Ipsita Pal1, Maryam Safari2, Marko Jovanovic3, Susan E Bates2, Changchun Deng4. 1. Department of Medicine, Center for Lymphoid Malignancies, Columbia University Irving Medical Center, New York, NY, USA. 2. Divison of Hematology and Oncology, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA. 3. Department of Biological Sciences, Columbia University, New York, NY, USA. 4. Department of Medicine, Center for Lymphoid Malignancies, Columbia University Irving Medical Center, New York, NY, USA. cd2448@cumc.columbia.edu.
Abstract
PURPOSE OF REVIEW: To highlight recent results in targeting mRNA translation and discuss the results and prospects of translation inhibitors in cancer therapy. RECENT FINDINGS: Until recently, inhibitors of mRNA translation have been thought to likely lack a therapeutic window. In 2012, the Food and Drug Administration (FDA) approved omacetaxine mepesuccinate (homoharringtonine) for the treatment of adults with chronic myelogenous leukemia (CML) who are resistant to at least two tyrosine kinase inhibitors. Since then, a few drugs, notably tomivosertib (eFT-508), selinexor (KPT-330), and ribavirin, have entered clinical trials. These drugs are known to inhibit mRNA translation. More recently, a number of interesting studies report that discrete subsets of proteins in cancer cells may be selectively targeted at the translation step, through inhibiting signals such as phospho-4E-BP1, eIF4A, and eIF4E. Promising therapies using these strategies have demonstrated potent anti-tumor activity in preclinical cancer models. The growing number of translation inhibitors with diverse mechanisms, coupled with emerging insights into translational regulation of different cancer-promoting genes, suggests a bright new horizon for the field of therapeutic targeting of mRNA translation in cancer.
PURPOSE OF REVIEW: To highlight recent results in targeting mRNA translation and discuss the results and prospects of translation inhibitors in cancer therapy. RECENT FINDINGS: Until recently, inhibitors of mRNA translation have been thought to likely lack a therapeutic window. In 2012, the Food and Drug Administration (FDA) approved omacetaxine mepesuccinate (homoharringtonine) for the treatment of adults with chronic myelogenous leukemia (CML) who are resistant to at least two tyrosine kinase inhibitors. Since then, a few drugs, notably tomivosertib (eFT-508), selinexor (KPT-330), and ribavirin, have entered clinical trials. These drugs are known to inhibit mRNA translation. More recently, a number of interesting studies report that discrete subsets of proteins in cancer cells may be selectively targeted at the translation step, through inhibiting signals such as phospho-4E-BP1, eIF4A, and eIF4E. Promising therapies using these strategies have demonstrated potent anti-tumor activity in preclinical cancer models. The growing number of translation inhibitors with diverse mechanisms, coupled with emerging insights into translational regulation of different cancer-promoting genes, suggests a bright new horizon for the field of therapeutic targeting of mRNA translation in cancer.
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