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The Benefits of Preventing DNA Repair

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ASCO 2009

There are a few properties that distinguish cancer cells from normal cells, and these differences are critical to understanding how to target cancer cells while sparing normal tissue and minimizing toxicity.  One of these differences in a cancer cell is the loss of the machinery to repair DNA.  Traditional chemotherapies commonly attempt to kill cancer cells by inducing DNA damage, with the expectation that normal cells have multiple DNA repair enzymes that can repair such damage, while cancer cells are unable to adequately repair this damage.  In the event that DNA damage cannot be repaired, cells undergo cell death.  

Research being presented during this meeting suggests a promising new approach to exploit these critical differences between cancer and normal cells.  One of these DNA repair enzymes, PARP, appears to play a critical role in DNA repair in tumor cells.  In normal cells, there are many repair enzymes with overlapping function, so that the loss of one does not cause significant difficulty in DNA repair.  In cancer cells, however, there is already a loss of several of the DNA repair enzymes, implying that further inhibition of the remaining enzymes will result in impaired ability to repair DNA damage.  As described by Dr. Litton in her blog, breast cancer researchers have recently reported that the combination of DNA injuring chemotherapy and an inhibitor of the DNA repair enzyme PARP, BSI-201, showed remarkable activity in a phase II study.  It appears that by preventing the cancer cell from repairing the damage to this chemotherapy, the cancer cell developed such high levels of DNA damage that cell death was inevitable.  As a result of these results and earlier basic science research, further research is being pursued to combine DNA damaging chemotherapy with PARP inhibitors in other tumor types. One such study, being conducted by Dr. Stacey Moulder at M. D. Anderson combines irinotecan with BSI-201.

However, additional research suggests that PARP inhibitors may be particularly beneficial in patients who inherit a defect in one of the other DNA repair enzymes.  This defect, called BRCA mutations, results in a family predisposition to certain cancers.  When given alone in patients without this mutation, there was no evidence of clinical benefit for this PARP inhibitor, as I presented at last year's ASCO.  However, in patients whose tumor contains this mutation, there is evidence of activity in breast and ovarian cancer, as presented again this year at ASCO.  There is a subset of pancreatic cancer patients who have mutation in BRCA, and an ongoing trial at MDACC, lead by Dr. David Fogelman, is exploring the combination of BSI-201 and gemcitabine in this patient group.  We are excited by this trial as it combines a DNA damaging chemotherapy with the PARP inhibitor in patients predicted to be most sensitive to this approach.

Whether by combination with DNA damaging chemotherapy, or when given to a uniquely susceptible subgroup of patients, this research strategy is certainly raising our hopes for adding another targeted treatment to our armamentarium in the clinic.



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