MicroRNAs contribute to the pathogenesis of human cancer by regulating the expression of oncogenes and tumor suppressor genes. In fact, loss of miR-15a and miR-16-1 leads to overexpression of BCL2 and MCL1 and the development of CLL, while overexpression of miR-155 leads to the development of aggressive B cell malignancies, possibly through suppression of SHIP1 phosphatase. We have shown loss of miR-29s in lung cancer, AML and the aggressive form of CLL. We have also shown that miR-29s target directly the de novo DNA methyltransferases (DNMT3A and 3B) and indirectly the maintenance DNA methyltransferase 1 (DNMT1) and that loss of miR-29 family members results in overexpression of DNMT3A, 3B and 1. This leads to silencing of tumor suppressors through methylation of CpG islands of their promoters that can be reversed by transfection with miR-29s. Thus, loss of miR-29s and overexpression of DNMTs seem to cause epigenetic changes associated with tumor development. We are proposing three small clinical trials to validate that loss of miR-29 is a predictor of response to demethylating agents such as 5-azacytidine (5-Aza) and decitabine in lung cancer, AML and the aggressive form of CLL. We are also planning to validate the results of these trials in mouse models of the diseases. Thus, this program will result in major research and development innovations that will effectively be linked to long term improvement and growth in oncology, public health and health care delivery.
We have observed striking responses to demethylating agents in tumors that have lost the expression of microRNAs (miR-29s) that target the DNA methyltransferases. We propose to carry out three small clinical trials to show that patients with lung cancer, AML and the aggressive form of CLL should be stratified on the basis of miR-29 expression, since the tumor cells that have lost mir-29s are killed by demethylating agents. We also intend to validate our hypothesis in mouse models.
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