Measuring cellular senescence to predict and prevent peripheral neuropathy

测量细胞衰老以预测和预防周围神经病变

• 批准号: 10482353
• 负责人: Natalia Mitin
• 金额: $ 90.35万
• 依托单位: SAPERE BIO, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10482353
• 关键词: Acute; Adherence; Affect; Aftercare; Age; Aging; Alzheimer' s Disease; Behavioral; Biological Assay; Biological Markers; Breast Cancer Patient; CDKN2A gene; Cell Aging; Cells; Chemotherapy-Oncologic Procedure; Chemotherapy-induced peripheral neuropathy; Chronic; Chronic Disease; Chronology; Cisplatin; Clinic; Clinical; Clinical Data; Clinical Research; Conflict (Psychology); Data; Development; Diabetes Mellitus; Diagnosis; Diagnostic; Dimensions; Disease; Etiology; Foundations; Frequencies; Functional disorder; Gene Expression; Genetic; Health Care Costs; Heterogeneity; Immune; Incidence; Individual; Inflammation; Kidney Failure; Linear Regressions; Long-Term Effects; Malignant Neoplasms; Measurement; Measures; Methods; Modeling; Multiple Sclerosis; Mus; Neurodegenerative Disorders; Neurons; Neuropathy; Oncologist; Oncology; Outcome; Paclitaxel; Pain management; Parkinson Disease; Patient Outcomes Assessments; Patient risk; Patients; Performance; Peripheral Nervous System Diseases; Persons; Pharmaceutical Preparations; Phase; Pilot Projects; Population; Prevalence; Prevention; Process; Prospective Studies; Quality of life; Quantitative Reverse Transcriptase PCR; Regimen; Reporting; Research; Risk; Risk Factors; Role; Sensory; Specificity; Symptoms; Syndrome; Techniques; Toxic effect; Translating; Trauma; Treatment Efficacy; Validation; Work; age related; base; body system; cancer therapy; cancer type; chemotherapy; clinical application; clinical practice; clinically relevant; commercialization; comorbidity; debilitating pain; design; diabetic patient; docetaxel; expectation; experience; fall risk; health care service utilization; high risk; immunosenescence; improved; individual patient; injured; innovation; malignant breast neoplasm; neurotoxic; older patient; opioid use; patient stratification; personalized medicine; predictive modeling; prevent; prospective; prototype; risk prediction; risk prediction model; risk stratification; senescence; success; survivorship; taxane; tool; validation studies

ABSTRACT Peripheral neuropathy is a debilitating pain syndrome that is prevalent in older patients and that can severely impact patients’ quality of life, increasing their risk of falls, opioid usage, and healthcare costs. It can be incited by neurotoxic drugs, chronic age-related conditions such as diabetes and kidney failure, and trauma, among other etiologies. Current therapies to treat peripheral neuropathy are largely ineffective, thereby rendering prevention particularly important. However, there are currently no good methods to identify patients at high risk of developing neuropathy, as risk factors beyond the inciting agents are poorly understood. Aging as a risk factor appears central to neuropathy progression; however, clinical data regarding the contribution of aging are conflicting, possibly due to the heterogeneity of the aging process. Thus, there is a high unmet need to understand risk factors associated with peripheral neuropathy, including whether and how disease-agnostic mechanisms of aging such as senescence reflect individual vulnerability. Cellular senescence, has been implicated in the etiology of common neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and multiple sclerosis, and more recently cisplatin-induced peripheral neuropathy. To understand risk factor of peripheral neuropathy, aside from inciting factors, and lay the groundwork for applications across causes of peripheral neuropathy, initial studies must be conducted in a population that does not have neuropathy at baseline, develops it with treatment, and experiences chronic, ongoing peripheral neuropathy. Therefore, CIPN is an optimal first indication for both risk stratification and actionability. Understanding the risk of CIPN is particularly important in breast cancer given (a) cancer prevalence and the high incidence of CIPN, (b) common use of neurotoxic taxanes in nearly all chemotherapy regimens, (c) choice of multiple regimens with similar efficacy but different CIPN risks, and (d) long survivorship requiring ongoing management of CIPN which often persists for years after chemotherapy. Only through understanding a patient’s individual CIPN risk can clinicians make informed decisions about which chemotherapy regimen will best maximize efficacy and minimize CIPN risk for that person, thus offering more precise, personalized medicine in the clinic. Our data in a prospective study of patient with early stage breast cancer who received taxanes-containing chemotherapy demonstrate that expression of cellular senescence biomarker, p16 correlated with acute CIPN. In this Direct to Phase 2 proposal, we propose to build on our pilot data to create the first clinically validated model for predicting CIPN risk and to identify patients who are at risk for developing acute CIPN as well as patients whose symptoms may not resolve after chemotherapy completion (chronic CIPN). With the aims of this proposal completed, we will be ready to design and execute a clinical validation study of CIPN-Sapere, essential for commercialization. By enabling CIPN prevention, CIPN-Sapere has the potential to: (1) improve treatment efficacy by allowing more patients to complete the planned chemotherapy regimen; (2) save millions of dollars in healthcare costs associated with short- and long-term treatment of CIPN; and (3) improve patients’ long-term QoL in survivorship. We hope to extend this work to CIPN in other cancer types in order to diminish the incidence of this debilitating and long-lasting toxicity, while improving chemotherapy adherence and corresponding efficacy. Ultimately, we hope this foundational work will lead to improved diagnosis and treatment of peripheral neuropathy across etiologies.

抽象的 周围神经病是一种令人衰弱的疼痛综合征，在老年患者中很普遍，并且可能严重 影响患者的生活质量，增加跌倒，阿片类药物使用和医疗保健费用的风险。它可以合并 通过神经毒性药物，慢性年龄相关的疾病，例如糖尿病和肾衰竭，创伤以及创伤 其他病因。当前治疗周围神经病变的疗法在很大程度上无效，从而呈现 预防特别重要。但是，目前尚无识别高风险患者的好方法 关于神经病的发展，作为煽动剂以外的危险因素的理解很少。衰老作为危险因素 似乎是神经病进展的核心；但是，有关衰老贡献的临床数据是 矛盾，由于衰老过程的异质性而可能。那是一个很高的未满足的需求 了解与周围神经病变相关的危险因素，包括疾病不合时宜的 衰老的机制，例如感应反映了个体脆弱性。细胞感应，已经 在常见神经退行性疾病的病因中实施，例如阿尔茨海默氏症，帕金森氏症和多种 硬化症，以及最近的顺铂诱导的周围神经病。 了解外周神经病的危险因素，除了煽动因素，并为 跨周围神经病原因的应用，必须在人群中进行初步研究 基线时没有神经病，通过治疗进行发展，并且经历了慢性，持续的周围 神经病。因此，CIPN是风险分层和可行性的最佳第一指示。 在给定（a）癌症患病率和 CIPN的高入射，（b）在几乎所有化学疗法方案中的神经毒性群的常见使用，（c）选择 具有相似效率但CIPN风险不同的多个方案的态度，以及（d）长期生存需要持续的 CIPN的管理通常在化学疗法后持续多年。仅通过了解患者的 单个CIPN风险罐头临床医生就哪种化学疗法方案做出明智的决定 最大化效率并最大程度地降低该人的CIPN风险，从而提供更精确的个性化药物 诊所。 我们在接受早期乳腺癌患者的前瞻性研究中的数据 化学疗法表明，细胞敏感生物标志物的表达与急性CIPN相关。 在直接到第2阶段的建议中，我们建议以我们的飞行员数据为基础，以创建第一个经过临床验证的 用于预测CIPN风险并确定有急性CIPN风险的患者以及 化疗完成后症状可能无法缓解的患者（慢性CIPN）。 为了完成该提案的目的，我们将准备设计和执行一项临床验证研究 CIPN-SAPERE，对于商业化至关重要。通过启用CIPN预防，CIPN-SAPERE有可能： （1）通过允许更多患者完成计划的化学疗法方案来提高治疗效率； （2） 节省数百万美元与CIPN的短期和长期治疗相关的医疗费用； （3） 改善患者的长期质量生存期。我们希望将这项工作扩展到其他癌症类型的CIPN 为了减少这种衰弱和持久毒性的事件，同时改善化学疗法 依从性和相应的有效性。最终，我们希望这项基础工作能够改善诊断 以及跨病因的周围神经病的治疗。