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Mar 17, 2014

Mutational Whac-A-Mole May Account for Failures of Targeted Cancer Therapy

  • In the fight against cancer, the targeting of specific cellular pathways has had mixed success. For example, such therapies have had little or no success against angiosarcoma, a rare and highly aggressive cancer of blood vessels. A possible explanation for angiosarcoma’s resistance to targeted therapy has emerged in a study published March 16 in Nature Genetics. This study, the work of scientists based at the Wellcome Trust Sanger Institute, finds that the “driver landscape” behind angiogenesis may explain why targeted therapy sometimes fails. The problem isn’t that the targeted therapies lack punch. Rather, the targets that must be struck down may simply be too numerous, or emerge from too many places.

    The authors of the study agree with the basic idea of targeted therapy. “Because this cancer doesn’t respond well to traditional chemotherapy and radiotherapy, it makes sense to develop drugs that target pathways that control blood vessel formation,” says Peter Campbell, Ph.D., co-lead author from the Wellcome Trust Sanger Institute. The authors, however, also have come to believe that it may be necessary to think more broadly to find a suitable treatment.

    These authors, in their study, which is entitled “Recurrent PTPRB and PLCG1 mutations in angiosarcoma,” explain that previous research has “identified aberrant angiogenesis, including occasional somatic mutations in angiogenesis signaling genes, as a key driver of angiosarcoma.” Hoping to extend this work, the authors employed "whole-genome, whole-exome, and targeted sequencing to study the somatic changes underpinning primary and secondary angiosarcoma.”

    The researchers found two novel cancer genes that control blood vessel formation that are mutated in angiosarcoma and that could be targeted for treatment: “We identified recurrent mutations in two genes, PTPRB and PLCG1, which are intimately linked to angiogenesis. The endothelial phosphatase PTPRB, a negative regulator of vascular growth factor tyrosine kinases, harbored predominantly truncating mutations in 10 of 39 tumors (26%). PLCG1, a signal transducer of tyrosine kinases, encoded a recurrent, likely activating p.Arg707Gln missense variant in 3 of 34 cases (9%).”

    In essence, the researchers found that in some patients, multiple mutations in the pathway of aberrant angiogenesis controls blood vessel growth. These multiple mutations may make drugs developed for a single target ineffective in some patients.

    “This study really highlights the power that a limited number of samples can have to influence the clinical and biological understanding of a rare disease, in this case angiosarcoma,” says Professor Adrian Harris, co-lead author from the University of Oxford. “Not only does our study change the way people view the biology of this tumor, it acts as a guide for future drug trials in angiosarcoma patients.”

    This study emphasizes the need to take into account the effects multiple, co-operating mutations can have when designing targeted treatments for patients. “The next challenge,” the authors assert, “will be to functionally explore these findings in appropriate angiosarcoma models that accommodate the complexity of the driver mutation landscape we report here. It is now indicated to determine the clinical usefulness of PTPRB and PLCG1 as possible biomarkers of secondary disease and as novel therapeutic targets in angiosarcoma.”



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