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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.