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Rat DRG CIPN versus Vehicle-treatment_DIA-MS

ABSTRACT: Chemotherapy-induced peripheral neuropathy (CIPN) is a serious side effect of cancer treatment, often leading to cessation of therapy due to lack of adequate treatment options. In the peripheral nervous system the chemotherapeutic agent paclitaxel impairs mitochondrial function and induces vast changes in gene expression. However, changes at the protein level remain so far unexplored. Here we used an unbiased approach of quantitative proteome profiling in a clinically-relevant rat model of paclitaxel-induced peripheral neuropathy. We analysed two critical timepoints: (1) day 7, equivalent to 1 day after cessation of paclitaxel treatment, prior to neuropathy development; (2) approximately 4 weeks after paclitaxel initiation, when neuropathy has developed.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Rattus Norvegicus (rat)

TISSUE(S): Root, Dorsal Root Ganglion

SUBMITTER: Christin Kappert

LAB HEAD: Manuela Schmidt

PROVIDER: PXD028356 | Pride | 2022-03-24

REPOSITORIES: Pride

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Project description:We report the RNA sequencing data from the REPEAT study, in which patients with beyond first-line esophagogastric cancer were treated with regorafenib and paclitaxel. For the RNA sequencing, biopsies from metastatic lesions were obtained on baseline (n=21) and fifteen days following treatment initiation (n=13). PURPOSE: Regorafenib monotherapy, a multikinase-inhibitor of angiogenesis, tumor microenvironment, and oncogenesis, showed promising results in gastric cancer. We aimed to assess the tolerability of regorafenib and paclitaxel in advanced esophagogastric cancer (EGC) patients refractory to first-line treatment, and explore potential biomarkers. METHODS: Patients received paclitaxel (80 mg/m2) on days 1, 8, and 15 of a 28-day cycle and regorafenib (80/120/160 mg) on day 1-21 in the dose-escalation cohort, and the maximum-tolerated dose (MTD) in the dose-expansion cohort. Exploratory, overall- (OS) and progression-free survival (PFS) were compared to a propensity-score matched cohort receiving standard second/third line systemic treatment. Paclitaxel pharmacokinetics were assessed using D1 and D15 samples. We performed ELISA measurements of galectin-1, RNA sequencing and shallow whole-genome sequencing of metastatic tumor biopsies for biomarker analyses. RESULTS: In the dose-escalation cohort (n=14), the MTD of regorafenib was 120 mg. Thirty-four patients were enrolled in the dose-expansion cohort. Most common toxicities (all grades; grade ≥3) were fatigue (79%; 4%) and sensory neuropathy (63%; 4%). Best responses achieved were partial response (28%) and stable disease (54%). Median OS and PFS were 7.8 and 4.2 months, respectively (median follow-up 7.8 months). OS (p=0.08) and PFS (p=0.81) were not significantly improved compared to the matched cohort. Paclitaxel concentrations were significantly increased with regorafenib (D15) compared with paclitaxel only (D1; p<0.05); no associations were observed with toxicity or efficacy. An increase in circulating galectin-1 compared to baseline was associated with shorter OS (p<0.01). Enrichment of angiogenesis-related gene expression was observed in short-survivors measured by RNA sequencing. Chromosome 19q13.12-q13.2 amplification was associated with shorter OS (p=0.02) and PFS (p=0.02). CONCLUSION: Treatment with regorafenib and paclitaxel is tolerable and shows promising efficacy in advanced EGC refractory to first-line treatment. Galectin-1 and chromosome 19q13.12-q13.2 amplification could serve as negative predictive biomarkers for treatment response.

			Action	DRS
	05_run3_P1P_2.raw	Raw
	05_run3_P3P_2.raw	Raw
	05_run3_V1P_2.raw	Raw
	05_run3_V3P_2.raw	Raw
	07_run4_P2D7_2.raw	Raw

Dataset Information

Rat DRG CIPN versus Vehicle-treatment_DIA-MS

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