Gene Could Become Path to Mesothelioma Therapies, Study Reports

Gene Could Become Path to Mesothelioma Therapies, Study Reports

A gene known as platelet-derived growth factor receptor beta (PDGFRB) could become the basis of therapies for malignant pleural mesothelioma (MPM), according to an early preclinical study.

The research, “Inhibition of the platelet-derived growth factor receptor beta (PDGFRB) using gene silencing, crenolanib besylate, or imatinib mesylate hampers the malignant phenotype of mesothelioma cell lines,” was published in Genes & Cancer.

Previous research has shown that 20% to 40% of MPM tissue has elevated levels, or overexpression,  of PDGFRB, a gene implicated in the progression of several other cancer types.

In MPM the reasons for such overexpression are poorly understood.  Unlike in gastrointestinal stromal tumors (GIST), high PDGFRB levels in MPM are the result of neither somatic mutations nor the presence of more than one copy of the gene, studies have indicated.

Using MPM cell lines, researchers showed that PDGFRB expression is increased in MPM cell lines, compared with normal, non-cancerous cell lines.  To better understand how PDGFRB promotes MPM progression, scientists decreased PDGFRB expression by administering siRNA (siPDGFRB), or silencing RNA, to cell lines, which briefly interfered with gene expression. Expression is the process by which information from a gene is used to create a functional product, like a protein.

SiRNA led to a significant reduction in the proliferation rate of MPM cells, compared with cells that served as controls.  In addition, in all MPM cell lines tested, PDGFRB silencing reduced clonogenicity, or the ability of tumor cells to produce progeny from single cells, a hallmark of cancer.

In-depth analysis of cell proliferation also showed that loss of PDGFRB expression inhibits cell cycle progression at the G2 checkpoint.  This causes the cells to stop proliferating at that point, and undergo a form of programmed cell death called apoptosis.  Indeed, subsequent analysis showed that MPM cells with reduced expression also have higher rates of cell death.

Another feature of cancer cells is their ability to move about in the body.  In one of the MPM cell lines, downregulating PDGFRB expression reduced the cells’ ability to migrate, compared with control cells. Downregulation occurs when, in response to an external prompt or stimulus, a cell produces less of a given product, such as RNA or protein.

Finally, PDGFRB depletion reduced the tumorigenic potential of MPM cells in a laboratory setting, assessed by testing the ability of cells to grow in suspension as single colonies.

Several PDGF/PDGRF inhibitors are either available or in clinical trials for other cancers, such as leukemia, glioma or GIST. Researchers sought to establish whether any of the PDGFR inhibitors could block MPM cell-line tumor properties. They identified two, crenolanib and imatinib, that could.

Both inhibitors were able to reduce cell proliferation in a similar manner to siRNA treatment, although the effect of crenolanib was much stronger than imatinib.  Treatment with crenolanib or imatinib also increased the number of apoptotic cells and decreased the ability of MPM cells to migrate. Like decreasing PDGFRB expression, crenolanib and imatinib reduced the in vitro tumorigenic potential of MPM cells.

“This study highlights the importance of the role played by PDGFRB in the MPM malignancy, and has provided a rationale for its use as a potential therapeutic target,” the researchers said. They also suggested that “crenolanib could be an important therapeutic option for MPM patients, which warrants further investigation in order to explore its usefulness as a form of personalized therapy for this cancer type.”

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