Treatment of Chondrosarcoma by YAP siRNA Nanoparticles in a Novel Chondrosarcoma Mouse Model
Abstract
Chondrosarcoma is a type of malignant and rare cancer that affects the bones and joints. It accounts for approximately two new cases per million population per year and is diagnosed in approximately 600 patients each year in the United States. Chondrosarcoma typically affects adults between the ages of 20 and 60 years old. So far, the cause of the chondrosarcoma is not clear. Clinically, chondrosarcomas are resistant to chemotherapy and radiotherapy, therefore wide surgical excision is recognized as the best therapeutic option; however, local recurrence can occur even 10 years after surgery. Moreover, there is no treatment for the patients with an unresectable or metastatic tumor. Hence, management of this disease remains an ongoing challenge, and the development of new treatment options is urgently needed. To discover new therapeutic drugs, a most important requirement is to have an animal model which closely resembles human chondrosarcoma. However, only few chondrosarcoma animal models are currently available. Moreover, these kinds of models are less relevant to the human chondrosarcoma. Thus, more clinically relevant models of chondrosarcoma are urgently required for discovery of ideal drugs. Our most recent research results showed that deletion of two suppressors (p53 and Rb1) in joint cells causes spontaneous chondrosarcoma and lung metastasis. Additionally, our pilot animal study indicated that ablation of YAP in this novel chondrosarcoma model markedly inhibited tumor growth. Consistently, when we inhibited YAP in the chondrosarcoma cells in vitro using RNA interference (a gene silence technology) the chondrosarcoma cells growth, migration, and invasion were significantly inhibited. Moreover, by collaborating with a bioengineering scientist, Dr. Mitchell, the team engineered a novel ionizable lipid nanoparticles (LNPs) small interfering RNA (siRNA) delivery system for inhibition of YAP in chondrosarcoma mouse model. Thus, the goal of this project is to characterize tumorigenesis and progression mechanism using this new pre-clinical chondrosarcoma mouse model and further characterize the efficacy of LNPs mediated YAP siRNA for treatment of chondrosarcoma. Thus, these studies fit the major focus areas of Research Model, Biology and Etiology and Therapy in Fiscal Year 2020 Rare Cancer Research Program Idea Development Award. This study will provide a new and valuable chondrosarcoma animal model that closely mimics human chondrosarcoma and will significantly benefit to the research community for discovery of new drugs for chondrosarcoma. Moreover, this proposal will use nanotechnology to develop a novel ionizable lipid nanoparticle delivery system for delivery of siRNA, mRNA, and other drug targets to chondrosarcoma, which is expected to provide effective and safe therapeutic tools for chondrosarcoma. In addition, we will characterize YAP as a novel potential drug target for chondrosarcoma. Currently, treatment strategies for rare cancers, especially chondrosarcoma are facing enormous challenges due to therapy resistance, unresectable, and lung metastasis. To date, no therapeutic agents have been shown to effectively inhibit chondrosarcoma and lung metastasis. Importantly, increasing evidence demonstrate that ionizable LNPs are one of most promising delivery systems, which are generally non-toxic and well-tolerated and can effectively encapsulate and protect nucleic acids from degradation and mediate their delivery to cancer cells. Encouragingly, an LNP-based siRNA drug developed by Alnylam was approved by the U.S. Food and Drug Administration in 2018. Thus, developing this novel YAP siRNA Lipid nanoparticles will provide a novel molecular therapeutic target for chondrosarcoma, which will have great translational value and premise for treatment of the chondrosarcoma and other cancers.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210542
Entities
People
- Shuying Yang
Organizations
- United States Army
- University of Pennsylvania