Measuring cellular senescence to predict and prevent peripheral neuropathy

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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.