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

TitleTherapeutic Antibody Targeting Tumor- and Osteoblastic Niche-Derived Jagged1 Sensitizes Bone Metastasis to Chemotherapy.
Publication TypeJournal Article
Year of Publication2017
AuthorsZheng, H, Bae, Y, Kasimir-Bauer, S, Tang, R, Chen, J, Ren, G, Yuan, M, Esposito, M, Li, W, Wei, Y, Shen, M, Zhang, L, Tupitsyn, N, Pantel, K, King, C, Sun, J, Moriguchi, J, Jun, HToni, Coxon, A, Lee, B, Kang, Y
JournalCancer Cell
Volume32
Issue6
Pagination731-747.e6
Date Published2017 Dec 11
ISSN1878-3686
KeywordsAnimals, Antibodies, Monoclonal, Antineoplastic Agents, Bone Neoplasms, Humans, Jagged-1 Protein, Mice, Mice, Transgenic, Osteoblasts, Xenograft Model Antitumor Assays
Abstract

<p>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.</p>
DOI10.1016/j.ccell.2017.11.002
Alternate JournalCancer Cell
PubMed ID29232552
PubMed Central IDPMC5729937
Grant ListR01 CA212410 / CA / NCI NIH HHS / United States
T32 GM007388 / GM / NIGMS NIH HHS / United States