Therapeutic Antibody Targeting Tumor- and Osteoblastic Niche-Derived Jagged1 Sensitizes Bone Metastasis to Chemotherapy
Posted October 19, 2018
Yibin Kang, Ph.D., Princeton University
More than 70% of late-stage breast cancer patients suffer from metastasis to the bones, which causes pain, fracture, and potentially lethal hypercalcemia. These complications arise due to osteolysis, or the breakdown of bone, by way of tumor-initiated hyperactivity of bone resorbing osteoclast cells. Current treatments that combine chemotherapy with a blockade of osteoclast activation ameliorate these morbidities, but they fail to offer patients additional survival benefits. Recent reports suggest disseminated tumor cells (DTC) from breast cancers that express the Notch signaling pathway ligand, Jagged1, facilitate a pro-tumor niche in the bone by activating a positive feedback loop where both the resident bone-building osteoblasts and bone-destroying osteoclasts become activated, causing release of tumor cell survival factors from the bone. General Notch pathway inhibitors have failed clinically due to severe gastrointestinal tract toxicity. However, Jagged1’s seemingly high importance in breast cancer metastases establishes it as a strong candidate for the development of new targeted therapies. With a fiscal year 2012 (FY12) Breast Cancer Research Program (BCRP) Collaborative Scholars and Innovators Award, Dr. Yibin Kang sought to exploit the expression of Jagged1 in DTCs and successfully developed a fully humanized monoclonal antibody, 15D11, with high affinity for human Jagged1 and, most importantly, low toxicity in preclinical studies.
As demonstrated in their recent Cancer Cell study, pre-treatment with 15D11 prevented the establishment of bone metastases in mice injected with human breast cancer cells overexpressing Jagged1. 15D11 pre-treatment also demonstrated a protective effect in bones from excessive osteoclast-induced osteolysis. To determine whether 15D11 would be effective at eliminating already established bone metastases, a model of late stage disease, 15D11 was administered in combination with the chemotherapeutic agent, paclitaxel (PTX). Strikingly, a combination of 15D11 and PTX resulted in a synergistic 100-fold reduction of bone metastases in mice injected with high Jagged1 -expressing breast tumor cells. Unexpectedly, 15D11 and PTX in combination also produced a synergistic reduction of metastasis and osteolysis in the low Jagged1-expressing breast tumor setting. Further investigation into why the low Jagged1-expressing bone metastases responded to combination therapy led the team to discover that chemotherapy induced an upregulation of Jagged1 in osteoblast cells which in turn provided survival signals to the tumor cells and mediated their ability to become resistant to PTX treatment; this phenotype could be reversed upon administration of 15D11 with PTX.
The chemotherapeutic induction of Jagged1 in osteoblast cells was also found to occur in clinical samples from patients. Bone tumor biopsies were obtained before and after initiation of adjuvant chemotherapy of carboplatin and PTX, and levels of Jagged1 were measured in osteoblast cells. Jagged1 was found to be upregulated in osteoblasts after chemotherapy treatment.
Fundamentally, Dr. Kang’s work demonstrates a previously unknown metastatic reliance of primary breast cancers on an upregulation of Jagged1 in osteoblasts in response to conventional chemotherapy. As the current standard of care for many breast cancer patients is prophylactic chemotherapy, even in early stages, Dr. Kang’s work suggests that this may actually favor bone metastases even as it suppresses primary tumor growth. Based upon the superior preclinical safety profile of 15D11, Dr. Kang’s team has provided evidence for further clinical development of this potentially powerful new therapeutic to both prevent metastatic recurrences to the bone and to combat established bone metastases in breast cancer patients.
Zheng 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, Toni Jun H, Coxon A, Lee B, and Kang Y. 2017. Therapeutic antibody targeting tumor- and osteoblastic niche-derived jagged1 sensitizes bone metastasis to chemotherapy. Cancer Cell 32(6):731-747.
Last updated Friday, October 19, 2018