Combination of MEK/ERK Inhibitor and mTOR/P13K Inhibitor

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Some cell-based assay labs have explored the biology of PARP inhibitors, alone and in combination, in actual human tumor primary culture micro-speheroids (microclusters), in breast, ovarian and other cancers. In these investigations, the lab applies the functional profiling platform to understand how PARP inhibitors enhance the effects of drugs and drug combinations.

As seen with PARP inhibitors, mutations work with other proteins. Genes do not operate alone within the cell but in an intricate network of interactions.

To date, one lab has observed good activity for the PARP inhibitors as single agents in BRCA1 positive patients and in some triple negative patients. Work is ongoing with these BRCA1 positive patients as wells as other tumor types where the PARP inhibitors may prove useful in the future. The PARP inhibitors are turning out to be very useful.

On April 3rd, Dr. Robert Nagourney, medical director at Rational Therapeutics and instructor in Pharmacology at the University of California, Irvine School of Medicine, will have a Poster Session at the 102nd Annual Meeting of the American Association for Cancer Research (AACR) in Orlando, Florida on the most recent findings on novel compounds that target two parallel pathways in cancer cells.

Dr. Nagourney will report the results of functional analysis with the mTOR/P13K and MEK/ERK inhibitors, BEZ235 and AZD6244, alone and in combination in human tumor primary culture micro-spheroids (microclusters): Exploration of horizontal pathway targeting. While the profiles of each drug alone are of interest, the profiles of the drugs in combination are better still.

The phenomenon of cross-talk defines an escape mechanism whereby cancer cells blocked from one passage, find a second. When clinical therapists have the capacity to block more than one pathway, the cancer cell is trapped and often dies.

This is what has been observed with these duel inhibitor combinations.

What is interesting is the fact that the activities cut across tumor types. Melanomas, colon cancers and lung cancers seem to have similar propensities to drive along these paths. Once again, we find that cancer biology is non-linear.

Moreover, cancers share pathways across tumor types, pathways that might not intuitively seem related. This is the beauty of cell-based functional profiling platform. It allows the exploration of drugs and combinations that most oncologists wouldn't think of.

It is these counterintuitive explorations that will likely lead to meaningful advances.

Functional profiling measures biological signals rather than DNA indicators, which plays an important role in cancer drug selection and is demonstrably greater and more compelling data currently generated from DNA analyses.

The results of their investigation support the clinical relevance of targeting the MEK/ERK and PI3K/mTOR pathways and more importantly, suggest "dual" pathway inhibition (horizontal) to be a productive strategy for further clinical development. Disease specific profiles and sequence dependence are being explored and will be reported.

Most solid tumors reveal complex interactions between signal pathways that cross talk at points of commonality. To examine the clinical potential of BEZ235 and AZD6244 - inhibitors of PI3K and MEK/ERK pathways - they applied cell function analysis of programmed cell death to tumor micro-spheroids (microclusters) isolated from 24 patients. Drugs were tested alone and in combination.

According to researcher, Professor Alan Ashworth, director of the Breaktrhough Breast Cancer Research Centre in London, the BRCA1 and BRCA2 genes are involved in a repair pathway for double-strand DNA breaks that occur very close to each other. An elaborate mechanism called homologous recombination fixes some of these double-strand breaks, and BRCA2 and BRCA1 are critical for homologous recombination.

PARP is a very active enzyme involved in the repair of single-strand breaks in DNA or modified bases. It binds to DNA damage and adds multiple sugar molecules to the DNA that act as a beacon to recruit other components of DNA repair.

Emerging work on assays (PARP levels correlating with response to PARP inhibitors) have shown pretty good response with PARP inhibitors as single agents in BRCA1 positive patients and in some triple negative patients. There has been some results combining the PARP inhbitors with mustard alkylators, platins and drug combinations to optimize PARP inhibitor combinations.

These molecules have also been the subject of investigation using functional 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 and Iniparib, 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 analyses.

Source: Robert A. Nagourney, Paula Bernard, Federico Francisco, Ryan Wexler, Steve Evans, Rational Therapeutics, Long Beach, CA. Proceedings of AACR - Volume 52 - April 2011.

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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.

Poster from Rational Therapeutics Session at 2011 AACR Meeting

http://robertanagourney.wordpress.com/2011/04/28/poster-from-rational-therapeutics-session-at-2011-aacr-meeting/

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What happened to iniparib in breast cancer?

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, in retrospect, a direct comparision of olaparib to inapaprib revealed no correlation. Thus, human tumor primary culture analysis scooped the investigators. 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