Update on Repurposed Cancer Therapeutics Research Project
17 Sep 2017
Harrison's Fund, alongside other charities, is involved in this research project led by Professor Steve Winder of Sheffield, on Repurposed Cancer Therapeutics as Treatments for DMD. The below report covers the 6 month period from February to August 2017.
Annual Report covering the 6 month period February 2017 to August 2017
Repurposed Cancer Therapeutics as Treatments for DMD
The original aims of the project were:
1. Assess the long-term efficacy of the tyrosine kinase inhibitors Dasatinib, Saracatinib and Bosutinib in reducing the dystrophic patho-physiology in mdx mice.
2. Assess the long-term efficacy of the proteasome inhibitor Carfilzomib in reducing the dystrophic patho-physiology in mdx mice.
3. Assess the possible synergistic effect of tyrosine inhibitors combined with proteasome inhibitors in further reducing the dystrophic patho-physiology in mdx mice..
During the last 6 months, the RA supported by this grant has had several health-related absences, meaning that we have lost 3 months working time on the project. Nonetheless, with support from other staff members in my lab and myself, all in vivo animal studies in relation to the original aims have now been completed. Some analysis from aim 1 remains to be finished off, but this will be combined with the same type of analysis also being conducted on the samples from aims 2 and 3, making for some efficiency savings. The RA is currently on a 50% phased return, and due to return to full-time working on 11th September. It should be able to complete all remaining analysis in the last 2 months of the project.
The proteasome inhibitor carfilzomib (Carf: 2.5 mg/kg), Src tyrosine kinase inhibitor bosutinib (Bos1: 25 mg/kg) and a combination of carfilzomib plus bosutinib (Carf+Bos: 2.5 + 25 mg/kg respectively) showed no improvement in physical performance over 12 weeks, in fact compared to control (Cont) there was a significant deterioration. This is in marked contrast to the significant improvement seen with bosutinib at the higher dose of 50mg/kg (Bos2). Analysis of the other parameters (in progress), such as serum biomarkers, central nucleation, inflammation and fibrosis will be informative in revealing possible reasons for the drop in performance. The data do highlight the need for more in depth dose-response studies than have so far been possible. Particularly with respect to bosutinib which over a two-fold concentration range, went from a 50% reduction to a 150% increase in physical performance. The carfilzomib data were disappointing, especially given the promising results of experiments carried out in zebrafish. Nonetheless, the reduced physical activity from either drug alone was not worsened when in combination, suggesting that at the right dose combination there still could be benefit to administration of both drugs together. However we should await the more in depth histopathological analysis before drawing frim conclusions.
Steve Winder Sheffield
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