Gastrointestinal Stromal Tumor (GIST) is the most common human sarcoma. While the small molecule drug imatinib has served as the paradigm for tyrosine kinase inhibition and has been effective in GIST, most patients will eventually develop drug resistance and disease progression. Our lab prioritizes the use of multiple immunocompetent genetically engineered mouse models of GIST to study in vivo tumor biology and immunology. The goal of our lab is to develop novel therapies, with a particular focus on immunotherapy, to overcome imatinib resistance. Multiple therapies identified in our mouse models have been translated into clinical trials for GIST patients.
Ronald P. DeMatteo, MD. FACS - Principal Investigator
DeMatteoLab@pennmedicine.upenn.edu
Room 446A, Stemmler Hall, 3450 Hamilton Walk
Our research is made possible with generous donations from the David Foundation,
Betsy Levine Brown and Marc Brown, and the GIST Cancer Research Fund.
Dr. DeMatteo is the John Rhea Barton Professor and Chairman of Surgery at the University of Pennsylvania. He has trained over twenty surgical residents in his laboratory who have gone into academic careers in Surgical Oncology. Dr. DeMatteo earned his undergraduate degree from The Johns Hopkins University and his medical degree from the Weill Medical College of Cornell University. He completed his residency in General Surgery at the University of Pennsylvania and then a fellowship in Surgical Oncology at Memorial Sloan Kettering Cancer Center. Dr. DeMatteo served as the principle investigator on three national trials for the adjuvant drug imatinib in GIST following surgery, which has led to its approval for adjuvant use by the FDA and became the standard of care.
Current Lab Members
Ferdinando Rossi
Senior Scientist
Susan Zeng
Senior Scientist
Hyunjee Kwak
UPenn Fellow
Katherine Tardy
UPenn Fellow
Kevin Do
Research Technician
Laura Wang
Research Technician
Resident Applications
We are now accepting applications from surgical residents to join our basic and translational research lab. Residents will spend a minimum of 2 years studying GIST and tumor immunology under the mentorship of Dr. DeMatteo. Funding is provided.
All interested applicants should send a cover letter and CV to Andrew.Tieniber@Pennmedicine.upenn.edu
Previous Lab Members
Previous Scientist
Susan Zeng (2010-2017), Senior Scientist, Emory University
Previous Fellows
Mark Etherington (2018-2020) University of Pennsylvania, Resident
Marion Liu (2017-2019) Cornell University, Resident
Gerardo Vitiello (2016-2018) University of New York, Resident
Timothy Bowler (2016-2018) Regeneron Pharm Inc, Medical Director
Benjamin Medina (2015-2017), Memorial Sloan Kettering Cancer Center, Fellow
Jennifer Zhang (2014-2017), Memorial Sloan Kettering Cancer Center, Fellow
Adam Levy (2014-2015), UCLA School of Medicine, Fellow
Michael Beckman (2013-2015), Carolinas Medical Center, Attending
Juan Santamaria (2013-2015), University of Nebraska Medical Center, Assistant Professor of Surgery
Adrian Seifert (2012-2015), Asklepios-ASB Klinik Radeberg, Senior Physician
Noah Cohen (2012-2014), Mount Sinai, Attending
Jonathan Greer (2011-2014), Johns Hopkins, Attending
Teresa Kim (2011-2013), University of Washington, Seattle, Attending
Eric Sorenson (2010-2013), Intermountain Healthcare, UT, Attending
Michael Cavnar (2009-2012), University of Kentucky, Attending
Lee Ocuin (2008-2011), Carolinas Healthcare System, NC, Attending
Vinod Balachandran (2008-2010), Memorial Sloan Kettering Cancer Center, Attending
Zubin Bamboat (2007-2009), Summit Medical Group, NJ, Attending
Bryan Burt (2006-2008), Baylor University, Attending
George Plitas (2006-2008), Memorial Sloan Kettering Cancer Center, Attending
Hoang Nguyen (2006-2008), Sanford Health, SD, Attending
T. Peter Kingham, Memorial Sloan Kettering Cancer Center, Attending
Jennifer Stableford, Darmouth-Hitchcock, Attending
Umer Chaudhry (2004-2006), Kaiser Permanente Anaheim, CA, Attending
Steve Katz (2003-2005), TriSalus Life Sciences, Chief Medical Officer
Josh Bleier (2002-2004), University of Pennsylvania, Attending
Venu Pillarisetty (2001-2004), University of Washington, Seattle, Attending
George Miller (2000-2002), New York University, Attending
Previous Technicians
Lillian Levin (2019-2021) University of Pennsylvania, Research Specialist B
Mia DiLolle (2018-2019)
Nesteene Param (2016-2018) University of Pennsylvania, Research Specialist
Jennifer Loo (2014-2017), University at Buffalo, Medical Student
Joanna Maltbaek (2014-2016), University of Washington, PhD Candidate
Benjamin Green (2012-2014), Temple University, Medical Student
Megan Crawley (2012-2014), Massachusetts General Hospital, Genetic Counseling
Rachel Popow (2010-2012), Rutgers University, Medical Student
Hebroon Obaid (2008-2010), Stamford, CT, General Surgeon
Alexander Welles (2006-2008) US Army Research Institute of Environmental Medicine
Jesse Raab (2004-2006) University of North Carolina at Chapel Hill, Assistant Professor
Alaap B. Shah (2002-2004)
Svenja Lahrs (2002-2004)
Projects
Gastrointestinal Stromal Tumor (GIST) and the Immune System
Our laboratory discovered that imatinib changes the intratumoral immune environment by activating cytotoxic CD8+ T cells and inducing apoptosis of anti-inflammatory regulatory T cells through the inhibition of tumor-derived Ido. The immune-mediated anti-tumor effects of imatinib are enhanced when combined with immunotherapy such as CTLA-4 blockade, which led to a clinical trial in human GIST patients. Other cells in the tumor microenvironment, including macrophages, DCs, and stromal cells, also mediate tumor growth and destruction. We seek to better understand the role of the immune system in GIST, with the intention of developing novel molecular and immune-based treatment strategies.
GIST and Oncogene Signaling
Nearly 75% of GISTs contain an activating Kit mutation, while 10% have a mutation in platelet derived growth factor receptor alpha (PDGFRa). Imatinib inhibits both Kit and PDGFRa oncoproteins and has improved survival in metastatic GIST, but patients eventually develop resistance and tumor progression. We have studied the effect of imatinib on Kit signaling and on various compensatory oncogene signaling pathways, including MET. Currently, we are interested in the role of endogenous Kit ligand signaling in the presence of a constitutively active mutation with respect to imatinib resistance.
Selected Publications
2009
Gold, J. S., M. Gonen, A. Gutierrez, J. M. Broto, X. Garcia-del-Muro, T. C. Smyrk, R. G. Maki, S. Singer, M. F. Brennan, C. R. Antonescu, J. H. Donohue, and R. P. DeMatteo. 2009. ‘Development and validation of a prognostic nomogram for recurrence-free survival after complete surgical resection of localised primary gastrointestinal stromal tumour: a retrospective analysis’, Lancet Oncol, 10: 1045-52.
Dematteo, R. P., K. V. Ballman, C. R. Antonescu, R. G. Maki, P. W. Pisters, G. D. Demetri, M. E. Blackstein, C. D. Blanke, M. von Mehren, M. F. Brennan, S. Patel, M. D. McCarter, J. A. Polikoff, B. R. Tan, K. Owzar, and Gist Study Team American College of Surgeons Oncology Group Intergroup Adjuvant. 2009. ‘Adjuvant imati-nib mesylate after resection of localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebo-controlled trial’, Lancet, 373: 1097-104.
2011
Balachandran, V. P., M. J. Cavnar, S. Zeng, Z. M. Bamboat, L. M. Ocuin, H. Obaid, E. C. Sorenson, R. Popow, C. Ariyan, F. Rossi, P. Besmer, T. Guo, C. R. Antonescu, T. Taguchi, J. Yuan, J. D. Wolchok, J. P. Allison, and R. P. DeMatteo. 2011. ‘Imatinib potentiates antitumor T cell responses in gastrointestinal stromal tumor through the inhibition of Ido’, Nat Med, 17: 1094-100.
2012
McCarter, M. D., C. R. Antonescu, K. V. Ballman, R. G. Maki, P. W. Pisters, G. D. Demetri, C. D. Blanke, M. von Mehren, M. F. Brennan, L. McCall, D. M. Ota, R. P. DeMatteo, and Team American College of Surgeons Oncol-ogy Group Intergroup Adjuvant Gist Study. 2012. ‘Microscopically positive margins for primary gastrointestinal stromal tumors: analysis of risk factors and tumor recurrence’, J Am Coll Surg, 215: 53-9; discussion 59-60.
2013
Cavnar, M. J., S. Zeng, T. S. Kim, E. C. Sorenson, L. M. Ocuin, V. P. Balachandran, A. M. Seifert, J. B. Greer, R. Popow, M. H. Crawley, N. A. Cohen, B. L. Green, F. Rossi, P. Besmer, C. R. Antonescu, and R. P. DeMatteo. 2013. ‘KIT oncogene inhibition drives intratumoral macrophage M2 polarization’, J Exp Med, 210: 2873-86.
2014
Kim, T. S., M. J. Cavnar, N. A. Cohen, E. C. Sorenson, J. B. Greer, A. M. Seifert, M. H. Crawley, B. L. Green, R. Popow, N. Pillarsetty, D. R. Veach, A. T. Ku, F. Rossi, P. Besmer, C. R. Antonescu, S. Zeng, and R. P. Dematteo. 2014. ‘Increased KIT inhibition enhances therapeutic efficacy in gastrointestinal stromal tumor’, Clin Can-cer Res, 20: 2350-62.
Corless, C. L., K. V. Ballman, C. R. Antonescu, V. Kolesnikova, R. G. Maki, P. W. Pisters, M. E. Blackstein, C. D. Blanke, G. D. Demetri, M. C. Heinrich, M. von Mehren, S. Patel, M. D. McCarter, K. Owzar, and R. P. DeMatteo. 2014. ‘Pathologic and molecular features correlate with long-term outcome after adjuvant therapy of resected primary GI stromal tumor: the ACOSOG Z9001 trial’, J Clin Oncol, 32: 1563-70.
2015
Cohen, N. A., S. Zeng, A. M. Seifert, T. S. Kim, E. C. Sorenson, J. B. Greer, M. J. Beckman, J. A. Santamaria-Barria, M. H. Crawley, B. L. Green, F. Rossi, P. Besmer, C. R. Antonescu, and R. P. DeMatteo. 2015. ‘Pharmacological Inhibition of KIT Activates MET Signaling in Gastrointestinal Stromal Tumors’, Cancer Res, 75: 2061-70.
2017
Zeng, S., A. M. Seifert, J. Q. Zhang, T. S. Kim, T. G. Bowler, M. J. Cavnar, B. D. Medina, G. A. Vitiello, F. Rossi, J. K. Loo, N. J. Param, and R. P. DeMatteo. 2017. ‘ETV4 collaborates with Wnt/beta-catenin signaling to alter cell cycle activity and promote tumor aggressiveness in gastrointestinal stromal tumor’, Oncotarget, 8: 114195-209.
Seifert, A. M., S. Zeng, J. Q. Zhang, T. S. Kim, N. A. Cohen, M. J. Beckman, B. D. Medina, J. H. Maltbaek, J. K. Loo, M. H. Crawley, F. Rossi, P. Besmer, C. R. Antonescu, and R. P. DeMatteo. 2017. ‘PD-1/PD-L1 Blockade Enhances T-cell Activity and Antitumor Efficacy of Imatinib in Gastrointestinal Stromal Tumors’, Clin Cancer Res, 23: 454-65.
Bosbach, B., F. Rossi, Y. Yozgat, J. Loo, J. Q. Zhang, G. Berrozpe, K. Warpinski, I. Ehlers, D. Veach, A. Kwok, K. Manova, C. R. Antonescu, R. P. DeMatteo, and P. Besmer. 2017. ‘Direct engagement of the PI3K pathway by mutant KIT dominates oncogenic signaling in gastrointestinal stromal tumor’, Proc Natl Acad Sci U S A, 114: E8448-E57.
Zeng, S., A. M. Seifert, J. Q. Zhang, M. J. Cavnar, T. S. Kim, V. P. Balachandran, J. A. Santamaria-Barria, N. A. Cohen, M. J. Beckman, B. D. Medina, F. Rossi, M. H. Crawley, J. K. Loo, J. H. Maltbaek, P. Besmer, C. R. Antonescu, and R. P. DeMatteo. 2017. ‘Wnt/beta-catenin Signaling Contributes to Tumor Malignancy and Is Targetable in Gastrointestinal Stromal Tumor’, Mol Cancer Ther, 16: 1954-66.
2018
Vitiello, G. A., B. D. Medina, S. Zeng, T. G. Bowler, J. Q. Zhang, J. K. Loo, N. J. Param, M. Liu, A. J. Moral, J. N. Zhao, F. Rossi, C. R. Antonescu, V. P. Balachandran, J. R. Cross, and R. P. DeMatteo. 2018. ‘Mitochondrial Inhibition Augments the Efficacy of Imatinib by Resetting the Metabolic Phenotype of Gastrointestinal Stromal Tumor’, Clin Cancer Res, 24: 972-84.
Zhang, J. Q., S. Zeng, G. A. Vitiello, A. M. Seifert, B. D. Medina, M. J. Beckman, J. Loo, J. Santamaria-Barria, J. H. Maltbaek, N. J. Param, J. A. Moral, J. N. Zhao, V. Balachandran, F. Rossi, C. R. Antonescu, and R. P. DeMatteo. 2018. ‘Macrophages and CD8+ T cells mediate the anti-tumor efficacy of combined CD40 ligation and imatinib therapy in gastrointestinal stromal tumors’, Cancer Immunol Res.
2019
Medina, B. D., M. Liu, G. A. Vitiello, A. M. Seifert, S. Zeng, T. Bowler, J. Q. Zhang, M. J. Cavnar, J. K. Loo, N. J. Param, J. H. Maltbaek, F. Rossi, V. Balachandran, and R. P. DeMatteo. 2019. 'Oncogenic kinase inhibition limits Batf3-dependent dendritic cell development and antitumor immunity', J Exp Med.
Cavnar, M. J., K. Seier, C. Curtin, V. P. Balachandran, D. G. Coit, S. S. Yoon, A. M. Crago, V. E. Strong, W. D. Tap, M. Gonen, C. R. Antonescu, M. F. Brennan, S. Singer, and R. P. DeMatteo. 2019. 'Outcome of 1000 Patients With Gastrointestinal Stromal Tumor (GIST) Treated by Surgery in the Pre and Post-imatinib Eras', Ann Surg.
Etherington, M. S., and R. P. DeMatteo. 2019. 'Tailored management of primary gastrointestinal stromal tumors', Cancer.
Vitiello, G. A., T. G. Bowler, M. Liu, B. D. Medina, J. Q. Zhang, N. J. Param, J. K. Loo, R. L. Goldfeder, F. Chibon, F. Rossi, S. Zeng, and R. P. DeMatteo. 2019. 'Differential immune profiles distinguish the mutational subtypes of gastrointestinal stromal tumor', J Clin Invest.
2020
Zhang, Jennifer Q., Benedikt Bosbach, Jennifer K. Loo, Gerardo A. Vitiello, Shan Zeng, Adrian M. Seifert, Benjamin D. Medina, Nesteene J. Param, Joanna H. Maltbaek, Ferdinand Rossi, Cristina R. Antonescu, Peter Besmer, and Ronald P. DeMatteo. 2020. "The V654A Second-site KIT Mutation Increases Tumor Oncogenesis and STAT Activation in a Mouse Model of Gastrointestinal Stromal Tumor." Oncogene, 39.49: 7153-165.
Moral, John Alec, Joanne Leung, Luis A. Rojas, Jennifer Ruan, Julia Zhao, Zachary Sethna, Anita Ramnarain, Billel Gasmi, Murali Gururajan, David Redmond, Gokce Askan, Umesh Bhanot, Ela Elyada, Youngkyu Park, David A. Tuveson, Mithat Gönen, Steven D. Leach, Jedd D. Wolchok, Ronald P. DeMatteo, Taha Merghoub, and Vinod P. Balachandran. 2020. "ILC2s Amplify PD-1 Blockade by Activating Tissue-specific Cancer Immunity." Nature, 579.7797: 130-35.
2021
Liu, Mengyuan, Mark S. Etherington, Andrew Hanna, Benjamin D. Medina, Gerardo A. Vitiello, Timothy G. Bowler, Nesteene J. Param, Lillian Levin, Ferdinand Rossi, and Ronald P. DeMatteo. 2021. "Oncogenic KIT Modulates Type I IFN–Mediated Antitumor Immunity in GIST." Cancer Immunology Research.
Ye, Shuai, Dinara Sharipova, Marya Kozinova, Lilli Klug, Jimson D’Souza, Martin G. Belinsky, Katherine J. Johnson, Margret B. Einarson, Karthik Devarajan, Yan Zhou, Samuel Litwin, Michael C. Heinrich, Ronald DeMatteo, Margaret Von Mehren, James S. Duncan, and Lori Rink. 2021. "Identification of Wee1 as a Target in Combination with Avapritinib for Gastrointestinal Stromal Tumor Treatment." JCI Insight, 6.2.