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: 10324366
• 负责人: Natalia Mitin
• 金额: $ 91.47万
• 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/10324366
• 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; 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; 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 周围神经病变是一种使人衰弱的疼痛综合征，常见于老年患者，可严重影响患者的健康。 影响患者的生活质量，增加跌倒风险、阿片类药物使用和医疗费用。是可以被煽动的 神经毒性药物、慢性年龄相关疾病（如糖尿病和肾衰竭）以及创伤等 其他病因。目前治疗周围神经病的疗法基本上无效，从而导致 预防尤为重要。但目前尚无好的方法来识别高危患者 神经病的发展，因为我们对诱发因素之外的危险因素知之甚少。衰老是一个危险因素 似乎是神经病进展的核心；然而，有关衰老影响的临床数据是 矛盾的，可能是由于衰老过程的异质性。因此，存在高度未满足的需求 了解与周围神经病变相关的危险因素，包括是否以及如何与疾病无关 衰老等衰老机制反映了个体的脆弱性。细胞衰老， 与阿尔茨海默病、帕金森病和多种神经退行性疾病的病因学有关 硬化症，以及最近顺铂引起的周围神经病变。 了解周围神经病变的危险因素，除了诱发因素外，为周围神经病变的预防奠定基础 在周围神经病的各种病因中应用，初步研究必须在确实存在的人群中进行 基线时没有神经病变，但随着治疗而发展，并且经历慢性、持续的外周神经病变 神经病。因此，CIPN 是风险分层和可操作性的最佳首选指标。 鉴于 (a) 癌症患病率和乳腺癌的发病率，了解 CIPN 风险对于乳腺癌尤为重要 CIPN 发生率高，(b) 几乎所有化疗方案中普遍使用神经毒性紫杉烷类药物，(c) 选择 具有相似疗效但不同 CIPN 风险的多种治疗方案，以及 (d) 需要持续的长期生存 CIPN 的治疗通常在化疗后持续数年。只有了解患者的情况 临床医生可以根据个体 CIPN 风险做出明智的决定，确定哪种化疗方案最有效 最大限度地提高疗效并最大限度地降低患者的 CIPN 风险，从而为患者提供更精确、个性化的医疗 诊所。 我们对接受含紫杉烷类药物治疗的早期乳腺癌患者进行的一项前瞻性研究中的数据 化疗证明细胞衰老生物标志物 p16 的表达与急性 CIPN 相关。 在这个直接进入第二阶段的提案中，我们建议以我们的试点数据为基础，创建第一个经过临床验证的 预测 CIPN 风险并识别有发生急性 CIPN 风险的患者的模型 化疗完成后症状可能未缓解的患者（慢性 CIPN）。 随着该提案的目标完成，我们将准备设计并执行一项临床验证研究 CIPN-Sapere，对于商业化至关重要。通过实现 CIPN 预防，CIPN-Sapere 有潜力： （1）通过让更多的患者完成计划的化疗方案来提高治疗效果； (2) 节省与 CIPN 短期和长期治疗相关的数百万美元的医疗费用；和（3） 改善患者的长期生存质量。我们希望将这项工作扩展到其他癌症类型的 CIPN 为了减少这种使人衰弱且持久的毒性的发生率，同时改善化疗 依从性和相应的功效。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。