Measuring cellular senescence to predict and prevent peripheral neuropathy

摘要 周围神经病变是一种使人衰弱的疼痛综合征，在老年患者中普遍存在， 影响患者的生活质量，增加他们的福尔斯风险、阿片类药物使用和医疗保健费用。它可以被煽动 神经毒性药物、糖尿病和肾衰竭等与年龄有关的慢性疾病以及创伤， 其他病因。目前治疗周围神经病变的疗法在很大程度上是无效的，从而使患者的神经功能受损。 预防尤为重要。然而，目前还没有很好的方法来识别高危患者 发展神经病变，作为风险因素以外的煽动剂知之甚少。老龄化是一个风险因素 似乎是神经病变进展的中心;然而，关于衰老作用的临床数据是 这可能是由于衰老过程的异质性。因此，有一个高度未满足的需求， 了解与周围神经病变相关的风险因素，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，一直是 与常见神经退行性疾病如阿尔茨海默氏症、帕金森氏症和多发性硬化症的病因学有关。 硬化症，以及最近的顺铂诱导的周围神经病变。 了解周围神经病变的危险因素，排除诱发因素， 应用于周围神经病变的病因，初步研究必须在这样的人群中进行， 基线时无神经病变，在治疗期间发生，并发生慢性、持续性周围神经病变 神经病变因此，CIPN是风险分层和可行性的最佳首选适应症。 了解CIPN的风险在乳腺癌中特别重要，因为（a）癌症患病率和 CIPN发生率高，（B）几乎所有化疗方案中神经毒性紫杉烷类的普遍使用，（c）选择 疗效相似但CIPN风险不同的多种治疗方案，以及（d）长期生存需要持续 CIPN的管理通常在化疗后持续多年。只有通过了解病人的 个体CIPN风险可以使临床医生做出关于哪种化疗方案最好的明智决定。 最大限度地提高疗效，最大限度地降低CIPN风险，从而提供更精确，个性化的药物， 诊所 我们的数据在一项前瞻性研究中的早期乳腺癌患者接受含紫杉烷类药物 化疗证实细胞衰老生物标志物p16表达与急性CIPN相关。 在这个直接进入第二阶段的建议中，我们建议建立在我们的试点数据的基础上，创建第一个临床验证的 用于预测CIPN风险的模型，并识别处于发展急性CIPN风险的患者，以及 化疗完成后症状可能未消退的患者（慢性CIPN）。 随着本提案目标的完成，我们将准备设计和执行以下临床验证研究： CIPN-Sapere，对于商业化至关重要。通过实现CIPN预防，CIPN-Sapere有可能： (1)通过让更多患者完成计划的化疗方案来提高治疗效果;（2） 节省与CIPN的短期和长期治疗相关的数百万美元的医疗费用;以及（3） 提高患者生存长期生活质量。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和持久毒性的发生率，同时改善化疗， 依从性和相应的疗效。最终，我们希望这项基础性工作将导致改善诊断 和治疗各种病因的周围神经病变。

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.