Novel therapeutic targets for the treatment of vincristine induced peripheral neuropathy

Abstract

Vincristine is used especially for the treatment of a variety of paediatric cancers including leukaemias and brain tumours. Unfortunately, up to 90% of vincristine-treated patients develop peripheral neuropathy characterized by sensory, motoric and autonomic symptoms. The sensory symptoms include pain, in particular hypersensitivity to light touch, as well as loss of sensory discrimination to detect vibration and touch. The symptoms of vincristine-induced neuropathy are only poorly controlled by currently available analgesics and therefore often necessitate dose reductions or even cessation of treatment. The aim of this thesis was to identify new therapeutic targets for the treatment of vincristine-induced peripheral neuropathy (VIPN) by combining behavioural experiments, histology, transcriptomics and pharmacology and extending the knowledge to oxaliplatin and cisplatin induced neuropathy management.In chapter one I present a general literature review that addresses the mode of action, genomics, clinical presentation, pathophysiology and treatment of chemotherapy induced peripheral neuropathy (CIPN) caused by the most commonly used anticancer-agent groups; vinca alkaloids, platinum derivates and taxanes. In chapter two I present the development and characterisation of a novel mouse model of VIPN based on local intraplantar injections of vincristine that allowed me to reproduce several symptoms of VIPN and allowed me to compare, in chapter three, differential gene expression profiles in DRG following vincristine, oxaliplatin or cisplatin administration. The transcriptomic analysis revealed predominant effects on genes associated with the immune system after treatment with vincristine, while oxaliplatin treatment affected mainly neuronal genes. Treatment with cisplatin resulted in a mixed gene expression signature. Specifically, vincristine induced a striking upregulation of inflammatory genes in DRGs involved in regulation and activation of macrophages and interleukin one receptor signalling. In chapter four, I demonstrate that vincristine-induced peripheral neuropathy is driven by activation of the NLRP3 inflammasome and subsequent release of interleukin-1s, with mechanical allodynia and gait disturbances significantly reduced in knockout mice lacking canonical NLRP3 signalling pathway components or after treatment with the NLRP3 inhibitor MCC950. Moreover, treatment with the interleukin-1 receptor antagonist anakinra prevented the development of vincristine-induced neuropathy without adversely affecting chemotherapy efficacy or tumour progression in patient-derived medulloblastoma xenograph models. These results detail for the first time the molecular neuro-inflammatory mechanisms leading to vincristine-induced mechanical allodynia and gait disturbances and suggest that repurposing the biological disease modifying anti-rheumatic anakinra may be an effective and safe treatment strategy for vincristine-induced peripheral neuropathy.In summary, data presented in this thesis provide invaluable insights in the mechanism of vincristine induced peripheral neuropathy and provide preliminary data for future basic research and clinical studies.