Editors' ChoiceLeukemia/Lymphoma

A Silver Bullet for T Cell Malignancies?

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Science Translational Medicine  29 Aug 2012:
Vol. 4, Issue 149, pp. 149ec155
DOI: 10.1126/scitranslmed.3004809

Just like the werewolves of old legends, T cell malignancies present a mortal danger to humans, with poor survival rates even with the best treatments available. Current therapies also have substantial short-term and potential long-term side effects. Now, Guo et al. identify and characterize a selective inhibitor of Itk kinase, CTA056, which has potential for treating T cell malignancies.

Itk is a tyrosine kinase that is important for T cell signaling and is aberrantly activated in multiple types of T cell malignancies. The researchers screened a small-molecule library, searching for inhibitors of Itk. They identified CTA056, which binds to the adenosine 5´-triphosphate (ATP)–binding pocket of Itk and specifically inhibits the ability of Itk to phosphorylate itself, thus preventing its activation. In vitro, CTA056 inhibited the growth of human cancer cell lines derived from T cell acute lymphoblastic leukemias (T-ALL) and cutaneous T cell lymphomas that expressed high levels of Itk. CTA056 was highly specific for T cell–derived cancer cells and did not affect the growth of non–T cell–derived cancer cells that did not express Itk, or noncancer cells. The authors found that CTA056 caused growth inhibition by inducing the T cell–derived cancer cells to undergo apoptosis. CTA056 also decreased activation and cytokine release from the malignant T cells, down-regulated oncogenic micro RNAs (miRNAs), and up-regulated miRNAs that switch on the expression of tumor suppressor genes. Last, the researchers demonstrated that CTA056 blocked tumor growth in mice transplanted with human T-ALL without evidence of major side effects.

These findings represent a promising first step toward the development of a new treatment modality for T cell malignancies. More studies are needed to further validate the therapeutic potential of CTA056 in vivo, but a silver bullet may yet be in sight for this particular werewolf.

W. Guo et al., Molecular characteristics of CTA056, a novel Itk inhibitor which selectively targets malignant T cells and modulates oncomirs. Mol. Pharmacol., 16 August 2012 (10.1124/mol.112.079889). [PubMed]

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