Targeting ROR1 and a two-drug approach to cure CLL

Carlo Croce, MD of The Ohio State University, Columbus, OH provides an overview of microRNA and ROR1 as part of an overview of his research on the epigenetics and genetic of chronic lymphocytic leukemia (CLL) while at the 2016 International Workshop of the German CLL Study Group (GCLLSG) in Cologne, Germany. Prof. Croce explains that microRNA have a number of targets and that there could be other genes besides BCL2 that are dysregulated because of the loss of the microRNA. This led to the discovery of MCL1. He explains that his talk at GCLLSG was about another target, ROR1, which was discovered by Tom Kipps. It is an antigen on the cell surface and seems to be expressed only on leukemic cells. When investigating the question if there are any CLL cells that are ROR1 negative, they found that 10% of CLL cells are indeed ROR1 negative. Prof. Croce screened samples of ROR1 positive and ROR1 negative cells for ROR1 microRNA. The difference between ROR1 positive and negative cells were miR-15 and miR-16 whereby the ROR1 positive cells are the ones which lost miR-15 and miR-16. The loss of miR-15 and miR-16 in CLL leads to the overexpression of BCL2, MCL1 and ROR1. Prof. Croce believes that cytotoxic antibodies can be made against ROR1. The problem with targeted therapy, as Prof. Croce points out, is that there is always some mutant resistant to therapy. However, you can target the same cells with two drugs and he believes that with this approach, the cells will not be able to survive and therefore it will become possible to cure patients.

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