Investigator, Hale Family Center For Pancreatic Cancer Research
Department Of Medical Oncology, Dana-Farber Cancer Institute
Assistant Professor Of Medicine, Harvard Medical School
Associate Member, Broad Institute
Dr. Andrew Aguirre is a physician-scientist with a focus on cancer biology and translational oncology and is committed to improving the diagnosis and treatment of gastrointestinal malignancies, particularly pancreatic cancer. Dr. Aguirre trained in internal medicine at Massachusetts General Hospital and in medical oncology at the Dana-Farber/Partners Cancer Care Program. He is now an Assistant Professor Of Medicine at Dana-Farber Cancer Institute and Harvard Medical School, as well as an Associate Member of the Broad Institute of Harvard and M.I.T.
The Aguirre Lab at Dana-Farber Cancer Institute is a basic and translational oncology laboratory focused on studying pancreatic cancer and other RAS-driven malignancies. We utilize genomic, functional genetic, molecular and cell biology approaches to understand the genetics and biology of pancreatic cancer and to identify novel therapeutic strategies to evaluate in patient-derived models or genetically engineered mouse models of the disease. We actively collaborate with clinical, laboratory, and computational colleagues to perform multi-disciplinary basic and translational research.
Pancreatic cancer is a devastating disease and is currently the third leading cause of cancer-related death in the United States. There is an urgent need for new therapies to improve the lives of pancreatic cancer patients. Our lab utilizes functional genetic screens and computational approaches to discover cancer cell vulnerabilities and to identify new biomarker-linked therapeutic targets in pancreatic cancer. We leverage human organoid models and genetically engineered mouse models of pancreatic cancer to investigate the mechanisms of cancer cell dependency on these new targets, with the ultimate goal of advancing new drug development programs with academic and industry collaborators. The KRAS oncogene is mutated in the majority of pancreatic cancers and is the major driver of this disease. We use pancreatic cancer as a model system to study how KRAS mediates cancer cell proliferation and survival and drives tumor progression, and we have a particular interest in identifying synthetic lethal vulnerabilities with the KRAS oncogene that may represent new therapeutic avenues. Moreover, with the recent development of a novel class of direct KRAS inhibitors, we are actively studying mechanisms of resistance to these inhibitors using functional genetic approaches.
Our laboratory also utilizes genomic and functional approaches to understand the molecular and phenotypic heterogeneity of pancreatic cancer. In collaboration with the laboratory of Dr. Brian Wolpin, we collect serial tumor biopsies and blood samples from pancreatic cancer patients throughout their treatment course to study how genetic and biologic features of a patient’s tumor impact treatment response and disease progression. We have extensive experience in culturing human organoid models of pancreatic cancer and have developed a translational research program to investigate ex vivo therapeutic response to inform improved therapeutic selection. Moreover, we utilize DNA and RNA sequencing as well as single cell genomic studies to define the genetic, cellular, and immunologic features that drive the aggressive course of this disease. Through serial studies of patients throughout treatment with standard and experimental therapies, we seek to track the evolution of these features and define mechanisms of response and resistance to therapy.
Giacomelli AO, Yang X, Lintner RE, McFarland JM, Duby M, Kim J, Howard TP, Takeda DY, Ly SH, Kim E, Gannon HS, Hurhula B, Sharpe T, Goodale A, Fritchman B, Steelman S, Vazquez F, Tsherniak A, Aguirre AJ, Doench JG, Piccioni F, Roberts CWM, Meyerson M, Getz G, Johannessen CM, Root DE, Hahn WC. Mutational processes shape the landscape of TP53 mutations in human cancer. Nat Genet. 2018;50(10):1381-7. Epub 2018/09/19. doi: 10.1038/s41588-018-0204-y. PubMed PMID: 30224644; PMCID: PMC6168352.
Aguirre AJ, Nowak JA, Camarda ND, Moffitt RA, Ghazani AA, Hazar-Rethinam M, Raghavan S, Kim J, Brais LK, Ragon D, Welch MW, Reilly E, McCabe D, Marini L, Anderka K, Helvie K, Oliver N, Babic A, Da Silva A, Nadres B, Van Seventer EE, Shahzade HA, St Pierre JP, Burke KP, Clancy T, Cleary JM, Doyle LA, Jajoo K, McCleary NJ, Meyerhardt JA, Murphy JE, Ng K, Patel AK, Perez K, Rosenthal MH, Rubinson DA, Ryou M, Shapiro GI, Sicinska E, Silverman SG, Nagy RJ, Lanman RB, Knoerzer D, Welsch DJ, Yurgelun MB, Fuchs CS, Garraway LA, Getz G, Hornick JL, Johnson BE, Kulke MH, Mayer RJ, Miller JW, Shyn PB, Tuveson DA, Wagle N, Yeh JJ, Hahn WC, Corcoran RB, Carter SL, Wolpin BM. Real-time Genomic Characterization of Advanced Pancreatic Cancer to Enable Precision Medicine. Cancer Discov. 2018;8(9):1096-111. Epub 2018/06/16. doi: 10.1158/2159-8290.CD-18-0275. PubMed PMID: 29903880.
Yurgelun MB, Chittenden AB, Morales-Oyarvide V, Rubinson DA, Dunne RF, Kozak MM, Qian ZR, Welch MW, Brais LK, Da Silva A, Bui JL, Yuan C, Li T, Li W, Masuda A, Gu M, Bullock AJ, Chang DT, Clancy TE, Linehan DC, Findeis-Hosey JJ, Doyle LA, Thorner AR, Ducar MD, Wollison BM, Khalaf N, Perez K, Syngal S, Aguirre AJ, Hahn WC, Meyerson ML, Fuchs CS, Ogino S, Hornick JL, Hezel AF, Koong AC, Nowak JA, Wolpin BM. Germline cancer susceptibility gene variants, somatic second hits, and survival outcomes in patients with resected pancreatic cancer. Genet Med. 2018. Epub 2018/07/03. doi: 10.1038/s41436-018-0009-5. PubMed PMID: 29961768.
Wang B, Krall EB, Aguirre AJ, Kim M, Widlund HR, Doshi MB, Sicinska E, Sulahian R, Goodale A, Cowley GS, Piccioni F, Doench JG, Root DE, Hahn WC. ATXN1L, CIC, and ETS Transcription Factors Modulate Sensitivity to MAPK Pathway Inhibition. Cell Rep. 2017;18(6):1543-57. doi: 10.1016/j.celrep.2017.01.031. PubMed PMID: 28178529; PMCID: PMC5313047.
Qian ZR, Rubinson DA, Nowak JA, Morales-Oyarvide V, Dunne RF, Kozak MM, Welch MW, Brais LK, Da Silva A, Li T, Li W, Masuda A, Yang J, Shi Y, Gu M, Masugi Y, Bui J, Zellers CL, Yuan C, Babic A, Khalaf N, Aguirre A, Ng K, Miksad RA, Bullock AJ, Chang DT, Tseng JF, Clancy TE, Linehan DC, Findeis-Hosey JJ, Doyle LA, Thorner AR, Ducar M, Wollison B, Laing A, Hahn WC, Meyerson M, Fuchs CS, Ogino S, Hornick JL, Hezel AF, Koong AC, Wolpin BM. Association of Alterations in Main Driver Genes With Outcomes of Patients With Resected Pancreatic Ductal Adenocarcinoma. JAMA Oncol. 2017. doi: 10.1001/jamaoncol.2017.3420. PubMed PMID: 29098284.
Krall EB, Wang B, Munoz DM, Ilic N, Raghavan S, Niederst MJ, Yu K, Ruddy DA, Aguirre AJ, Kim JW, Redig AJ, Gainor JF, Williams JA, Asara JM, Doench JG, Janne PA, Shaw AT, McDonald Iii RE, Engelman JA, Stegmeier F, Schlabach MR, Hahn WC. KEAP1 loss modulates sensitivity to kinase targeted therapy in lung cancer. Elife. 2017;6. doi: 10.7554/eLife.18970. PubMed PMID: 28145866; PMCID: PMC5305212.
Kim JW, Abudayyeh OO, Yeerna H, Yeang CH, Stewart M, Jenkins RW, Kitajima S, Konieczkowski DJ, Medetgul-Ernar K, Cavazos T, Mah C, Ting S, Van Allen EM, Cohen O, McDermott J, Damato E, Aguirre AJ, Liang J, Liberzon A, Alexe G, Doench J, Ghandi M, Vazquez F, Weir BA, Tsherniak A, Subramanian A, Meneses-Cime K, Park J, Clemons P, Garraway LA, Thomas D, Boehm JS, Barbie DA, Hahn WC, Mesirov JP, Tamayo P. Decomposing Oncogenic Transcriptional Signatures to Generate Maps of Divergent Cellular States. Cell Syst. 2017;5(2):105-18 e9. doi: 10.1016/j.cels.2017.08.002. PubMed PMID: 28837809; PMCID: PMC5639711.
Ilic N, Birsoy K, Aguirre AJ, Kory N, Pacold ME, Singh S, Moody SE, DeAngelo JD, Spardy NA, Freinkman E, Weir BA, Tsherniak A, Cowley GS, Root DE, Asara JM, Vazquez F, Widlund HR, Sabatini DM, Hahn WC. PIK3CA mutant tumors depend on oxoglutarate dehydrogenase. Proc Natl Acad Sci U S A. 2017;114(17):E3434-E43. doi: 10.1073/pnas.1617922114. PubMed PMID: 28396387; PMCID: PMC5410781.
Aguirre AJ, Hahn WC. Synthetic Lethal Vulnerabilities in KRAS-Mutant Cancers. Cold Spring Harb Perspect Med. 2017. doi: 10.1101/cshperspect.a031518. PubMed PMID: 29101114.
Kim JW, Botvinnik OB, Abudayyeh O, Birger C, Rosenbluh J, Shrestha Y, Abazeed ME, Hammerman PS, DiCara D, Konieczkowski DJ, Johannessen CM, Liberzon A, Alizad-Rahvar AR, Alexe G, Aguirre A, Ghandi M, Greulich H, Vazquez F, Weir BA, Van Allen EM, Tsherniak A, Shao DD, Zack TI, Noble M, Getz G, Beroukhim R, Garraway LA, Ardakani M, Romualdi C, Sales G, Barbie DA, Boehm JS, Hahn WC, Mesirov JP, Tamayo P. Characterizing genomic alterations in cancer by complementary functional associations. Nat Biotechnol. 2016;34(5):539-46. doi: 10.1038/nbt.3527. PubMed PMID: 27088724; PMCID: PMC4868596.
Howard TP, Vazquez F, Tsherniak A, Hong AL, Rinne M, Aguirre AJ, Boehm JS, Hahn WC. Functional Genomic Characterization of Cancer Genomes. Cold Spring Harb Symp Quant Biol. 2016;81:237-46. doi: 10.1101/sqb.2016.81.031070. PubMed PMID: 27815544.
Aguirre AJ, Meyers RM, Weir BA, Vazquez F, Zhang CZ, Ben-David U, Cook A, Ha G, Harrington WF, Doshi MB, Kost-Alimova M, Gill S, Xu H, Ali LD, Jiang G, Pantel S, Lee Y, Goodale A, Cherniack AD, Oh C, Kryukov G, Cowley GS, Garraway LA, Stegmaier K, Roberts CW, Golub TR, Meyerson M, Root DE, Tsherniak A, Hahn WC. Genomic Copy Number Dictates a Gene-Independent Cell Response to CRISPR/Cas9 Targeting. Cancer Discov. 2016;6(8):914-29. doi: 10.1158/2159-8290.CD-16-0154. PubMed PMID: 27260156; PMCID: PMC4972686.