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.

项目摘要 口咽癌（OPC）是美国第9大常见癌症，26%的患者没有 由于癌症的严重性和治疗并发症，在诊断后的第一年存活。非裔美国人（AA） 发生OPC的人的生存率始终低于白人。监测评估， 流行病学和最终结果（SEER）数据显示，白人OPC患者的5年相对生存率 接近57%，而AA的存活率接近33%。癌症治疗后并发症占大多数 不同种族的低OPC生存率的结果。虽然OPC的放射治疗可以提高生存率， 颌骨放射性骨坏死（ORN）和生活质量的改变是不幸的结果。辐射促进 成骨细胞和骨细胞凋亡并诱导颌骨（口面）间充质干细胞的G 0 G1细胞周期阻滞 （OFMSC）以消耗颌骨骨祖细胞。AA中循环祖细胞水平较低是一个既定的 造成健康差距。再加上与其他骨骼部位相比，颌骨对ORN的易感性较高， AA OPC患者具有发展ORN并发症和较差OPC存活率的较高缺点 结果。了解OFMSC治疗循环祖细胞较低的AA患者ORN的功效 改善OPC结果至关重要。可注射的骨合成代谢药物是促进骨的有吸引力的疗法 愈合的放射性损伤的骨，但他们往往是负担不起的AA从低社会经济群体， 患者依从性差。宾夕法尼亚大学创新与精密牙科中心开创了 植物叶绿体（莴苣叶）中的蛋白质药物（PD）用于口服递送， 有效治疗多种疾病。新型E肽生物胶囊化去糖基化IGF-1的口服给药 在糖尿病小鼠模型中，植物细胞恢复了骨愈合，骨体积、密度和面积增加， 骨折总的来说，这些结果表明，用移植的OFMSCs和口服的OFMSCs增强骨生成， 递送IGF-1是修复颌骨ORN、最大化OPC治疗指数的有前景的新方法 放疗和减少种族差异的OPC结果。在目标1中，将使用以下方法在大鼠模型中修复颌骨ORN： 移植来自两个种族组（AA对高加索人）的OFMSC作为补救疗法。目标2将评估 口服生物可利用的IGF-1和组合的IGF-1/OFMSC（AA对高加索人）以减轻颌ORN。我们预测 不同种族的OFMSC和口服生物可利用的IGF-1的治疗应用将通过以下方式促进愈合： 保护颌骨细胞免受辐射诱导的凋亡。这种新型治疗模型的结果是 预计将提高负担能力和患者依从性，特别是在贫困和低社会地位的人群中， 与大多数不良OPC生存结局相关的经济人群。