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Some cancer drugs may block cellular cross talk but not kill cancer cells
By Dross at 2010-12-23 03:57
Some cancer drugs may block cellular cross talk but not kill cancer cells

New data from the University of Colorado Cancer Center could alter how drugs are evaluated 

12/22/2010 

AURORA, Colo. (Dec. 22, 2010)—A class of drugs thought to kill cancer cells may in fact block “cross talk” between the cancer cell and normal immune cells, resulting in reduced cancer growth and spread—a discovery that could significantly alter the way cancer drugs are evaluated in the future.

Researchers at the University of Colorado Cancer Center demonstrated the discovery in bladder cancer, the fifth most common cancer in the United States. Bladder cancer will kill about 14,000 Americans this year, most of whom will die as a result of the disease’s spread to other organs in a process called metastasistermterm.

The scientists showed that endothelin-A receptor antagonist drugs are only effective at blocking the start of cancer spread to other organs, not treating large, established primary-or distant-site tumors. The study was published online Dec. 22, 2010, in the Journal of Clinical Investigation.

“We discovered that these drugs block the ‘tumor host interactions’ found at sites of metastasis, which is what reduces tumor growth at these sites,” said lead author Dan Theodorescu, MD, PhD, director of the University of Colorado Cancer Center and professor of surgery and pharmacology at the University of Colorado School of Medicine. “However, unless the drugs are used early, they have minimal or no effect.”

Endothelin-A receptor antagonist drugs block the action of a protein called endothelin 1 [ET-1], thought to be involved in stimulating cancer cell growth and spread. Theodorescu’s lab discovered that ET-1 attracts immune cells called macrophages to cancer cells lodged in the lungs. The macrophages start making factors that stimulate the cancer cells in the lungs to grow—called metastaticterm colonization—which significantly decreases the patient’s chance of survival.

In the past decade, two endothelin-A receptor antagonist drugs—Abbott’s atrasentan and AstraZeneca’s zibotentan—have had difficulties in large phase 3 clinical trials. Both drugs were tested in a large number of patients with advanced cancer, and neither drug attained its desired effects. Most likely, Theodorescu said, the drugs were given after the window of opportunity for them to work had closed.

“Had we known this before the trials, we wouldn’t have used them to try to reduce large, established tumors,” he said. “We would have used them to try to suppress the appearance of metastasis. This new information has important implications for how we test drugs for effectiveness before human use and then on how we select patients in clinical trials with these agents, especially since many types of cancer secrete ET-1.”



3 comments | 8363 reads

by gdpawel on Fri, 2010-12-24 02:04
Cancer cells utilize cross talk and redundancy to circumvent therapies. They back up, zig-zag and move in reverse, regardless of what the sign posts say. Using genomic signatures to predict response is like saying that Dr. Seuss and Shakespeare are truly the same because they use the same words. The building blocks of human biology are carefully construed into the complexities that we recognize as human beings. However appealing gene profiling may appear to those engaged in this field it will be years, perhaps decades, before these profiles can approximate the vagaries of human cancer.

In recent years, personalized care has come to be considered synonymous with genomic profiling. While breakthroughs in human genomics is applauded, there is no molecular platform that can match patients to treatments. The objective response rate of just 10 percent, almost all in breast and ovarian cancer patients in one study (Von Hoff J Clin Oncol 2010 Nov 20:28(33): 4877-83), suggests that cancer biology is demonstrably more complex than an enumeration of its constituent DNA base pairs.

On the other hand, functional profiling, which measures biological signals rather than DNA indicators, will continue to provide clinically validated information and play an important role in cancer drug selection. For example, Iressa has the ability to eliminate cross-talk (between human chromosome ends and the protein complexes central to the stability of the entire human genome, a 'chat' that contributes to cancer development) and restore tamoxifen's antitumor effects are tested and analysed in cell culture labs.

The data that support functional profiling analysis is demonstrably greater and more compelling than any data currently generated from DNA analyses. Functional profiling remains the most validated technique for selecting effective therapies for cancer patients.

Signal transduction pathways are important targets in cancer therapy. Small molecule inhibitors for the tyrosine kinase and serine threonine kinase pathways are already available for clinical therapy. Additionally, compounds targeting the PI3K, AKT and MEK pathways will be available in the coming years. To explore the interaction of these parallel survival pathways, clinicians at Rational Therapeutics have compared activity and combined these inhibitors in human tissues - the results were instructive.

Their findings include favorable interactions between EGFR tyrosine kinase inhibitors and compounds that block the PI3K pathways. The most active combinations were those that inhibited the cross-talk between pathways (horizontal inhibition) over drug combinations that targeted the same pathway at different downstream points (vertical inhibition). Similar observations have been made combining PI3k inhibitors and MEK inhibitors. One such report in PNAS (May 10, 2010) closely paralleled the work conducted in their laboratory that they reported at the American Association for Cancer Research (AACR).

Noteworthy, a series of studies utilizing these combinations, indicate that certain tumors respond to their drug exposure by undergoing autophagic death, not necrotic or apoptotic. This distinction is possible, as the cell function analysis of programmed cell death platform has the capacity to measure all forms of cell death - apoptotic and non-apoptotic.

by gdpawel on Thu, 2011-05-19 21:51
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, had 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 reported 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 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 reported in the Proceedings of the American Society of Clinical Oncology, Dr. Nagourney found activity for Olaparnib and Inaparib, 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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