Jagged1, a marker and therapeutic target for breast cancer bone metastasis

Princeton Docket # 11-2669

Although several molecular contributors of bone metastasis have been identified, effective therapies still await a more comprehensive understanding of the complex molecular and cellular networks of tumor stromal interactions in bone metastasis. Researchers in the Department of Molecular Biology, Princeton University have discovered that (1) elevated expression of the Notch pathway ligand Jagged1 is associated with decreased relapse-free or bone metastasis-free survival in patients, (2) tumor-derived Jagged1 promotes bone metastasis of breast cancer through the use of in vitro and in vivo xenograft models, and 3) Tumor-derived Jagged1 promote bone metastasis by engaging bone stromal cells through Notch signaling.  Jagged1 promotes osteoclast differentiation independently of RANKL signal, and stimulates the expression of IL-6 from osteoblasts to further increase tumor growth. 

This invention is a method to use Jagged1 as a prognostic marker for the risk of bone metastasis in breast cancer patients.  It also presents a novel method to treat breast cancer bone metastasis by targeting the Jagged1/Notch signaling in the bone stroma.  In addition, Jagged1 may serve as a diagnostic marker to identify patients whose bone metastasis may be refractory to currently available RANKL targeting treatments (e.g. denosumab) but may instead benefit from Jagged1/Notch targeting treatments, such as gamma secretase inhibitors or monoclonal antibodies targeting Jagged1 or Notch.

 Applications  

 ·         Poor-prognostic marker for higher risk of bone metastasis

·         Therapeutic target for breast cancer metastasis

·         Predictive marker to identify breast cancer patients who may be non-responsible to RANKL   targeting treatment  but may benefit from Jagged1/Notch targeting treatments

Publications:

Sethi N, Dai X, Winter CG, Kang Y, Tumor-Derived Jagged 1 Promotes Osteolytic bone Metastasis of Breast Cancer by Engaging Notch Signaling in Bone Cells, Cancer Cell, 19,192-205, February 15, 2011

Background

In breast cancer patients, certain pathways are aberrantly activated leading to not only primary tumor progression but also distant metastasis with particular tropism to the bone.  The Notch pathway has been implicated in breast cancer primary tumor development, but has never been shown to contribute to metastasis.  Moreover, the existing paradigm suggests that the Notch pathway is activated in the tumor cells, whereas our study has established a new model in which this pathway is activated in the tumor associated stromal microenvironment.  Here, we discovered that the Notch pathway ligand Jagged1 is upregulated in breast cancer cells that have greater metastatic ability.  Independent patient data sets also demonstrated that elevated Jagged1 expression is associated with decreased relapse-free or bone metastasis-free survival.  We further elucidated the molecular mechanisms by which tumor derived Jagged1 activate osteoclast differentiation and promote tumor growth through stromal feedback.

The Inventor

Yibin Kang is an associate professor of molecular biology and a lead expert in cancer metastasis. The central theme of his research is a multidisciplinary and integrative approach to the analysis of the molecular basis of cancer metastasis, combining molecular biology and genomics tools with animal models and advanced in vivo imaging technologies. His work is focused on the identification of metastasis genes and functional characterization of their involvement in tumor-stromal interactions during the formation of metastasis in different organs and is also interested in regulators of mammary gland development and early oncogenic events that may have significant impact on tumor progression and metastasis. 

Intellectual Property & Development status

Patents protection is pending.

Contact:

Laurie Tzodikov

Princeton University Office of Technology Licensing ¿ (609) 258-7256¿ tzodikov@princeton.edu

Shan Wan

Princeton University Office of Technology Licensing ¿ (609) 258-5579¿ shanwan@princeton.edu

PU #11-2669