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Cancer Cell. 2017 Dec 11;32(6):731-747.e6. doi: 10.1016/j.ccell.2017.11.002.

Therapeutic Antibody Targeting Tumor- and Osteoblastic Niche-Derived Jagged1 Sensitizes Bone Metastasis to Chemotherapy.

Author information

1
Department of Molecular Biology, Princeton University, Washington Road, LTL 255, Princeton, NJ 08544, USA.
2
Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Room R814 BCM225, Houston, TX 77030, USA.
3
Department of Gynecology and Obstetrics, University Hospital Essen, Essen, Germany.
4
Department of Pathology, University Medical Center of Princeton, Plainsboro, NJ, USA; Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA.
5
Laboratory of Hematopoiesis Immunology, Cancer Research Center, Moscow, Russia.
6
Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Center of Experimental Medicine, Hamburg, Germany.
7
Oncology Research, Amgen Inc., Thousand Oaks, CA 91320, USA.
8
MabVax Therapeutics Holdings, Inc., San Diego, CA 92121, USA.
9
Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Room R814 BCM225, Houston, TX 77030, USA. Electronic address: blee@bcm.edu.
10
Department of Molecular Biology, Princeton University, Washington Road, LTL 255, Princeton, NJ 08544, USA; Cancer Metabolism and Growth Program, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA. Electronic address: ykang@princeton.edu.

Abstract

Bone metastasis is a major health threat to breast cancer patients. Tumor-derived Jagged1 represents a central node in mediating tumor-stromal interactions that promote osteolytic bone metastasis. Here, we report the development of a highly effective fully human monoclonal antibody against Jagged1 (clone 15D11). In addition to its inhibitory effect on bone metastasis of Jagged1-expressing tumor cells, 15D11 dramatically sensitizes bone metastasis to chemotherapy, which induces Jagged1 expression in osteoblasts to provide a survival niche for cancer cells. We further confirm the bone metastasis-promoting function of osteoblast-derived Jagged1 using osteoblast-specific Jagged1 transgenic mouse model. These findings establish 15D11 as a potential therapeutic agent for the prevention or treatment of bone metastasis.

KEYWORDS:

Jagged1; bone metastasis; breast cancer; chemoresistance; neutralizing antibody; osteoblastic niche; osteoblasts

PMID:
29232552
PMCID:
PMC5729937
DOI:
10.1016/j.ccell.2017.11.002
[Indexed for MEDLINE]
Free PMC Article

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