Toward a Precision Medicine Approach to Medication-Related Osteonecrosis of the Jaw

针对药物相关颌骨坏死的精准医学方法

• 批准号: 10427077
• 负责人: Yan Gong
• 金额: $ 33.7万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-07 至 2023-09-06
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10427077
• 关键词: Adopted; Adverse event; Angiogenesis Inhibitors; Biological Markers; Bone necrosis; Breast; Cancer Patient; Caring; Clinical; Data; Data Set; Development; Discipline; Disease; Dose; Drug Exposure; Etiology; FRAP1 gene; Femoral Fractures; Functional disorder; Future; Genes; Genetic; Genetic Markers; Genetic Predisposition to Disease; Goals; Health Care Costs; Healthcare; Individual; Intervention; Intravenous; Jaw; Knowledge; Lead; Ligands; Link; Lung; Malignant Bone Neoplasm; Malignant Neoplasms; Meta-Analysis; Metastatic Neoplasm to the Bone; Methods; Mission; Morbidity - disease rate; Multiple Myeloma; Nuclear; Oral; Oral Medicine; Oral Pathology; Osteoporosis; Participant; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacogenomics; Population; Postmenopause; Predisposition; Prostate; Public Health; Quality of life; Reporting; Research; Research Personnel; Risk; SIRT1 gene; Serum; Steroids; Testing; United States National Institutes of Health; Vascular blood supply; bisphosphonate; bone; bone turnover; clinical biomarkers; clinical implementation; extracellular vesicles; farnesyl pyrophosphate; genetic variant; genome wide association study; improved; inhibitor/antagonist; innovation; interest; knowledge base; mortality; multidisciplinary; novel; precision medicine; predictive modeling; prevent; receptor; response; risk minimization; risk prediction; skeletal; soft tissue

There is a fundamental gap in understanding how certain individuals treated with antiresorptives such as bisphosphonates and denosumab developed medication-related osteonecrosis of the jaw (MRONJ) while others do not. Without this knowledge, it is difficult to use the antiresorptives in a safe manner. Our long term research goal is to identify, validate and implement clinically useful biomarkers of MRONJ and ultimately, to proactively provide a Precision Medicine approach for antiresorptive therapies while minimizing the risk of MRONJ. Built upon compelling preliminary findings, our overall objectives are to further validate pharmacogenomic markers that predispose patients to bisphosphonates-related ONJ, to identify genetic and serum biomarkers for denosumab-related ONJ, and to create a predictive model for future clinical implementation of a Precision Medicine strategy for antiresorptive therapies. Our central hypothesis is that MRONJ is the result of interplay between genetic predisposition and drug exposure, and that because of their differing mechanisms of action, the genetic predispositions for MRONJ linked to bisphosphonates and denosumab differ. We have assembled a multidisciplinary team to carry out the following specific aims: 1). Identify genetic variants associated with bisphosphonate-related ONJ. 2). Identify genetic and serum biomarkers for denosumab-related ONJ. 3). Build and validate predictive models for MRONJ. This project is significant because study proposed study will not only identify validated genetic and/or serum biomarkers for MRONJ and advance the understanding of the pathophysiology of MRONJ but also have translational importance in the antiresorptive treatments for a wide range of diseases. The proposed study is innovative because: First, this is the first pharmacogenomic study for denosumab-related MRONJ. Second, using bone turnover markers as biomarkers for MRONJ is novel. Third, Using RANK and RANKL-containing extracellular vesicles as biomarkers is novel. Fourth, identifying biomarkers unique for BP-related vs. DEN-related MRONJ for clinical implementation is novel. Lastly, we will not only use a commonly adopted method for risk prediction analyses but also two advanced methods that are capable of considering non-linear and interaction effects. In summary, we believe our proposed studies will identify biomarkers for MRONJ, enhance our understanding of the underlying mechanisms of MRONJ development, and provide an opportunity to improve treatment of osteoporosis and cancer patients needing antiresorptive therapy in a personalized manner.

理解某些人如何接受反侵害的人（例如 双膦酸盐和denosumab开发了与药物有关的颌骨（MRONJ），而 其他人没有。没有这些知识，很难以安全的方式使用抗吸收剂。我们的长期 研究目标是识别，验证和实施MRONJ的临床有用的生物标志物，并最终识别和实施 主动为抗吸收疗法提供精确的医学方法，同时最大程度地减少 mronj。基于引人注目的初步发现，我们的整体目标是进一步验证 药物基因组学标记物，使患者易于双膦酸盐相关的ONJ，以鉴定遗传和 与Denosumab相关的onj的血清生物标志物，并为将来的临床创建一个预测模型 实施抗吸收疗法的精确医学策略。我们的中心假设是 MRONJ是遗传易感性和药物暴露之间相互作用的结果，并且由于它们 不同的作用机理，MRONJ的遗传易感性与双膦酸盐和双膦酸盐和 Denosumab不同。我们已经组建了一个多学科团队来执行以下特定目标：1）。 确定与双膦酸盐相关的ONJ相关的遗传变异。 2）。识别遗传和血清 与Denosumab相关的生物标志物。 3）。建立和验证MRONJ的预测模型。这个项目是 重要的是因为研究提出的研究不仅会确定经过验证的遗传和/或血清生物标志物 Mronj并提高对MRONJ病理生理学的理解，但也具有翻译 在各种疾病的抗吸收治疗中的重要性。拟议的研究是创新的 因为：首先，这是针对Denosumab相关的MRONJ的首次药物基因组学研究。其次，使用骨头 作为MRONJ的生物标志物的营业额标记是新颖的。第三，使用含有等级和RAND的细胞外 囊泡作为生物标志物是新颖的。第四，识别与BP相关与DEN相关的MRONJ独特的生物标志物 对于临床实施是新颖的。最后，我们不仅将使用常用的方法进行风险预测 分析也可以考虑两种能够考虑非线性和相互作用效应的高级方法。在 总结，我们认为我们的拟议研究将确定MRONJ的生物标志物，增强我们对 MRONJ开发的基本机制，并提供了改善对待的机会 骨质疏松症和癌症患者需要以个性化的方式进行抗吸收治疗。