A NOTCH1 gene copy number gain is a prognostic indicator of worse survival and a predictive biomarker to a Notch1 targeting antibody in colorectal cancer
John J. Arcaroli
Division of Medical Oncology, University of Colorado Denver Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, CO
Search for more papers by this authorW.M. Tai
Division of Medical Oncology, University of Colorado Denver Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, CO
Search for more papers by this authorRyan McWilliams
Division of Medical Oncology, University of Colorado Denver Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, CO
Search for more papers by this authorStacey Bagby
Division of Medical Oncology, University of Colorado Denver Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, CO
Search for more papers by this authorPatrick J. Blatchford
Department of Biostatistics & Informatics, University of Colorado Denver Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, CO
Search for more papers by this authorMarileila Varella-Garcia
Division of Medical Oncology, University of Colorado Denver Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, CO
Search for more papers by this authorAlicia Purkey
Division of Medical Oncology, University of Colorado Denver Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, CO
Search for more papers by this authorKevin S. Quackenbush
Division of Medical Oncology, University of Colorado Denver Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, CO
Search for more papers by this authorEun-Kee Song
Division of Medical Oncology, University of Colorado Denver Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, CO
Search for more papers by this authorTodd M. Pitts
Division of Medical Oncology, University of Colorado Denver Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, CO
Search for more papers by this authorDexiang Gao
Department of Biostatistics & Informatics, University of Colorado Denver Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, CO
Search for more papers by this authorChris Lieu
Division of Medical Oncology, University of Colorado Denver Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, CO
Search for more papers by this authorMartine McManus
Division of Medical Oncology, University of Colorado Denver Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, CO
Search for more papers by this authorAik Choon Tan
Division of Medical Oncology, University of Colorado Denver Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, CO
Search for more papers by this authorXianxian Zheng
Pfizer Oncology Research Unit, Translational Research, Pfizer, La Jolla, CA
Search for more papers by this authorQin Zhang
Pfizer Oncology Research Unit, Translational Research, Pfizer, La Jolla, CA
Search for more papers by this authorMark Ozeck
Pfizer Oncology Research Unit, Translational Research, Pfizer, La Jolla, CA
Search for more papers by this authorPeter Olson
Pfizer Oncology Research Unit, Translational Research, Pfizer, La Jolla, CA
Search for more papers by this authorZhi-Qin Jiang
MD Anderson Cancer Center, Texas Medical Center, Houston, TX
Search for more papers by this authorScott Kopetz
MD Anderson Cancer Center, Texas Medical Center, Houston, TX
Search for more papers by this authorAntonio Jimeno
Division of Medical Oncology, University of Colorado Denver Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, CO
Search for more papers by this authorStephen Keysar
Division of Medical Oncology, University of Colorado Denver Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, CO
Search for more papers by this authorGail Eckhardt
Division of Medical Oncology, University of Colorado Denver Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, CO
Search for more papers by this authorCorresponding Author
Wells A. Messersmith
Division of Medical Oncology, University of Colorado Denver Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, CO
Correspondence to: Wells Messersmith, 12801 E 17th Ave, MS 8117, Aurora, CO 80045, USA, Tel.: +303-724-3808, Fax: +303-724-3892, E-mail: [email protected]Search for more papers by this authorJohn J. Arcaroli
Division of Medical Oncology, University of Colorado Denver Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, CO
Search for more papers by this authorW.M. Tai
Division of Medical Oncology, University of Colorado Denver Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, CO
Search for more papers by this authorRyan McWilliams
Division of Medical Oncology, University of Colorado Denver Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, CO
Search for more papers by this authorStacey Bagby
Division of Medical Oncology, University of Colorado Denver Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, CO
Search for more papers by this authorPatrick J. Blatchford
Department of Biostatistics & Informatics, University of Colorado Denver Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, CO
Search for more papers by this authorMarileila Varella-Garcia
Division of Medical Oncology, University of Colorado Denver Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, CO
Search for more papers by this authorAlicia Purkey
Division of Medical Oncology, University of Colorado Denver Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, CO
Search for more papers by this authorKevin S. Quackenbush
Division of Medical Oncology, University of Colorado Denver Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, CO
Search for more papers by this authorEun-Kee Song
Division of Medical Oncology, University of Colorado Denver Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, CO
Search for more papers by this authorTodd M. Pitts
Division of Medical Oncology, University of Colorado Denver Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, CO
Search for more papers by this authorDexiang Gao
Department of Biostatistics & Informatics, University of Colorado Denver Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, CO
Search for more papers by this authorChris Lieu
Division of Medical Oncology, University of Colorado Denver Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, CO
Search for more papers by this authorMartine McManus
Division of Medical Oncology, University of Colorado Denver Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, CO
Search for more papers by this authorAik Choon Tan
Division of Medical Oncology, University of Colorado Denver Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, CO
Search for more papers by this authorXianxian Zheng
Pfizer Oncology Research Unit, Translational Research, Pfizer, La Jolla, CA
Search for more papers by this authorQin Zhang
Pfizer Oncology Research Unit, Translational Research, Pfizer, La Jolla, CA
Search for more papers by this authorMark Ozeck
Pfizer Oncology Research Unit, Translational Research, Pfizer, La Jolla, CA
Search for more papers by this authorPeter Olson
Pfizer Oncology Research Unit, Translational Research, Pfizer, La Jolla, CA
Search for more papers by this authorZhi-Qin Jiang
MD Anderson Cancer Center, Texas Medical Center, Houston, TX
Search for more papers by this authorScott Kopetz
MD Anderson Cancer Center, Texas Medical Center, Houston, TX
Search for more papers by this authorAntonio Jimeno
Division of Medical Oncology, University of Colorado Denver Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, CO
Search for more papers by this authorStephen Keysar
Division of Medical Oncology, University of Colorado Denver Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, CO
Search for more papers by this authorGail Eckhardt
Division of Medical Oncology, University of Colorado Denver Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, CO
Search for more papers by this authorCorresponding Author
Wells A. Messersmith
Division of Medical Oncology, University of Colorado Denver Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, CO
Correspondence to: Wells Messersmith, 12801 E 17th Ave, MS 8117, Aurora, CO 80045, USA, Tel.: +303-724-3808, Fax: +303-724-3892, E-mail: [email protected]Search for more papers by this authorConflict of interest: Peter Olson is an employee of Pfizer and owns stock in Pfizer; Xianxian Zheng is an employee of Pfizer and owns stock in Pfizer; Qin Zhang is an employee of Pfizer and owns stock in Pfizer.
Abstract
Dysregulation of the Notch1 receptor has been shown to facilitate the development and progression of colorectal cancer (CRC) and has been identified as an independent predictor of disease progression and worse survival. Although mutations in the NOTCH1 receptor have not been described in CRC, we have previously discovered a NOTCH1 gene copy number gain in a portion of CRC tumor samples. Here, we demonstrated that a NOTCH1 gene copy number gain is significantly associated with worse survival and a high percentage of gene duplication in a cohort of patients with advanced CRC. In our CRC patient-derived tumor xenograft (PDTX) model, tumors harboring a NOTCH1 gain exhibited significant elevation of the Notch1 receptor, JAG1 ligand and cleaved Notch1 activity. In addition, a significant association was identified between a gain in NOTCH1 gene copy number and sensitivity to a Notch1-targeting antibody. These findings suggest that patients with metastatic CRC that harbor a gain in NOTCH1 gene copy number have worse survival and that targeting this patient population with a Notch1 antibody may yield improved outcomes.
Abstract
What's new?
There is mounting evidence that the Notch1 receptor is important in modulating tumor growth and an independent predictor of survival in colorectal cancer (CRC). While mutations in the NOTCH1 receptor have not yet been described in CRC, this study shows that a gain in NOTCH1 gene copy number is associated with worse survival. Targeting cells with a specific Notch1 antibody resulted in potent antitumor growth in a CRC patient-derived tumor xenograft model. A NOTCH1 gene copy number gain may thus be a prognostic marker for disease recurrence as well as a predictive biomarker of sensitivity to a Notch1 targeted therapy.
Supporting Information
Additional Supporting Information may be found in the online version of this article.
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