Cntnap4 Signaling in Osteosarcoma Disease Progression
Abstract
The proposed project directly relates to the Fiscal Year 2019 (FY19) Peer Reviewed Cancer Research Program (PRCRP) Topic Area of Cancer in children, adolescents, and young adults and rare cancer, and the FY19 PRCRP Military Health Focus Area of Gaps in cancer treatment and survivorship that impact on the health and well-being of military Service members, Veterans, and their beneficiaries. Scientific Objective/Rationale Osteosarcoma (OS) is the most common primary skeleton malignancy, and inordinately affects children and young adults. Despite improved outcomes with current multimodal care, the prognosis for patients with metastatic disease is grim with an overall 5-year survival rate less than 20%. Framed in another way, one life would be saved for every 1.8 patients in which metastasis is prevented. Thus, a key barrier to progress is the better understanding and prevention of invasion and metastasis in OS. Our research group has examined a novel osteogenic differentiation factor, NELL-1, and its potential applications in tissue engineering. In fact, until recently NELL-1 was simply known to regulate skeletal patterning and improve bone repair. Recently, our group has shown that NELL-1 is significantly upregulated across multiple OS cell lines and over 50 human high grade OS samples. Moreover, gene deletion of NELL-1 significantly impairs OS cellular proliferation, migration, invasion, and attachment. Despite many years of research, the precise cell surface receptor which transduces NELL-1 signaling remained elusive. Recently, we have determined that NELL-1 binds to Cntnap4 (Contactin-associated protein-like 4) which propagates downstream signaling pathways responsible for its cellular effects. Collectively, the NELL-1 / Cntnap4 signaling axis has emerged as a novel and targetable pathways in human osteosarcoma. In a comprehensive, in vitro / in vivo proposal, we will now interrogate the role of NELL-1 / Cntnap4 signaling in the positive regulation of osteosarcoma disease progression. Applicability of Research Intensive multi-agent chemotherapy has improved survival for osteosarcoma, with an approximate 68% overall 5-year survival with non-metastatic disease. Patients with metastatic OS have a grim survival rate of 11% and a median survival of 20 months. Unfortunately, it has been over 30 years since the last breakthrough in osteosarcoma treatment. With these sobering statistics in mind, novel adjunctive therapies to reduce OS disease progression are urgently needed. In addition, we have observed that other malignant skeletal tumors such as chondrosarcoma have high levels of NELL-1 over-expression. It is possible that manipulation of NELL-1 / Cntnap4 signaling has therapeutic promise across several skeletal sarcomas.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010302
Entities
People
- Aaron W James
Organizations
- Johns Hopkins University
- United States Army