Targeting ADAM17 inhibits human colorectal adenocarcinoma progression and tumor-initiating cell frequency

// Joseph Dosch 1, * , Elizabeth Ziemke 1, * , Shanshan Wan 2 , Kathryn Luker 1 , Theodore Welling 2 , Karin Hardiman 2 , Eric Fearon 3 , Suneetha Thomas 4 , Matthew Flynn 4 , Jonathan Rios-Doria 4 , Robert Hollingsworth 4 , Ronald Herbst 4 , Elaine Hurt 4, # and Judith Sebolt-Leopold 1, # 1 Department of Radiology, University of Michigan, Ann Arbor, MI 48109, USA 2 Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA 3 Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA 4 Department of Oncology Research, MedImmune, LLC, Gaithersburg, MD 20878, USA * These authors contributed equally to this work # Co-senior authors Correspondence to: Judith Sebolt-Leopold, email: jssl@med.umich.edu Keywords: ADAM17, TACE, colorectal, stem cell, Notch Received: November 24, 2016      Accepted: April 03, 2017      Published: May 10, 2017 ABSTRACT ADAM17 (a disintegrin and metalloproteinase 17)/TACE (TNFα converting enzyme) has emerged as a potential therapeutic target in colorectal cancer (CRC) and other cancers, due in part to its role in regulating various tumor cell surface proteins and growth factors and cytokines in the tumor microenvironment. The emergence of MEDI3622, a highly potent and specific antibody-based ADAM17 inhibitor, has allowed testing of the concept that targeting ADAM17 may be an important new therapeutic approach for CRC patients. We demonstrate that MEDI3622 is highly efficacious on tumor growth in multiple human CRC PDX models, resulting in improved survival of animals bearing tumor xenografts. MEDI3622 was further found to impact Notch pathway activity and tumor-initiating cells. The promising preclinical activity seen here supports further clinical investigation of this treatment approach to improve therapeutic outcome for patients diagnosed with metastatic CRC, including patients with KRAS-mutant tumors for whom other therapeutic options are currently limited.