Development of an Integrated Risk Prediction Model of Taxane-induced Peripheral Neuropathy

紫杉烷诱发的周围神经病变综合风险预测模型的开发

• 批准号: 10566077
• 负责人: Daniel Louis Hertz
• 金额: $ 60.12万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10566077
• 关键词: Activities of Daily Living; Age; Amino Acids; Antineoplastic Agents; Biological Markers; Breast; Carcinogens; Clinical; Clinical Practice Guideline; Clinical Research; Clinical Trials; DNA; Data; Development; Diet; Dose; Funding; Generations; Genes; Genetic; Genetic Markers; Genotype; Goals; Histidine; Intervention; Knowledge; Life; Link; Lipids; Lung; Machine Learning; Malignant Neoplasms; Manuals; Measures; Mission; Neuropathy; Nutrient; Outcome; Outcomes Research; Ovarian; Paclitaxel; Patients; Peripheral Nervous System Diseases; Pharmaceutical Preparations; Phospholipids; Physiological; Plasma; Predictive Value; Prevention; Prevention strategy; Process; Quality of life; Race; Recommendation; Research; Risk; Sampling; Southwest Oncology Group; Sphingomyelins; Testing; Translating; Treatment Effectiveness; Treatment outcome; United States; Variant; Vitamin D; Vitamins; Work; candidate marker; chemotherapy; clinical practice; cohort; docetaxel; experience; genome-wide; genomic data; hereditary neuropathy; improved; individual patient; insight; lifestyle factors; lipidomics; novel; predictive marker; predictive modeling; premature; prevent; preventive intervention; prospective; risk prediction; risk prediction model; side effect; taxane; treatment strategy; tumor

Abstract Several anticancer agents cause a side effect known as peripheral neuropathy that can permanently diminish patient’s functional ability and quality of life. Since there are no effective strategies to prevent or treat peripheral neuropathy, clinical practice guidelines recommend withholding or dose-reducing chemotherapy, which reduces patient survival. Clinical and lifestyle factors do not adequately predict risk of taxane-induced peripheral neuropathy (TIPN). Therefore, there is a critical need to validate clinically useful and mechanistically informative predictive TIPN biomarkers in order to develop effective TIPN prevention strategies that improve taxane treatment outcomes. Dysregulation of nutrients including vitamin D, histidine, and sphingomyelin, and variants in genes linked to hereditary neuropathy conditions, have been identified as candidate biomarkers of TIPN. Confirming these biomarker candidates as predictors of TIPN risk requires a large cohort of taxane- treated patients with biospecimens and detailed TIPN data. The overarching objective of this proposal is to identify clinically-useful and mechanistically-informative TIPN biomarkers and develop an Integrated TIPN Risk Prediction Model that can predict an individual patient’s TIPN risk. We will extend the value of SWOG 1714 (S1714), which is a large (n=1,336) NCI-funded prospective clinical study that collected biospecimens and detailed TIPN data to create a Clinical TIPN Prediction Model. Our central hypothesis is that our physiologic (e.g., vitamin D, histidine, sphingomyelin) and genetic (e.g., EPHA5) biomarker candidates are predictive TIPN biomarkers and will enrich the Clinical TIPN Prediction Model. We will conduct targeted and comprehensive “omics” analyses of S1714 biospecimens to validate clinically useful and mechanistically informative predictive TIPN biomarkers and develop an Integrated TIPN Risk Prediction Model to complete the following specific aims: Aim 1: Assess the predictive value of key nutrients and lipids on TIPN risk. Aim 2: Determine genetic features that contribute to TIPN risk. Aim 3: Develop an Integrated TIPN Prediction Model. The primary expected outcomes of this research are the: 1) confirmation of clinically useful predictive TIPN biomarkers, 2) generation of new knowledge of the mechanistic processes that contribute to TIPN, and 3) creation of an Integrated TIPN Prediction Model. These outcomes will provide critical insight to develop novel agents and biomarker-informed treatment strategies that the study team can test in prospective clinical trials to prevent TIPN. If successful, these strategies could be translated into clinical practice to prevent TIPN and improve long-term clinical outcomes in the nearly one million patients with cancer who receive taxane treatment each year in the United States.

抽象的 几种抗癌剂会导致一种称为周围神经病的副作用，可以永久减少 患者的功能能力和生活质量。由于没有有效的策略来预防或治疗 外周神经病，临床实践指南建议预扣或减少剂量化疗， 这降低了患者的生存。临床和生活方式因素不能充分预测紫杉烷引起的风险 周围神经病（TIPN）。因此，迫切需要验证临床有用和机械机理 提供丰富的预测性提示生物标志物，以制定有效的预防策略以改进 紫杉烷治疗结果。营养素的失调，包括维生素D，组氨酸和鞘氨质素，以及 与遗传神经病疾病相关的基因的变体已被确定为候选生物标志物 提示。确认这些生物标志物候选者为TIPN风险的预测因素，需要大量紫杉烷 - 用生物测量和详细的TIPN数据治疗患者。该提议的总体目标是 识别临床上使用和机械信息的TIPN生物标志物并发展综合的TIPN风险 可以预测个别患者的TIPN风险的预测模型。我们将延长1714年摇摆的价值 （S1714），这是一项大型（n = 1,336）NCI资助的前瞻性临床研究，该研究收集了生物测量和 详细的TIPN数据以创建临床TIPN预测模型。我们的中心假设是我们的生理学 （例如，维生素D，组氨酸，鞘磷脂）和遗传（例如Epha5）生物标志物候选者是预测性tipn 生物标志物并将丰富临床尖端预测模型。我们将进行有针对性的全面 对S1714生物测量的“ OMICS”分析，以验证临床上有用且具有机械丰富的预测性 TIPN生物标志物并开发一个集成的TIPN风险预测模型，以完成以下特定 目的：目标1：评估关键营养素和脂质对TIPN风险的预测价值。目标2：确定 造成TIPN风险的遗传特征。目标3：开发一个集成的TIPN预测模型。这 这项研究的主要预期结果是：1）确认临床上有用的预测提示 生物标志物，2）生成有助于提示的机械过程的新知识，3） 创建集成的TIPN预测模型。这些结果将为发展小说提供关键的见解 研究团队可以在前瞻性临床试验中测试的代理商和生物标志物的治疗策略 防止提示。如果成功，这些策略可以转化为临床实践，以防止Tipn和 改善接收紫杉烷的近一百万癌症患者的长期临床结果 每年在美国的治疗。