PARP Inhibitors in Breast Cancer

gdpawel said:

PARP Inhibitors in Breast Cancer
LOL! You have a way with words. But I believe you've hit the proverbial nail right on the head!

gdpawel said:

Other researchers looking into it
I see where Sanofi-aventis and its subsidiary, BiPar Sciences, announced on January 27th that a randomized Phase III trial evaluating Iniparib (BSI-201) in patients with metastatic triple-negative breast cancer (mTNBC) did not meet the pre-specified criteria for significance for co-primary endpoints of overall survival and progression-free survival.

Importantly, the results of a pre-specified analysis in patients treated in the second- and third-line setting demonstrate an improvement in overall survival and progression-free survival, consistent with what was seen in the Phase II study. The overall safety analysis indicates that the addition of Iniparib (BSI-201) did not significantly add to the toxicity profile of gemcitabine and carboplatin.

"While this trial did not meet its primary goal, we believe that the improvement in overall survival and progression-free survival in patients in the second- and third-line setting are important findings," said Dr. Debasish Roychowdhury, Senior Vice President and Head of sanofi-aventis Oncology. "We are conducting in-depth analysis to gain further insight into these Phase III results. Sanofi-aventis remains committed to improving outcomes for patients with triple-negative breast cancer where there is high unmet medical need."

Sanofi-aventis plans to discuss these data with United States and European health authorities in the near future. Full study results will be presented at an upcoming major oncology conference. Patients with questions are encouraged to consult with their treating physicians, or call 1-800-633-1610. The current clinical development program for Iniparib (BSI-201) continues in breast, lung and other cancers.

The study enrolled 519 women with mTNBC from 109 sites in the United States. Patients were randomized to receive a standard chemotherapy regimen (gemcitabine and carboplatin) on days one and eight of each 21-day cycle, with or without iniparib (BSI-201) 5.6 mg/kg, which was administered on days one, four, eight and 11 of each 21-day cycle. Patients in the study had received up to two previous lines of chemotherapy in a metastatic setting. The co-primary endpoints were overall survival and progression-free survival.

Iniparib (BSI-201) is a novel investigational anti-tumor agent with poly (ADP-ribose) polymerase (PARP) inhibitory activity in preclinical models. Iniparib (BSI-201) is in Phase III trials for patients with squamous non-small cell lung cancer, as well as in Phase II trials for patients with breast, lung and other cancers. Iniparib is the United States Adopted Name (USAN) for the investigational agent BSI-201.

However, these molecules have also been the subject of investigation using functional profiling analysis in the laboratory of Dr. Nagourney. As will be reported in the Proceedings of the American Society of Clinical Oncology, Dr. Nagourney found activity for Olaparnib (AZD-2281) and Iniparib (BSI201), in patients with BRCA mutation and in some triple negative breast cancer patients. This is a fertile area of investigation and a highly informative application of human tumor microspheroid (microcluster) analyses.

gdpawel said:

Psychological well-being
laughs

This just came out. Thought you'd like to read it.

Art in Oncology: How Patients Add Life to Their Days

http://jco.ascopubs.org/content/29/10/1392.full

Greg

gdpawel said:

American Association of Cancer Research (AACR) Meeting 2011
The Sunday, April 3, 2011, experimental and molecular therapeutics poster session at the AACR 102nd annual meeting included Dr. Robert Nagourney's Rational Therapeutics presentation on signal transduction inhibitors. Using MEK/ERK and PI3K-MTOR inhibitors he explored the activities, synergies and possible clinical utilities of these novel compounds.

The findings were instructive. First, it saw a good signal for both compounds utilizing the Ex-vivo Analysis of Programmed Cell Death (EVA-PCD) platform (functional profiling). Second, it saw disease-specific activity for both compounds. For the MEK/ERK inhibitor, melanoma appeared to be a favored clinical target. This is highly consistent with expectations. After all, many melanomas carry mutations in the BRAF gene, and BRAF signals downstream to MEK/ERK. By blocking MEK/ERK, it appeared that his lab blocked a pathway fundamental to melanoma progression. Indeed, MEK/ERK inhibitors are currently under investigation for melanoma.

For PI3K inhibitors, the highest activity was observed in uterine cancers. This has interest, because uterine carcinomas are often associated with a mutation in the PTEN gene. PTEN is a phosphatase tumor suppressor that functions to block activation of the PI3K pathway. Thus, mutations in the tumor suppressor unleash PI3K signaling, driving tumors to grow and metastasize. Blocking PI3K provided a strong signal, indicating that this approach may be very active in tumors associated with these oncogenic events.

The third point of interest in the report was, perhaps, its most important. Specifically, that the lab can explore those diseases where MEK-ERK, PI3K and mTOR signaling are less established targets. Cancers of the lung, ovary, colon or breast all manifested profiles of interest. When they combined both pathway inhibitors in a process called horizontal inhibition, renal cell carcinoma popped up as the best target. These results, though exploratory, suggest a superior approach for drug development, allowing the lab to identify important leads much faster than the clinical trial process.

Source: Rational Therapeutics, Inc.

gdpawel said:

American Association of Cancer Research (AACR) Meeting 2011
The Sunday, April 3, 2011, experimental and molecular therapeutics poster session at the AACR 102nd annual meeting included Dr. Robert Nagourney's Rational Therapeutics presentation on signal transduction inhibitors. Using MEK/ERK and PI3K-MTOR inhibitors he explored the activities, synergies and possible clinical utilities of these novel compounds.

The findings were instructive. First, it saw a good signal for both compounds utilizing the Ex-vivo Analysis of Programmed Cell Death (EVA-PCD) platform (functional profiling). Second, it saw disease-specific activity for both compounds. For the MEK/ERK inhibitor, melanoma appeared to be a favored clinical target. This is highly consistent with expectations. After all, many melanomas carry mutations in the BRAF gene, and BRAF signals downstream to MEK/ERK. By blocking MEK/ERK, it appeared that his lab blocked a pathway fundamental to melanoma progression. Indeed, MEK/ERK inhibitors are currently under investigation for melanoma.

For PI3K inhibitors, the highest activity was observed in uterine cancers. This has interest, because uterine carcinomas are often associated with a mutation in the PTEN gene. PTEN is a phosphatase tumor suppressor that functions to block activation of the PI3K pathway. Thus, mutations in the tumor suppressor unleash PI3K signaling, driving tumors to grow and metastasize. Blocking PI3K provided a strong signal, indicating that this approach may be very active in tumors associated with these oncogenic events.

The third point of interest in the report was, perhaps, its most important. Specifically, that the lab can explore those diseases where MEK-ERK, PI3K and mTOR signaling are less established targets. Cancers of the lung, ovary, colon or breast all manifested profiles of interest. When they combined both pathway inhibitors in a process called horizontal inhibition, renal cell carcinoma popped up as the best target. These results, though exploratory, suggest a superior approach for drug development, allowing the lab to identify important leads much faster than the clinical trial process.

Source: Rational Therapeutics, Inc.

gdpawel said:

Where we are with breast cancer nowadays?
Dr. Joyce O’Shaughnessy reported Phase II data, first at the ASCO meeting, then in the NEJM, describing the efficacy of iniparib combined with carboplatin and gemcitabine in triple negative breast cancer (TNBC). Despite the enthusiasm that surrounded Dr. O’Shaughnessy’s initial observations, the confirmatory clinical trial using iniparib combined with carboplatin and gemcitabine, then compared with carboplatin and gemcitabine did not achieve statistical significance. That is, the trial was negative and the combo of iniparib with carboplatin plus gemcitabine was not proven superior.

Based on this, Dr. Robert Nagourney initiated a study of both iniparib and olaparib in human breast cancer specimens. His results were reported at the ASCO meeting. What happened? Quite a few things.

First, 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, Dr. Nagourney 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 his recommended dose in this patient population.

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

What has been learned? First, iniparib is not a true PARP inhibitor. Second, the combination of platins plus gemcitabine in breast cancer is synergistic, highly active and can be toxic (particularly at the doses chosen for this trial). Finally, 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.

Source: Rational Therapeutics