Novel therapeutic approaches to remediate radiotherapy-induced bone necrosis

项目总结 口咽癌(OPC)是美国第九大最常见的癌症，26%的患者不是 由于癌症严重程度和治疗并发症，在确诊后第一年存活。非裔美国人(AA) 患有OPC的人始终表现出比白人更差的存活率。对监控的评估， 流行病学和最终结果(SEER)数据显示，患有OPC的高加索人的5年相对存活率 接近57%，而AA的存活率接近33%。癌症治疗后并发症占多数 种族差异的糟糕的OPC生存结果。虽然放射治疗提高了OPC的存活率， 颌骨放射性骨坏死(ORN)和生活质量改变都是不幸的结果。辐射促进 成骨细胞和骨细胞凋亡诱导颌面间充质干细胞G0G1细胞周期停滞 (OFMSCs)耗尽颌骨成骨祖细胞。再生障碍性贫血患者循环中的祖细胞水平较低是一种既定的 造成健康差距的因素。再加上与其他骨骼部位相比，颌骨对ORN的易感性很高， 再障OPC患者有较高的ORN并发症和较差的OPC存活率 结果。了解OFMSC治疗外周血祖细胞较低的再生障碍性贫血的疗效 对改善OPC结果至关重要。注射用骨合成代谢药物是有吸引力的促骨疗法 修复放射性受损的骨骼，但低社会经济群体的AA往往负担不起这些费用 病人依从性差。宾夕法尼亚创新和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)口服给药，证明了生物利用度和 治疗几种疾病的疗效。新型糖基化E-肽口服胰岛素样生长因子-1的研究 在植物细胞中，随着糖尿病小鼠模型骨体积、密度和面积的增加，恢复了骨愈合 骨折。综上所述，这些都表明，通过移植的OFMSCs和口服促进成骨 IGF-1是治疗颌骨ORN、最大化OPC治疗指数的有前景的新方法 放射治疗和减少不同种族的OPC结果。在Aim 1中，将使用以下方法修复大鼠颌骨ORN模型 移植来自两个种族(AA和高加索)的OFMSCs作为抢救疗法。AIM 2将评估以下各项的疗效 口服生物利用型IGF-1和联合IGF-1/OFMSCs(AA与高加索人)可缓解颌骨ORN。我们预测 不同种族的OFMSCs和口服生物可用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。这种新的治疗模式的结果是 预计将提高负担能力和患者遵从性，特别是在贫困和低社会阶层 经济人口与大多数不良的OPC生存结果相关。

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.