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大癌症，26％的患者不在 由于癌症的严重程度和治疗并发症，诊断后的第一年生存。非裔美国人（AA） 与高加索人相比，OPC始终如一地表现出较差的生存率。评估监视， 流行病学和最终结果（SEER）数据表明，高加索人与OPC的相对生存率为5年 接近57％，而AA的存活率接近33％。癌后治疗并发症占多数 在种族不同的OPC生存结果上。虽然用于OPC的放射疗法可提高生存率，但 下颌的骨质体（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G0G1细胞周期颌骨（口面）间充质干细胞的停滞 （OFMSC）耗尽颌骨骨源细胞。 AA中循环祖细胞的较低水平是已建立的 健康差异的贡献者。与其他骨骼部位相比 AA OPC患者患ORN并发症和OPC生存不佳的缺点较高 结果。了解MSC疗法对ORN在AA中具有较低循环祖细胞的疗效是 对于改善OPC结果至关重要。可注射的骨代谢药物是促进骨骼的有吸引力的疗法 在无线电损坏的骨骼中愈合，但较低的社会经济群体的AA通常无法承受 在不良的患者遵守情况下。宾夕法尼亚州创新与精密牙科中心的表达率先 植物叶绿体（生菜叶）中的蛋白质药物（PDS），用于口服递送，表现出生物利用度和 治疗多种疾病的功效。用e肽生物包囊的新型糖基化IGF-1的口服递送 在植物细胞中，骨骼体积，密度和面积增加，恢复骨骼愈合 骨断裂。总的来说，这些表明用嫁接的ofMSC和口服增强骨生成 交付的IGF-1是有前途的新方法来补救下颌Orn，最大化OPC的治疗指数 放疗并减少种族歧视的OPC结果。在AIM 1中，将使用大鼠模型中的下巴补救 从两个种族组（AA与高加索人）作为救援疗法的MSC嫁接。 AIM 2将评估 口服生物利用的IGF-1和IGF-1/OFMSC（AA与高加索人）合并以减轻下颌Orn。我们预测 种族与MSC和口服生物利用的IGF-1的治疗应用将通过 保护颌骨细胞免受辐射诱导的凋亡。这个新颖的治疗模型的结果是 预计将提高可承受能力和患者的遵守情况，尤其是在贫困和社会较低的情况下 与大多数OPC生存结果相关的经济人口。