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.

摘要 几种抗癌药物会引起一种称为周围神经病变的副作用， 患者的功能和生活质量。由于没有有效的策略来预防或治疗 周围神经病变，临床实践指南建议暂停或减少化疗剂量， 这降低了患者的存活率。临床和生活方式因素不能充分预测紫杉烷诱导的 周围神经病变（TIPN）。因此，迫切需要验证临床上有用的和机械的， 提供信息的预测性TIPN生物标志物，以开发有效的TIPN预防策略， 紫杉烷治疗结果。营养素（包括维生素D、组氨酸和鞘磷脂）失调，以及 与遗传性神经病病症相关的基因的变体，已被鉴定为 TIPN。将这些生物标志物候选物证实为TIPN风险的预测因子需要大量的紫杉烷- 使用生物标本和详细的TIPN数据治疗患者。本提案的总体目标是 确定临床有用和机械信息TIPN生物标志物，并制定综合TIPN风险 可以预测个体患者TIPN风险的预测模型。我们将扩大SWOG 1714的价值 （S1714），这是一项大型（n= 1，336）由NCI资助的前瞻性临床研究，收集生物标本， 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 (e.g.,维生素D，组氨酸，鞘磷脂）和遗传（例如，EPHA 5）生物标志物候选物是预测性TIPN 生物标志物，并将丰富临床TIPN预测模型。我们将有针对性地全面开展 S1714生物标本的“组学”分析，以验证临床有用和机制信息预测 TIPN生物标志物，并开发一个综合的TIPN风险预测模型，以完成以下特定的 目的：目的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 导致TIPN风险的遗传特征。目标3：开发一个集成的TIPN预测模型。的 本研究的主要预期结果是：1）确认临床上有用的预测性TIPN 生物标志物，2）产生有助于TIPN的机制过程的新知识，以及3） 建立TIPN综合预测模型。这些结果将为开发新的 研究小组可以在前瞻性临床试验中测试的药物和生物标志物知情的治疗策略， 预防TIPN。如果成功，这些策略可以转化为临床实践，以预防TPN， 改善近百万接受紫杉烷治疗的癌症患者的长期临床结果 每年在美国接受治疗。