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.

项目概要 口咽癌 (OPC) 是美国第 9 大常见癌症，26% 的患者没有罹患此病 由于癌症严重程度和治疗并发症，诊断后存活第一年。非裔美国人 (AA) 患有 OPC 的人始终表现出比白种人更差的生存率。监测评估， 流行病学和最终结果 (SEER) 数据显示，OPC 白人的 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 种族差异的 OPC 生存结果不佳。虽然 OPC 放疗可提高生存率， 下颌放射性骨坏死（ORN）和生活质量改变是不幸的结果。辐射促进 成骨细胞和骨细胞凋亡并诱导颌（口面部）间充质干细胞的 G0G1 细胞周期停滞 （OFMSCs）消耗颌骨祖细胞。 AA 中循环祖细胞水平较低是公认的 造成健康差异的因素。与其他骨骼部位相比，下颌对 ORN 的敏感性较高， AA OPC 患者更容易发生 ORN 并发症且 OPC 生存率较差 结果。了解 OFMSC 疗法对循环祖细胞较低的 AA 中 ORN 的疗效是 对于改善 OPC 结果至关重要。注射型骨合成代谢药物是促进骨生长的有吸引力的疗法 放射损伤骨骼的愈合，但 AA 通常无法承担低社会经济群体的费用 患者依从性差。宾夕法尼亚大学创新与精密牙科中心率先表达了 植物叶绿体（生菜叶）中的蛋白质药物（PD）用于口服给药，显示出生物利用度和 具有治疗多种疾病的功效。口服生物封装 E 肽的新型非糖基化 IGF-1 在植物细胞中，糖尿病小鼠模型中的骨体积、密度和面积增加，恢复了骨愈合 骨折。总的来说，这些表明通过移植 OFMSC 和口服来增强成骨作用 递送 IGF-1 是修复颌 ORN、最大化 OPC 治疗指数的有前途的新方法 放疗并减少种族差异的 OPC 结果。目标 1 将使用以下方法修复大鼠模型中的下颌 ORN 移植来自两个种族群体（AA 与白种人）的 OFMSC 作为救援疗法。目标 2 将评估效果 口服生物可利用的 IGF-1 和联合 IGF-1/OFMSC（AA 与白种人）可减轻下颌 ORN。我们预测 种族不同的 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细胞凋亡。这种新颖的治疗模型的结果是 预计将提高负担能力和患者依从性，特别是在贫困和社会地位较低的地区 经济人口与大多数不良 OPC 生存结果相关。