Measuring cellular senescence to predict and prevent peripheral neuropathy

摘要 周围神经病是一种衰弱的疼痛综合征，在老年患者中普遍存在，严重 影响患者的生活质量，增加他们跌倒的风险、阿片类药物的使用和医疗成本。它可以被煽动 通过神经毒性药物，与年龄有关的慢性疾病，如糖尿病和肾衰竭，以及创伤，在 其他病因。目前治疗周围神经病的方法大多无效，从而使 预防尤为重要。然而，目前还没有好的方法来识别高危患者。 发生神经病变的危险因素，因为除了激动剂之外的危险因素还知之甚少。老龄化是一个风险因素 似乎是神经病变进展的中心；然而，关于衰老的临床数据是 相互冲突，可能是由于老化过程的异质性。因此，有一种高度未得到满足的需求 了解与周围神经病变相关的风险因素，包括疾病不可知性是否以及如何 衰老等衰老机制反映了个体的脆弱性。细胞衰老，一直以来 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。 了解周围神经病的危险因素，除诱发因素外，为 应用于周围神经病的病因，必须在这样做的人群中进行初步研究 没有基线的神经病变，随着治疗而发展，并经历慢性、持续的外周 神经病。因此，CIPN是风险分层和可操作性的最佳首选指征。 了解CIPN的风险在乳腺癌中尤为重要，因为：(A)癌症的发病率和 CIPN的高发病率，(B)几乎所有化疗方案中普遍使用神经毒性紫杉烷，(C)选择 疗效相似但CIPN风险不同的多种方案，以及(D)需要持续的长期生存 化疗后CIPN的处理通常持续数年。只有通过了解病人的 个人CIPN风险临床医生可以做出明智的决定，决定哪种化疗方案最好 最大限度地提高疗效并将CIPN风险降至最低，从而为患者提供更精确、更个性化的药物 诊所。 我们对接受紫杉烷类药物治疗的早期乳腺癌患者的前瞻性研究数据 化疗显示细胞衰老标志物p16的表达与急性CIPN相关。 在这份直接到第二阶段的计划中，我们建议在我们的试点数据的基础上创建第一个经过临床验证的 用于预测CIPN风险和识别有发展为急性CIPN风险的患者以及 化疗结束后症状可能无法缓解的患者(慢性CIPN)。 随着这项提案的目标完成，我们将准备设计和执行一项临床验证研究 CIPN-Sapere，商业化必不可少。通过启用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短期和长期治疗相关的数百万美元的医疗成本；以及(3) 改善患者长期生存生活质量。我们希望将这项工作扩展到其他癌症类型的CIPN 为了减少这种衰弱和持久的毒性的发生率，同时改进化疗 依从性和相应的疗效。最终，我们希望这项基础性工作将带来更好的诊断 以及跨病因的周围神经病的治疗。

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.