More Translational Medicine – a good example of the meaning – translating basic research to clinical application
Alan Ashworth, soon to lead the London Center for Molecular Pathology, leads the charge for the integration of bio-molecular research into clinical applications.[1]
Normal cells repair broken strands of DNA with two agents. PARP1, poly ADP ribose polymerase, does base excision repair at the broken ends, and BRCA does homologous recombination, putting the strand back together. When successful, this one-two punch repairs the break in the DNA.
Mutation of BRCA 1 and 2 are associated with cancer, especially breast cancer. Without the completion of the repair job by the mutated BRCA, the cell lives on and accumulates further damage over time with more and more breaks left un-repaired – increasing the risk of cancer.
Normally a cell dies when things go wrong, but with mutated BRCA and with PARP present, the self-destruct mechanism fails. The absence of both PARP1 and BRCA, however, does trigger cell death. In the phase I clinical trials of a PARP-inhibitor, 23 patients had mutations in one of their BRCA genes. 12 of these patients showed no progression of their disease after 4 months. In the phase II trials, more than a third of the patients on high doses of PARP-inhibitor showed some improvement.
The NEJM calls it Synthetic Lethality. Taking the unusual step of reporting an early-stage trial, NEJM reported on this promising therapy as, “a new direction in cancer drug development.”[2]
[1] Nature 463, 28 January 2010, 422-423
[2] NEJM- Dirk and Silver, Synthetic Lethality, 361, 189-191 9 July 2009
Normal cells repair broken strands of DNA with two agents. PARP1, poly ADP ribose polymerase, does base excision repair at the broken ends, and BRCA does homologous recombination, putting the strand back together. When successful, this one-two punch repairs the break in the DNA.
Mutation of BRCA 1 and 2 are associated with cancer, especially breast cancer. Without the completion of the repair job by the mutated BRCA, the cell lives on and accumulates further damage over time with more and more breaks left un-repaired – increasing the risk of cancer.
Normally a cell dies when things go wrong, but with mutated BRCA and with PARP present, the self-destruct mechanism fails. The absence of both PARP1 and BRCA, however, does trigger cell death. In the phase I clinical trials of a PARP-inhibitor, 23 patients had mutations in one of their BRCA genes. 12 of these patients showed no progression of their disease after 4 months. In the phase II trials, more than a third of the patients on high doses of PARP-inhibitor showed some improvement.
The NEJM calls it Synthetic Lethality. Taking the unusual step of reporting an early-stage trial, NEJM reported on this promising therapy as, “a new direction in cancer drug development.”[2]
[1] Nature 463, 28 January 2010, 422-423
[2] NEJM- Dirk and Silver, Synthetic Lethality, 361, 189-191 9 July 2009
Labels: Medicine
posted by Clancy Hughes | 2/14/2010 05:31:00 PM
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