R01CA261068

Sphingolipid Signaling and Chemotherapy-Induced Peripheral Neurotoxicity - Project Summary/Abstract

Chemotherapy-induced peripheral neuropathy is a common dose-limiting toxicity that can reduce therapeutic effectiveness and impact the quality of life for cancer patients. The overarching goal of this research is to determine the molecular basis of chemotherapy-induced peripheral neuropathy to support the development of targeted therapies to prevent and treat this toxicity.

The proposed studies are based on a reverse translational pharmacogenetic approach that uses genetic association findings to implicate critical pathways in peripheral neuropathy. Recent genetic association and functional validation findings support a role for sphingosine-1-phosphate (S1P) signaling in chemotherapy-induced neurotoxicity, which are consistent with previous studies in rodent models.

The studies proposed in this application will extend these findings and address a significant gap in our knowledge of S1P signaling in target cells for toxicity, peripheral sensory neurons. The central hypothesis that will be tested is that modulation of S1P signaling in peripheral sensory neurons by microtubule targeting agents plays a critical role in their neurotoxicity.

A human induced pluripotent stem cell-derived sensory neuron model of chemotherapy neurotoxicity (IPS-SNS) will be employed for all studies. Pharmacological and genetic approaches will be used to modulate S1P signaling and interrogate chemotherapy toxicity linked to this signaling pathway.

The three aims are complementary and address discrete functions of S1P. The first aim will investigate whether microtubule targeting agents alter sphingolipid metabolism in sensory neurons and will link specific S1P receptors to cytoskeletal changes.

The studies proposed in the second aim will focus on Rho GTPase signaling downstream of S1P receptors and will establish the S1P signaling axis that is critical for chemotherapy-induced changes in neurite structure and the development of retraction bulbs.

The third aim will use single-cell RNA sequencing (scRNA-Seq) and single-cell assay for transposase-accessible chromatin sequencing (sc-ATAC-Seq) to elucidate whether paclitaxel-induced changes in gene expression in IPS-SNS involve S1P effects on chromatin accessibility.

The ability of fingolimod, a multiple sclerosis therapy that targets S1P receptor signaling and is currently being tested for the prevention and treatment of paclitaxel-induced peripheral neuropathy, to protect against chemotherapy-induced neurotoxicity will be examined.

Collectively, these studies will reveal molecular mechanisms underlying the axon degeneration that occurs in sensory neurons in response to microtubule targeting agents and elucidate novel mechanisms for neuroprotection with fingolimod.

Ohio State University

TO DEVELOP THE MEANS TO CURE AS MANY CANCER PATIENTS AS POSSIBLE AND TO CONTROL THE DISEASE IN THOSE PATIENTS WHO ARE NOT CURED. CANCER TREATMENT RESEARCH INCLUDES THE DEVELOPMENT AND EVALUATION OF IMPROVED METHODS OF CANCER TREATMENT THROUGH THE SUPPORT AND PERFORMANCE OF BOTH FUNDAMENTAL AND APPLIED LABORATORY AND CLINICAL RESEARCH. RESEARCH IS SUPPORTED IN THE DISCOVERY, DEVELOPMENT, AND CLINICAL TESTING OF ALL MODES OF THERAPY INCLUDING: SURGERY, RADIOTHERAPY, CHEMOTHERAPY, AND BIOLOGICAL THERAPY INCLUDING MOLECULARLY TARGETED THERAPIES, BOTH INDIVIDUALLY AND IN COMBINATION. IN ADDITION, RESEARCH IS CARRIED OUT IN AREAS OF NUTRITIONAL SUPPORT, STEM CELL AND BONE MARROW TRANSPLANTATION, IMAGE GUIDED THERAPIES AND STUDIES TO REDUCE TOXICITY OF CYTOTOXIC THERAPIES, AND OTHER METHODS OF SUPPORTIVE CARE THAT MAY SUPPLEMENT AND ENHANCE PRIMARY TREATMENT. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.395 - Cancer Treatment Research

National Cancer Institute (NCI) [HHS - NIH]

Columbus, Ohio 43210 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the End Date has been extended from 03/31/26 to 03/31/27 and the total obligations have increased 431% from $571,041 to $3,031,672.