HER2 Support Group Forums - View Single Post - HER2 overexpression renders human breast cancers sensitive to PARP inhibition

gdpawel · 10-11-2013, 01:11 PM

A couple of years ago, Nagourney was explaining what happened to the PARP inhibitors in breast cancer.

It turned out that iniparib, a member of the benzamine chemical family, at physiological concentrations achievable in humans is not a PARP inhibitor. This, in retrospect, should have been obvious because a full-dose PARP inhibitor, plus a potent combination of carboplatin plus gemcitabine would not likely be tolerable if PARP inhibition were achieved.

Second, the patients receiving the drug are probably not a homogeneous population. That is, some TNBC patients may be similar to the BRCA patients, while others may not have the DNA repair deficiencies associated with PARP inhibitor response.

Finally, he originally reported the carboplatin plus gemcitabine combination in breast cancer, as a split-dose doublet in 2008 (Nagourney, Clin Breast Cancer Research, 2008). He observed, in that original clinical trial, that even a lower starting dose of gemcitabine (i.e. 800mg/ml2 vs. the O’Shaughnessy 1000 mg/m2) resulted in significant toxicity and in his concluding comments in that paper, he suggested 600mg/ml2. At 1000 mg/m2, Dr. O’Shaughnessy’s trial nearly doubled our recommended dose in this patient population.

He, like other investigators, entered into the original studies of these molecules believing iniparib to be a PARP inhibitor. To his surprise, a direct comparison of olaparib to inapaprib revealed no correlation. He described this in an abstract, “Of interest, BSI201 & AZD2281 activity did not correlate in parallel analyses (R = 0.07, P > 0.5).” The human tumor primary culture analysis scooped the other investigators.

So, what was earned? First, they learned that iniparib is not a true PARP inhibitor.
Second, they learned that the combination of platins plus gemcitabine in breast cancer is synergistic, highly active and can be toxic (particularly at the doses chosen for the trial).

Finally, they learned that TNBC, indeed all breast cancers, even more to the point, all cancers in general, are heterogeneous. That is precisely why the use of human tumor primary culture analyses are so instructive and should be incorporated into clinical trials for these and other targeted agents.

I know I'm preaching to the choir and I'm just as interested in a Battle of the Band clinical trial (if anything, in the memory of Ann). I would suspect that Vanguard has the interest, but whether they have the means. I think that something like $5 million would be minimum to start something like this. Looking for a Sugar Daddy!

10-11-2013, 01:11 PM	#7
gdpawel Senior Member Join Date: Aug 2006 Location: Pennsylvania Posts: 1,080	A couple of years ago, Nagourney was explaining what happened to the PARP inhibitors in breast cancer. It turned out that iniparib, a member of the benzamine chemical family, at physiological concentrations achievable in humans is not a PARP inhibitor. This, in retrospect, should have been obvious because a full-dose PARP inhibitor, plus a potent combination of carboplatin plus gemcitabine would not likely be tolerable if PARP inhibition were achieved. Second, the patients receiving the drug are probably not a homogeneous population. That is, some TNBC patients may be similar to the BRCA patients, while others may not have the DNA repair deficiencies associated with PARP inhibitor response. Finally, he originally reported the carboplatin plus gemcitabine combination in breast cancer, as a split-dose doublet in 2008 (Nagourney, Clin Breast Cancer Research, 2008). He observed, in that original clinical trial, that even a lower starting dose of gemcitabine (i.e. 800mg/ml2 vs. the O’Shaughnessy 1000 mg/m2) resulted in significant toxicity and in his concluding comments in that paper, he suggested 600mg/ml2. At 1000 mg/m2, Dr. O’Shaughnessy’s trial nearly doubled our recommended dose in this patient population. He, like other investigators, entered into the original studies of these molecules believing iniparib to be a PARP inhibitor. To his surprise, a direct comparison of olaparib to inapaprib revealed no correlation. He described this in an abstract, “Of interest, BSI201 & AZD2281 activity did not correlate in parallel analyses (R = 0.07, P > 0.5).” The human tumor primary culture analysis scooped the other investigators. So, what was earned? First, they learned that iniparib is not a true PARP inhibitor. Second, they learned that the combination of platins plus gemcitabine in breast cancer is synergistic, highly active and can be toxic (particularly at the doses chosen for the trial). Finally, they learned that TNBC, indeed all breast cancers, even more to the point, all cancers in general, are heterogeneous. That is precisely why the use of human tumor primary culture analyses are so instructive and should be incorporated into clinical trials for these and other targeted agents. I know I'm preaching to the choir and I'm just as interested in a Battle of the Band clinical trial (if anything, in the memory of Ann). I would suspect that Vanguard has the interest, but whether they have the means. I think that something like $5 million would be minimum to start something like this. Looking for a Sugar Daddy!