RNAi-based screening offers MPM treatment hope

Jan 31 2014

Research using RNA interference (RNAi)-based screening has identified several potential targets for the treatment of malignant pleural mesothelioma (MPM).

The study authors, led by Glen Reid of the University of Sydney in New South Wales, Australia, say that inhibition of the three targets – NDC80, CDK1, and PLK1 – could lead to much-needed new therapy options for the disease.

“With the advent of RNA interference[...] as a molecular tool, the suitability of specifically overexpressed genes as therapeutic targets can be rapidly assessed,” the team comments.

“However, this technique has only been used to investigate a few cases of MPM.”

They used results from previous gene expression profiling studies to select 40 targets to silence with small interfering (si)RNAs. In a panel of four MPM cell lines, knockdown of BIRC5, CDK1, CHEK1, NDC80, PLK1, RRM1, and RRM2 resulted in greater than 50% growth inhibition.

The team decided to investigate CDK1, NDC80, and PLK1 further, as small-molecule inhibitors have already been developed for the protein products of these targets. Transfection of siRNAs targeting these genes resulted in time- and dose-dependent growth inhibition for 5 days, which correlated with reductions in messenger RNA and protein. And, in two of the cell lines tested, the researchers found evidence that decreased expression of these targets led to induction of apoptosis.

Additionally, treatment with the CDK1 inhibitor roscovitine, and the NDC80 inhibitor INH1 inhibited the growth of all MPM cell lines, while the small molecular inhibitor of PLK1, BI 2536, did so in one of the cell lines. And, using two of the cell lines, the team showed that roscovitine could enhance cisplatin sensitivity up to fourfold and INH1 twofold.

Finally, using tumor samples from 154 patients with a median overall survival of 14.2 months, they found that patients with PLK1 expression greater than 10% had a significantly shorter overall survival, at 5.0 months compared with 15.5 months for patients with lower PLK1 expression (hazard ratio=2.05). CDK1 expression was also elevated, but did not correlate with survival.

Writing in the British Journal of Cancer, Reid et al say their results highlight the utility of RNAi screening to identify new therapeutic targets.

“The need for new treatment approaches for MPM is clear,” the team writes. “Given our promising findings, and the synergistic effects of small-molecule inhibitors of PLK1, CDK1 and NDC80 in combination with chemotherapy in other malignancies, further evaluation of these approaches in xenograft models is warranted.”

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