Targeting alternative splicing as a novel approach to chemotherapy induced peripheral neuropathy

Swift, Matthew N. (2021) Targeting alternative splicing as a novel approach to chemotherapy induced peripheral neuropathy. PhD thesis, University of Nottingham.

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Abstract

Chemotherapy induced peripheral neuropathy (CIPN) is one of the most prevalent adverse effects of many chemotherapy drugs. It is estimated that up to 85% of patients suffer from CIPN during treatment and in many patients, painful neuropathy can continue beyond cessation of chemotherapy. Common symptoms of CIPN include, thermal and mechanical allodynia and painful sensations that are commonly described as burning and shooting pain. CIPN is often a dose limiting factor in the provision of chemotherapy. Currently, there are no effective treatments capable of preventing or treating CIPN. Consequently, CIPN is becoming an increasingly significant healthcare burden.

As a result of this burden, there is a pressing need to develop novel therapeutic approaches with which to prevent and treat CIPN. In addition to this, development of chemotherapy agents that are as effective as traditional compounds but lack the severe adverse effects is also desirable. Recently, the neuroprotective and antinociceptive properties of alternatively spliced VEGF-A isoforms were identified in the context of diabetic and platinum chemotherapy neuropathy. VEGF-A isoform expression is governed by the activity of splicing kinase SRPK1 which phosphorylates splicing factor SRSF1 and controls the expression of VEGF-A isoforms by selection of the proximal or distal splicing site of exon 8 of the VEGFA gene. Inhibition of SRPK1 leads to distal splice site selection and the expression of VEGF-Axxxb isoforms which are neuroprotective and anti-nociceptive. Other splicing kinases with confirmed or putative roles in VEGF-A alternative splicing control include CLK1/CLK2 and DYRK1A. Therefore it has been proposed that novel compounds that inhibit these splicing kinases could have potential utility in preventing the onset of CIPN or be capable of reversing the neuropathy therapeutically via VEGF, or alternative splicing pathways.

This thesis investigated the anti-nociceptive and neuroprotective properties of 4 novel splicing kinase inhibitors in in vitro models of vincristine induced neuronal sensitisation and vincristine induced neurite dieback, using dissociated primary DRG neurons. Additionally, an early stage chemotherapy agent, jerantinine was used in the same models and was compared to the neurotoxic and sensitising effects of a traditional agent, vincristine. Alteration of splicing kinases SRPK1, CLK1, CLK2 and DYRK1A with the 4 compounds was able to significantly inhibit vincristine induced sensitisation, in addition to preventing neurite dieback in response to chemotherapy challenge whilst having little or no detrimental effect as independent treatments. Furthermore, jerantinine did not sensitise neurons to the same degree as vincristine and caused a milder degree of neurite dieback. Using a 3D tumour spheroid model, inhibition of all 4 kinases combined with vincristine treatment significantly reduced spheroid growth whilst inhibitors had no effect on spheroid growth in the absence of vincristine. These findings suggest that these compounds will not inhibit chemotherapy activity and appease concerns that they could drive tumour growth. These results demonstrate that control of alternative splicing via inhibition of multiple kinases could be a potentially beneficial in preventing or treating CIPN, and that the novel chemotherapy agent jerantinine is worth developing further due to its reduced adverse effects.

Item Type: Thesis (University of Nottingham only) (PhD)
Supervisors: Donaldson, Lucy F.
Bates, David O.
Keywords: Chemotherapy, Neuroscience, Neuropathy, Pain, Cancer, Vinca, Alkaloids, Peripheral Nervous System, Peripheral Neuropathy, Side Effects, Neurites, Sensitisation
Subjects: Q Science > QP Physiology > QP351 Neurophysiology and neuropsychology
Faculties/Schools: UK Campuses > Faculty of Medicine and Health Sciences > School of Life Sciences
Item ID: 65392
Depositing User: Swift, Matthew
Date Deposited: 04 Aug 2021 04:42
Last Modified: 04 Aug 2021 04:42
URI: http://eprints.nottingham.ac.uk/id/eprint/65392

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