Novel therapeutic approaches to remediate radiotherapy-induced bone necrosis

修复放射治疗引起的骨坏死的新治疗方法

• 批准号: 10912194
• 负责人: Sunday O Akintoye
• 金额: $ 20万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10912194
• 关键词: African American; African American population; Algorithms; American; Apoptosis; Area; Biological Availability; Biological Models; Black Populations; Bone Matrix; Bone Regeneration; Bone necrosis; Cancer Patient; Caucasians; Cell Cycle Arrest; Cells; Chloroplasts; Coupled; Data; Dentistry; Deposition; Diabetic mouse; Diagnosis; Disadvantaged; Disease; Fracture; Goals; Histologic; Human; Immunologics; Induction of Apoptosis; Injectable; Insulin-Like Growth Factor I; Jaw; Lettuce - dietary; Malignant Neoplasms; Mandible; Mesenchymal Stem Cells; Modeling; Molecular; Oral; Osteoblasts; Osteocytes; Osteogenesis; Osteoradionecrosis; Outcome; Patients; Peptides; Pharmaceutical Preparations; Plants; Population; Positron-Emission Tomography; Predisposition; Quality of life; Race; Radiation; Radiation therapy; Radio; Rattus; Reporting; SEER Program; Severities; Site; Survival Rate; System; Testing; Therapeutic; Therapeutic Index; Transplantation; United States; X-Ray Computed Tomography; bone; bone cell; bone healing; cancer radiation therapy; cancer therapy; comorbidity; compliance behavior; density; efficacy evaluation; functional disability; healing; health disparity; high risk; improved; improved outcome; innovation; insight; irradiation; low socioeconomic status; malignant oropharynx neoplasm; microCT; mouse model; novel; novel strategies; novel therapeutic intervention; novel therapeutics; orofacial; osteogenic; osteoprogenitor cell; preclinical efficacy; prevent; protein expression; racial disparity; racial population; remediation; skeletal; socioeconomics; stem cells; survival outcome; survivorship; translational applications

PROJECT SUMMARY Oropharyngeal cancer (OPC) is the 9th most common cancer in the United States, and 26% of patients do not survive the first year after diagnosis due to cancer severity and treatment complications. African-Americans (AA) who develop OPC consistently demonstrate poorer survival than Caucasians. Assessments of the Surveillance, Epidemiology, and End Results (SEER) data have shown that 5-year relative survival of Caucasians with OPC is close to 57% while AA had a survival rate close to 33%. Post-cancer therapy complications account for majority of the racially disparate poor OPC survival outcomes. While radiotherapy for OPC improves survival, osteoradionecrosis (ORN) of the jaw and altered quality of life are unfortunate outcomes. Radiation promotes osteoblast and osteocyte apoptosis and induces G0G1 cell cycle arrest of jaw (orofacial) mesenchymal stem cells (OFMSCs) to deplete jaw osteoprogenitor cells. Lower levels of circulating progenitor cells in AA is an established contributor to health disparities. Coupled with high jaw susceptibility to ORN compared to other skeletal sites, the AA OPC patient has higher disadvantage of developing ORN complications and poor OPC survival outcomes. Understanding efficacy of OFMSC therapy for ORN in AA with lower circulating progenitor cells is vital for improving OPC outcomes. Injectable osteoanabolic drugs are attractive therapies for promoting bone healing in radio-damaged bone, but they are often unaffordable by AA from low socioeconomic group resulting in poor patient compliance. Penn Center for Innovation and Precision Dentistry has pioneered expression of protein drugs (PDs) in plant chloroplasts (lettuce leaves) for oral delivery that demonstrated bioavailability and efficacy to treat several diseases. Oral delivery of a novel aglycosylated IGF-1 with E-peptide bioencapsulated in plant cells restored bone healing with increased bone volume, density, and area in diabetic mouse model of bone fracture. Collectively, these suggest that enhancing osteogenesis with grafted OFMSCs and orally delivered IGF-1 are promising novel approaches to remediate jaw ORN, maximize therapeutic index of OPC radiotherapy and reduce racially disparate OPC outcomes. In Aim 1 will remediate jaw ORN in a rat model using grafted OFMSCs from two racial groups (AA vs. Caucasian) as rescue therapy. Aim 2 will evaluate efficacy of orally bioavailable IGF-1 and combined IGF-1/OFMSCs (AA vs. Caucasians) to mitigate jaw ORN. We predict that therapeutic applications of racially distinct OFMSCs and orally bioavailable IGF-1 will promote healing by protecting jaw bone cells from radiation-induced apoptosis. The outcome of this novel therapeutic models is expected to increase affordability and patient compliance, especially in the underprivileged and low socio- economic populations associated with majority of the poor OPC survival outcomes.

项目总结