Department of Medical Oncology
Dana-Farber Cancer Institute
Assistant Professor of Medicine, Harvard Medical School
Associate Member, Broad Institute of MIT and Harvard
Dr. Aguirre has dedicated his career to becoming a physician-scientist with a focus on cancer biology and translational oncology. He has a longstanding interest in gastrointestinal (GI) malignancies, particularly pancreatic ductal adenocarcinoma, from originally studying the biology and genetics of pancreatic cancer in graduate school with Dr. Ronald DePinho, to later training in internal medicine at Massachusetts General Hospital and in medical oncology at the Dana-Farber/Partners Cancer Care Program.
Dr. Aguirre utilizes functional genetic screens to identify critical signaling pathways in pancreatic cancer, with the goal of finding novel therapeutic approaches to this intractable disease. Additionally, he is an active member of the GI medical oncology division and leads translational research efforts for genomics studies of freshly collected human pancreatic and colon cancer specimens, as well as generation of in vitro and in vivo models of these diseases.
He actively collaborates with the Center for Cancer Precision Medicine and the Shalek Lab to perform single-cell RNA sequencing of neoplastic and non-neoplastic cell types from freshly resected primary tumors and needle biopsies of colon and pancreatic cancer. His training in genomic and functional analysis of human tumors allows him to pursue his longstanding interest in the genetics and biology of GI cancers.
The Aguirre Lab is committed to identifying novel therapeutic targets for pancreatic cancer, understanding heterogeneity of the disease, and building pre-clinical model systems that most accurately reflect the patient tumors.
We have a long-standing interest in the KRAS signaling proteins and KRAS downstream effector molecules, since KRAS is mutated in >90% of pancreatic cancers but is currently undruggable. While MEK inhibitors have been successful in other solid tumors, they are not effective in pancreatic cancer, and we have, therefore, screened for modifiers of MEK inhibitor sensitivity to identify future combination therapies. We are also searching genome-scale with CRISPR-Cas9 libraries and loss-of-function screens to identify novel targets for pancreatic cancer.
Together with the Hahn and the Wolpin Labs, as well as Dr. Sicinska, we are continuously preparing more patient-derived cell lines, tumor organoids, and patient-derived xenografts (PDXs) as part of a future “biobank.” We are currently comparing the pros and cons of each model system with regard to testing of chemical compounds.
Additionally, in collaboration with the Shalek Lab at MIT, we are using single-cell RNA sequencing to understand tumor cell heterogeneity, which may also inform us about resistance mechanisms to specific drugs used for treatment.
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.