The vascular contribution in chemotherapy-induced painful peripheral neuropathy: beyond the neurocentric view and towards novel therapeutic targets

Abstract

Chemotherapy-induced peripheral painful neuropathy (CIPPN) with severe and long lasting debilitating consequences on cancer patients represents “THE” most problematic side effect of chemotherapy. Nevertheless, since CIPPN pathogenesis remains elusive, effective neuroprotective strategies are not available so far and the only option to prevent severe and permanent neurological deficits is to reduce or withdraw the anticancer treatment, thus impacting on the oncological outcome. Even if peripheral neurons have, for a long time, been considered the only reasonable target of investigations for CIPPN pathogenesis, our preliminary data support the hypothesis that angiogenesis in the vascular network plays a pivotal role along the somatosensory pathway impacting on the “neuro-glial-vascular unit”.

This will potentially raise relevant new therapeutics for CIPPN patients. In this project we aim at the identification of:

-morphostructural vascular abnormalities related to CIPPN development and chronicization over time

-molecular key actors/new pathways involved in its pathogenesis, in order to identify new druggable targets and test new useful therapeutic strategies.

In order to achieve our aims, this project will develop around 4 pillars:

1.Ad hoc preclinical models of CIPPN faithfully reproduce the clinical phenomenology in patients. Two animal models of CIPPN, with or without a severe pain component, will be employed and characterized in terms of events, timings and features to define the relationship between neuropathic symptoms, neural activity and vascular changes in the CNS/PNS.

2.Vascular compartment has a critical role in the so-called “neuro-glial-vascular unit” whose components’ interplay is hypothesized being pivotal in CIPPN pathogenesis. The vascular contribution to CIPPN will be analyzed through Sinchrotron-based X-Ray Computer-assisted Microtomography (XCPT) over time. Vascular measurements will be associated with in vivo extracellular recordings in the CNS somatosensory centers and with neuropathic pain (as well as neurotoxicity) development.

3.Next generation sequencing and immunolabeling will unveil the molecular pathways involved in CIPPN pathogenesis, enriching morphostructural and functional evaluations. Gene expression profiles in target CNS/PNS areas (by single-nuclei RNAseq) will allow us to understand the genetic signature of CIPPN over time with particular attention to molecules involved in angiogenic processes. A post-translational approach by immunolabeling (2D/3D) will complete the analysis.

4.The modifications of angiogenic factors as well as of other key molecules during CIPPN will prospect new effective therapeutic strategies. In vitro advanced combined models of peripheral neurons and endothelial cells will be established to corroborate the new pathogenetic pathways identified in vivo and finally test compounds able to counteract vascular changes induced by chemotherapy