Genetic mutations reduce the efficacy of an anti-cancer drug


Azacitidine (AZA) is an anti-cancer drug that is approved by the US FDA for the treatment of myelodysplastic syndrome (MDS). Sometimes, it is also used to treat acute myeloid leukemia (AML). So far, the factors that affect patients' response to it and the mechanisms by which it works have not been fully understood.

Some reports suggested that co-administration of an anti-cancer drug called vorinostat (VOR) may enhance the efficacy of AZA. A clinic trial, called RAvVA, is designed to evaluate the effect of AZA monotherapy compared to a combination therapy of AZA and VOR. This trial showed that with regards to AML and MDS, VOR did not improve the efficacy of AZA. Interestingly, the trial discovered that mutations in the CDKN2A, IDH1 and TP53 genes are correlated with reduced survival in AZA-treated patients.

The trial was conducted by researchers from the University of Birmingham, University of Oxford, Queen's University, and several other research institutions. Findings of the trial were published online in Clinical Cancer Research on August 1, 2017.

The trial enrolled 259 patients diagnosed with AML or high-risk MDS. All the patients were randomly assigned to receive either AZA alone or AZA in conjunction with VOR. The researchers found that the overall response rate and overall survival rate of the two groups of patients were similar, suggesting that VOR did not enhance the effectiveness of AZA.

In the study, the researchers also analyzed bone marrow samples collected from the patients. Using next-generation sequencing and other analytic methods, the researchers found that patients carrying mutations in CDKN2A, IDH1 or TP53 tended to have a poor outcome. This discovery would help predict which patients with AML and MDS will respond to AZA.

According to first author Prof. Charles Craddock, the findings may lead to better treatment combinations for MDS and AML. Given that CDKN2A, IDH1 or TP53 have an impact on treatment response, more emphasis should be put on studying the roles of these genes in cancer.
 
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