Disorders

Neuromuscular incl. Muscular Dystrophies, Myopathies & Neuropathies - 2021

Dr Susanna Park was the recipient of Brain Foundation grant funding in 2021

Neuromuscular incl. Muscular Dystrophies, Myopathies & Neuropathies

Neuromuscular incl. Muscular Dystrophies, Myopathies & Neuropathies
Measuring Nerve Damage After Chemotherapy Treatment
Dr Susanna Park
Brain and Mind Centre, University of Sydney, NSW
Co-Investigators : Dr Hannah Timmins, Ms Tiffany Li

Significant advances in cancer diagnosis and treatment mean that there are now an estimated 32 million cancer survivors worldwide, with >1 million in Australia. Chemotherapy-induced nerve damage or peripheral neuropathy (CIPN) is a major side effect of cancer treatment, leading to early cessation of treatment and long-lasting disability. Despite successful treatment and long-term survival prospects, up to 40% of cancer survivors may be left with long-term disability and reduced quality of life due to CIPN following treatment with neurotoxic chemotherapies. Patients with CIPN have significant functional disability, pain, loss of sensation and increased falls risk, significantly contributing to the health burden of cancer survival. Despite this high burden, there remain no methods to identify which patients are at-risk, no objective assessment tools and no treatment or preventative approaches to stop long-lasting toxicity. The only current strategy to reduce toxicity is chemotherapy dose reduction, which often has implications for survival.

Critically there remains a lack of mechanistic understanding of how chemotherapy produces nerve damage. Multiple mechanisms are involved but the final common pathway is a type of nerve damage termed axonal degeneration. Developing sensitive markers of axonal degeneration will provide early identification of patients with CIPN as well as highlighting key mechanisms.

Over the past 15 years, our research team has pioneered novel clinical assessment tools for CIPN, undertaking large-scale studies of cancer survivors and neurological complications with in-depth phenotyping, demonstrating our strong capability. Essential to investigate axonal degeneration in CIPN, our research team has pioneered use of specialised neurophysiological techniques to probe axonal function – these tools can be used in the clinical setting non-invasively. We have previously used these techniques to identify nerve dysfunction in colorectal cancer patients treated with the neurotoxic chemotherapy oxaliplatin and found that a composite excitability score was a sensitive measure of axonal dysfunction that correlates to clinical severity of CIPN. Seperately, novel markers of nerve damage have been identified in animal studies and in patients with other neurological disorders. This marker is called neurofilament light chain (NfL), which is a key structural protein of nerves, released during injury. NfL has been identified as a marker of axonal damage in animal models of CIPN, but it has not been assessed in large-scale clinical studies. Further it has never been compared with sensitive neurophysiological measures of CIPN.

This project will define the trajectory of nerve degeneration in patients with CIPN through innovative methods of assessing nerve dysfunction, including neurophysiological studies and analysis of NfL levels in blood. Via our established collaborative network, we will recruit 100 cancer patients treated with the neurotoxic chemotherapy oxaliplatin. Using clinical phenotyping, longitudinal assessment, functional outcomes coupled with these specialised neurophysiological and protein biomarker approaches, this proposal will determine key mechanisms underlying the development of nerve damage following chemotherapy treatment, enabling quantification of markers of toxicity and optimisation of risk prediction for neurotoxicity. Patients will be assessed at the completion of treatment, with follow-up 3-months post treatment to enable analysis of longer term trajectory. The results from this innovative project will enable determination of the utility of these markers of axonal degeneration. Ultimately, this will enable quantification of neurological toxicity and development of targeted neuroprotective strategies to prevent nerve damage following chemotherapy. Further, this information will be valuable towards understanding how best to measure and monitor progression of axonal degeneration across multiple disorders.

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