Combination of MEK/ERK Inhibitor and mTOR/P13K Inhibitor
 

On April 3, 2011, Dr. Robert Nagourney will have a Poster Session at an American Association for Cancer Research (AACR) meeting on the most recent findings on novel compounds that target two parallel pathways in cancer cells. These small molecules drugs, disrupt the signal that drives cancer cell survival and proliferation.

Cell function analysis of the mTOR/P13K and MEK/ERK inhibitors, BEZ235 and AZD6244, alone and in combination in human tumor primary culture micro-spheroids: 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 selectlion and is demonstrably greater and more compelling data currently generated from DNA analyses.

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

Re: Combination of MEK/ERK Inhibitor and mTOR/P13K Inhibitor
 

This type of research indeed brings hope to those who are fighting the disease.

I wondered if those 'pathways' has anything to do with family clusters such as HNPCC (Hereditary Non-polyposis Colon Cancer) which increases the risks of cancers in the digestive tract, brain, breast, and other reproductive organs.

Hopefully pretty soon all of these can be sorted out and we'll have true targeted therapy/prevention for more and more types of cancer.

With faster comupting power and better understanging of cancer in the cellular level, 'personalized medicine' should become a reality fairly soon.

Re: Combination of MEK/ERK Inhibitor and mTOR/P13K Inhibitor
 

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.

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.

American Association of Cancer Research (AACR) Meeting 2011

http://robertanagourney.wordpress.co...-aacr-meeting/

Re: Combination of MEK/ERK Inhibitor and mTOR/P13K Inhibitor
 

"cancers share pathways across tumor types, pathways that might not intuitively seem related."

I sure like to see that as opposed to the idea that any given cancer is many diseases in one..
Go upstream, combination blockade at the highest branches.