale JW, Lunt SY, Maddocks OD, Malloy C, Metallo CM, Meuillet EJ, Munger J, Nöh K, Rabinowitz JD, Ralser M, Sauer U, Stephanopoulos G, St-Pierre J, Tennant DA, Wittmann C, Vander Heiden MG, Vazquez A, Vousden K, Young JD, Zamboni N, Fendt SM. A roadmap for interpreting (13)C metabolite labeling patterns from cells. Curr. Opin. Biotechnol. 2015; 34:189-201. PubMed
  • Cox AD, Fesik SW, Kimmelman AC, Luo J, Der CJ. Drugging the undruggable RAS: Mission Possible? Nat Rev Drug Discov 2014. PubMed
  • Mayers JR, Wu C, Clish CB, Kraft P, Torrence ME, Fiske BP, Yuan C, Bao Y, Townsend MK, Tworoger SS, Davidson SM, Papagiannakopoulos T, Yang A, Dayton TL, Ogino S, Stampfer MJ, Giovannucci EL, Qian ZR, Rubinson DA, Ma J, Sesso HD, Gaziano JM, Cochrane BB, Liu S, Wactawski-Wende J, Manson JE, Pollak MN, Kimmelman AC, Souza A, Pierce K, Wang TJ, Gerszten RE, Fuchs CS, Vander Heiden MG, Wolpin BM. Elevation of circulating branched-chain amino acids is an early event in human pancreatic adenocarcinoma development. Nat Med 2014; 20:1193-8. PubMed
  • Yang A, Kimmelman AC. Inhibition of autophagy attenuates pancreatic cancer growth independent of TP53/TRP53 status. Autophagy 2014; 10:1683-1684. PubMed
  • Viale A, Pettazzoni P, Lyssiotis CA, Ying H, Sánchez N, Marchesini M, Carugo A, Green T, Seth S, Giuliani V, Kost-Alimova M, Muller F, Colla S, Nezi L, Genovese G, Deem AK, Kapoor A, Yao W, Brunetto E, Kang Y, Yuan M, Asara JM, Wang YA, Heffernan TP, Kimmelman AC, Wang H, Fleming JB, Cantley LC, DePinho RA, Draetta GF. Oncogene ablation-resistant pancreatic cancer cells depend on mitochondrial function. Nature 2014. PubMed
  • Yang A, Rajeshkumar NV, Wang X, Yabuuchi S, Alexander BM, Chu GC, Von Hoff DD, Maitra A, Kimmelman AC. Autophagy Is Critical for Pancreatic Tumor Growth and Progression in Tumors with p53 Alterations. 2014. PubMed
  • Wolpin BM, Rubinson DA, Wang X, Chan JA, Cleary JM, Enzinger PC, Fuchs CS, McCleary NJ, Meyerhardt JA, Ng K, Schrag D, Sikora AL, Spicer BA, Killion L, Mamon H, Kimmelman AC. Phase II and Pharmacodynamic Study of Autophagy Inhibition Using Hydroxychloroquine in Patients With Metastatic Pancreatic Adenocarcinoma. Oncologist 2014; 19:637-8. PubMed
  • Cottini F, Hideshima T, Xu C, Sattler M, Dori M, Agnelli L, ten Hacken E, Bertilaccio MT, Antonini E, Neri A, Ponzoni M, Marcatti M, Richardson PG, Carrasco R, Kimmelman AC, Wong KK, Caligaris-Cappio F, Blandino G, Kuehl WM, Anderson KC, Tonon G. Rescue of Hippo coactivator YAP1 triggers DNA damage-induced apoptosis in hematological cancers. Nat Med 2014; 20:599-606. PubMed
  • Mancias JD, Wang X, Gygi SP, Harper JW, Kimmelman AC. Quantitative proteomics identifies NCOA4 as the cargo receptor mediating ferritinophagy. Nature 2014. PubMed
  • Sousa CM, Kimmelman AC. The Complex Landscape of Pancreatic Cancer Metabolism. Carcinogenesis 2014. PubMed
  • Akbay EA, Moslehi J, Christensen CL, Saha S, Tchaicha JH, Ramkissoon SH, Stewart KM, Carretero J, Kikuchi E, Zhang H, Cohoon TJ, Murray S, Liu W, Uno K, Fisch S, Jones K, Gurumurthy S, Gliser C, Choe S, Keenan M, Son J, Stanley I, Losman JA, Padera R, Bronson RT, Asara JM, Abdel-Wahab O, Amrein PC, Fathi AT, Danial NN, Kimmelman AC, Kung AL, Ligon KL, Yen KE, Kaelin WG, Bardeesy N, Wong KK. D-2-hydroxyglutarate produced by mutant IDH2 causes cardiomyopathy and neurodegeneration in mice. Genes Dev 2014; 28:479-90. PubMed
  • Bryant KL, Mancias JD, Kimmelman AC, Der CJ. KRAS: feeding pancreatic cancer proliferation. Trends Biochem Sci 2014; 39:91-100. PubMed
  • Wallner PE, Anscher MS, Barker CA, Bassetti M, Bristow RG, Cha YI, Dicker AP, Formenti SC, Graves EE, Hahn SM, Hei TK, Kimmelman AC, Kirsch DG, Kozak KR, Lawrence TS, Marples B, McBride WH, Mikkelsen RB, Park CC, Weidhaas JB, Zietman AL, Steinberg M. Current status and recommendations for the future of research, teaching, and testing in the biological sciences of radiation oncology: report of the American Society for Radiation Oncology Cancer Biology/Radiation Biology Task Force, executive summary. Int J Radiat Oncol Biol Phys 2013; 88:11-7. PubMed
  • Herter-Sprie GS, Korideck H, Christensen CL, Herter JM, Rhee K, Berbeco RI, Bennett DG, Akbay EA, Kozono D, Mak RH, Mike Makrigiorgos G, Kimmelman AC, Wong KK. Image-guided radiotherapy platform using single nodule conditional lung cancer mouse models. Nat Commun 2014; 5:5870. PubMed
  • Shimamura T, Chen Z, Soucheray M, Carretero J, Kikuchi E, Tchaicha JH, Gao Y, Cheng KA, Cohoon TJ, Qi J, Akbay E, Kimmelman AC, Kung AL, Bradner JE, Wong KK. Efficacy of BET bromodomain inhibition in Kras-mutant non-small cell lung cancer. Clin Cancer Res 2013; 19:6183-92. PubMed
  • Liu Y, Marks K, Cowley GS, Carretero J, Liu Q, Nieland TJ, Xu C, Cohoon TJ, Gao P, Zhang Y, Chen Z, Altabef AB, Tchaicha JH, Wang X, Choe S, Driggers EM, Zhang J, Bailey ST, Sharpless NE, Hayes DN, Patel NM, Janne PA, Bardeesy N, Engelman JA, Manning BD, Shaw RJ, Asara JM, Scully R, Kimmelman A, Byers LA, Gibbons DL, Wistuba II, Heymach JV, Kwiatkowski DJ, Kim WY, Kung AL, Gray NS, Root DE, Cantley LC, Wong KK. Metabolic and functional genomic studies identify deoxythymidylate kinase as a target in LKB1-mutant lung cancer. 2013; 3:870-9. PubMed
  • Lyssiotis CA, Son J, Cantley LC, Kimmelman AC. Pancreatic cancers rely on a novel glutamine metabolism pathway to maintain redox balance. Cell Cycle 2013; 12:1987-8. PubMed
  • Jeong SM, Xiao C, Finley LW, Lahusen T, Souza AL, Pierce K, Li YH, Wang X, Laurent G, German NJ, Xu X, Li C, Wang RH, Lee J, Csibi A, Cerione R, Blenis J, Clish CB, Kimmelman A, Deng CX, Haigis MC. SIRT4 has tumor-suppressive activity and regulates the cellular metabolic response to DNA damage by inhibiting mitochondrial glutamine metabolism. Cancer Cell 2013; 23:450-63. PubMed
  • O'Connor KW, Dejsuphong D, Park E, Nicolae CM, Kimmelman AC, D'Andrea AD, Moldovan GL. PARI Overexpression Promotes Genomic Instability and Pancreatic Tumorigenesis. Cancer Res 2013; 73:2529-39. PubMed
  • 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, Kimmelman AC. Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway. Nature 2013. PubMed
  • Berbeco RI, Korideck H, Ngwa W, Kumar R, Patel J, Sridhar S, Johnson S, Price BD, Kimmelman A, Makrigiorgos GM. DNA Damage Enhancement from Gold Nanoparticles for Clinical MV Photon Beams. Radiat Res 2012. PubMed
  • Li YH, Wang X, Pan Y, Lee DH, Chowdhury D, Kimmelman AC. Inhibition of non-homologous end joining repair impairs pancreatic cancer growth and enhances radiation response. PLoS ONE 2012; 7:e39588. PubMed
  • 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. Pancreatic cancers require autophagy for tumor growth. Genes Dev 2011; 25:717-29. PubMed
  • Kimmelman AC,Hezel AF,Aguirre AJ,Zheng H,Paik JH,Ying H,Chu GC,Zhang JX,Sahin E,Yeo G,Ponugoti A,Nabioullin R,Deroo S,Yang S,Wang X,McGrath JP,Protopopova M,Ivanova E,Zhang J,Feng B,Tsao MS,Redston M,Protopopov A,Xiao Y,Futreal PA,Hahn WC,Klimstra DS,Chin L,DePinho RA. Genomic alterations link Rho family of GTPases to the highly invasive phenotype of pancreas cancer. Proc Natl Acad Sci U S A 2008; 105:19372-7. PubMed
  • Zheng H,Ying H,Yan H,Kimmelman AC,Hiller DJ,Chen AJ,Perry SR,Tonon G,Chu GC,Ding Z,Stommel JM,Dunn KL,Wiedemeyer R,You MJ,Brennan C,Wang YA,Ligon KL,Wong WH,Chin L,DePinho RA. p53 and Pten control neural and glioma stem/progenitor cell renewal and differentiation. Nature 2008; 455:1129-33. PubMed
  • Martin ES, Tonon G, Sinha R, Xiao Y, Feng B, Kimmelman AC, Protopopov A, Ivanova E, Brennan C, Montgomery K, Kucherlapati R, Bailey G, Redston M, Chin L, DePinho RA. Common and distinct genomic events in sporadic colorectal cancer and diverse cancer types. Cancer Res 2007; 67:10736-43. PubMed
  • Stommel JM, Kimmelman AC, Ying H, Nabioullin R, Ponugoti AH, Wiedemeyer R, Stegh AH, Bradner JE, Ligon KL, Brennan C, Chin L, DePinho RA. Coactivation of receptor tyrosine kinases affects the response of tumor cells to targeted therapies. Science 2007; 318:287-90. PubMed
  • Chu GC, Kimmelman AC, Hezel AF, Depinho RA. Stromal biology of pancreatic cancer. J Cell Biochem 2007; 101:887-907. PubMed
  • Nuñez Rodriguez N, Lee IN, Banno A, Qiao HF, Qiao RF, Yao Z, Hoang T, Kimmelman AC, Chan AM. Characterization of R-ras3/m-ras null mice reveals a potential role in trophic factor signaling. Mol Cell Biol 2006; 26:7145-54. PubMed
  • Hezel AF, Kimmelman AC, Stanger BZ, Bardeesy N, Depinho RA. Genetics and biology of pancreatic ductal adenocarcinoma. Genes Dev 2006; 20:1218-49. PubMed
  • Kimmelman AC, Qiao RF, Narla G, Banno A, Lau N, Bos PD, Nuñez Rodriguez N, Liang BC, Guha A, Martignetti JA, Friedman SL, Chan AM. Suppression of glioblastoma tumorigenicity by the Kruppel-like transcription factor KLF6. Oncogene 2004; 23:5077-83. PubMed
  • Kimmelman AC, Nuñez Rodriguez N, Chan AM. R-Ras3/M-Ras induces neuronal differentiation of PC12 cells through cell-type-specific activation of the mitogen-activated protein kinase cascade. Mol Cell Biol 2002; 22:5946-61. PubMed
  • Chan TO, Rodeck U, Chan AM, Kimmelman AC, Rittenhouse SE, Panayotou G, Tsichlis PN. Small GTPases and tyrosine kinases coregulate a molecular switch in the phosphoinositide 3-kinase regulatory subunit. Cancer Cell 2002; 1:181-91. PubMed
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