HER2 overexpression renders human breast cancers sensitive to PARP inhibition

['lizbeth]

GDP,

Thanks for the postings.

I am watching the PARP inhibitors with interest. My friend - who has BRCA1 ovarian cancer was in a Stanford trial. In the beginning she had dramatic results, then the cancer took off like it was on steroids.

So again, the metabolomics trumped genetics, and the cancer triumphed in survival of the fittest.

I had mentioned that she had her initial tumor tested with Rational Therapeutics and Estrogen played a key role. When she developed resistance to the initial treatment (platinum salt and Tamoxifen I think) she thought that blocking the estrogen does not work.

In the clinical trial, I do not believe estrogen receptors were addressed. It was like Lani's example - this time the windows were shut, but the front door was left wide open. It only took a few months for the puppy (cancer) to figure out it could get out! If she had also been taking Tamoxifen, or an Aromatase Inhibitor – I wonder if the resistance would have been delayed or overcome. If I remember correctly it was a monotherapy, but I wasn’t privy to all the details, so I’m not sure.

I’m not knocking functional profiling. I’m with you – I want to see the Phase III Battle of the Bands. I’m sure I already know which band is going to come out on top.

I see that Susan G. Komen gave a significant amount to explore the Her2/Parp issue.

http://www.news-medical.net/news/201...nhibitors.aspx

I wonder what it takes to get these charities interested in supporting the Battle of the Band? I think one of the issues is that it is testing, and it is easier to envision the benefits of new treatments.

Do you have knowledge of who is supporting funding? Is it Vanguard Cancer Foundation? We need bigger guns to get the Phase III funded. If we could get one of the top charities interested supporting the Battle of the Bands – then personalized medicine could really get somewhere. It would potentially save many, many patients from needlessly suffering through ineffective & toxic treatments.

I mean think of it, in the doctor’s office: Well, Mrs. Smith you can go into this clinical trial and get randomized into a standard of care treatment that may or may not work for you, or you can get the arm that personalizes your treatment into the one that works best for you.

Of course, you could avoid the placebo effect by not telling the patient which arm they are in.

[gdpawel]

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!