Targeting ADAM17 inhibits human colorectal adenocarcinoma progression and tumor-initiating cell frequency
Autor: | Theodore H. Welling, Kathryn E. Luker, Robert E. Hollingsworth, Ronald Herbst, Judith S. Sebolt-Leopold, Jonathan Rios-Doria, Eric R. Fearon, Elizabeth Ziemke, Matt Flynn, Joseph Dosch, Suneetha Thomas, Elaine M. Hurt, Karin M. Hardiman, Shanshan Wan |
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Rok vydání: | 2017 |
Předmět: |
0301 basic medicine
Oncology medicine.medical_specialty Notch Colorectal cancer Notch signaling pathway 03 medical and health sciences Therapeutic approach 0302 clinical medicine Internal medicine medicine Colorectal adenocarcinoma colorectal ADAM17 TACE Tumor microenvironment business.industry medicine.disease Tumor initiating cell 3. Good health stem cell Specific antibody 030104 developmental biology 030220 oncology & carcinogenesis Immunology Stem cell business Research Paper |
Zdroj: | Oncotarget |
ISSN: | 1949-2553 |
Popis: | // 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. |
Databáze: | OpenAIRE |
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