Dishing out cancer treatment

[gdpawel]

Nature Biotechnology 31, 85 (2013) doi:10.1038/nbt.2516
Published online 07 February 2013

Despite their limitations, in vitro assays are a simple means for assessing the drug sensitivity of a patient's cancer. After consulting experts in the community, we think such assays deserve a second look.

Selecting the right course of chemotherapy and kinase inhibitor is a daunting task. Although we now have decades of collective experience describing the average best course of action for a given tumor type, in too many cases in a given cancer patient, the selected drug regimen proves ineffective. In recent years, the search for biomarkers that can predict sensitivity or resistance to specific drugs has intensified, but so far, useful molecular signatures predictive of treatment outcomes for patients are few and far between. As a patient's cancer cells are usually readily available from biopsies or surgically resected tumors, shouldn't it be possible to test therapies on the cancer cells isolated from patients and identify the most effective drug and regimens?

Clinicians and scientists have asked this question from the very beginning of the modern era of cancer medicine. Starting in the mid-1950s researchers began to develop methods to isolate and culture cancer cells for assessing their sensitivity to an ever-growing collection of anti-cancer agents. Early on, the assays measured the drugs' effect on cell proliferation or cell viability in short-term culture. Subsequently, with the first wave of the cancer stem cell theory in the 1970s, so-called clonogenic assays, which measured the number of cells able to grow into single cell–derived colonies in vitro, were pioneered by Salmon, Hamburger and others. However, enthusiasm about the application of these assays in the clinic was severely dampened in 1983 by two influential commentaries, which voiced skepticism about the likelihood of these assays improving the outcome of cancer treatment (N. Engl. J. Med. 308, 129–134; 154–155, 1983).

Thirty years later, though, the central conclusions from the original clonogenic assay articles still mainly hold. First, the correlation between drug resistance in vitro and in vivo is relatively high (up to 90% or more). Second, the correlation is lower for initial response of a tumor to a drug (40–70%) and many of the observed responses are transient and partial. Third, most clinical studies conducted to assess the utility of in vitro drug testing have been unsatisfactory because they were small, uncontrolled, nonrandomized and/or retrospective, or had other methodological problems. And fourth, there is enough evidence—albeit imperfect—that hints at the potential utility if the assays could be improved.

Unfortunately, the lack of immediate success led most of mainstream oncology to turn its back on in vitro drug sensitivity testing, and only incremental advances have been made in the development of the methods since the 1980s. This seems surprising as the technological advances of the past three decades offer the possibility to address many of the real or perceived weaknesses of existing cellular assays.

A key critique of the cultured tumor cell approach is that the cells are not representative of those in the patient. In the 1980s and 1990s, only relatively crude tests of cellular physiology and morphology were available to optimize protocols. Today, however, a whole gamut of genomic, transcriptomic, proteomic and metabolomic profiling technologies are available to systematically optimize the culture conditions and track cells in vitro so they resemble those in vivo.

Of course, we now know tumor cells are just part of the picture; a realistic assessment of drug sensitivity must provide a snapshot of the tumor microenvironment and its complex vasculature, stroma and immune cells. Although tumor cells have been co-cultured with various nonmalignant cells, and small fragments of cancer tissue have been cultured in collagen gels to approximate their native environment, much more effort is needed to cross-fertilize approaches in tissue engineering with those in cancer tissue preservation.

A place to start is likely to be hematological malignancies. Harvesting and culturing bloods cells is much easier than for solid tumors. In fact, blood cancers are the only types of tumors in which primary patient isolates are routinely used to validate lead compounds in the drug development process.

New methods for single-cell analysis should also enable assessment of the degree to which heterogeneity of the original tumor is retained in the in vitro model and of how different subpopulations of cancer cells are affected by the treatment regimen. This seems especially important as it might offer ways to find drug combinations that affect all cell populations and might result in more durable tumor responses than therapies that have large average effects but leave certain cancer cell populations unharmed (e.g., cancer stem cells). That said, in the clinic, obtaining samples that reflect the whole spectrum of tumor heterogeneity might be difficult, especially in cases where only miniscule amounts of tissue can be obtained or when much of the primary tumor is instead used for routine diagnostics.

A more intricate problem is determining the appropriate concentrations of drugs to test in vitro. Most cancer drugs have a very small therapeutic window, and the relationship between maximal serum concentrations and intra-tumor concentrations for any given tumor is not known. Here, advances in analytical and spatial computer simulation technology might be able to provide better estimates.

So will investing research funding in optimizing in vitro drug sensitivity assays provide more tangible benefits to patients than spending on existing approaches currently dominating cancer research, which focus on personal cancer genomes or biomarker discovery? At the moment, the jury is out on whether we can understand the biology underlying drug sensitivity or the likelihood that a complex phenotype can be boiled down to a limited number of molecular markers. In the meantime, optimizing in vitro screening methods might help us exploit our growing battery of drugs more efficiently until more rational ways of selecting drugs become available. After years spent on the sidelines, perhaps in vitro screening methods deserve another look.

http://www.nature.com/nbt/journal/v3...f/nbt.2516.pdf

[gdpawel]

Robert A. Nagourney, M.D.

An interesting editorial appeared in the February 2013 issue of Nature Biotechnology titled “Dishing out cancer treatment.” The lead line reads, “Despite their limitations, in-vitro assays are a simple means for assessing the drug sensitivity of a patient’s cancer . . . we think assays deserve a second look.”

The author describes the unequivocal appeal of laboratory analyses that are capable of selecting drugs and combinations for individual patients. At a time when 100’s of new drugs are in development, drug discovery platforms that can mimic human tumor response in the laboratory are becoming increasingly attractive to patients and the pharmaceutical industry.

While the author, rooted in contemporary molecular biology, examines the field through the lens of genomic, transcriptomic, proteomic and metabolomic profiling, he recognizes that these analyte-based approaches cannot capture the tumor in its microenvironment, yet we now recognize that these micro-environmental influences are critical to accurate response prediction.

As one reads this piece, it is instructive to remember that no other platform can examine the dynamic interaction between cells and their microenvironment. No other platform can examine drug synergy. And no other platform can examine drug sequence.

It is these complexities however, that will guide the next generation of drug tests and ultimately the process of drug discovery. Even the most ardent adherents to genomic profiling must ultimately recognize that genotype does not equal phenotype. Yet, it is the tumor phenotype that we must study.

I am gratified that the editors of so august a journal as Nature Biotechnology have taken the time to reexamine this important field. Perhaps, if our most scientific colleagues are beginning to recognize the importance of functional analyses, it may be only a matter of time before the clinical oncology community follows suit.

The editor’s final line is poignant, “After years spent on the sidelines, perhaps in-vitro screening methods deserve another look.” We couldn’t agree more.

[gdpawel]

Kinase inhibitors, a class of cutting-edge cancer medications, could keep patients alive for far longer than is currently possible after scientists from the University of Sussex and The Institute of Cancer Research, England, discovered how they attack tumors.

In what they describe as an "unexpected and exciting finding"- discovering the mechanism of action of these drugs - the researchers believe they can unlock the true potential of kinase inhibitors by altering the way they are used.

Their study, which is published in current issue of Nature Chemical Biology, was sponsored by the Wellcome Trust and Cancer Research UK. Kinase inhibitors have been heralded as the new kind of targeted therapies - there are 400 of them under development and 25 already in use. As more of them become approved by regulatory authorities, the scientists say the currently 5,000 to 10,000 patients being treated with such drugs in the UK annually is set to rise dramatically.

Kinase inhibitors are effective in treating a wide range of cancers, including cancers of the lung, kidney, breast and skin. However, they can usually only extend life by approximately three to six months.

The scientists tested four kinase inhibitors and unexpectedly found that their mechanisms of action were identical; all of them are currently being used as cancer treatments:

Erlotinib - for the treatment of non-small cell lung cancer

Lapatinib - used for treating HER2-positive breast cancer, an aggressive disease

Sorafenib - used for treating patients with kidney cancer, especially older patients.

Vemurafenib - treats malignancies caused by a BRAF gene mutation which affects many patients with skin cancer

Kinase inhibitors do more than just block kinase binding to ATP

The general assumption of how kinase inhibitors work against cancer cells tells only part of the story, the researchers found. It was believed that kinase inhibitors work only because they block the cell signalling function of kinases - types of enzymes which play a very active role in many cancers - by preventing them from binding to the basic unit of energy in cells, known as ATP.

However, the scientists found that when high doses of kinase inhibitors are administered, they prevent kinases from linking up with the Hsp90-Cdc37 chaperone system, a complex of molecules in cells which play a vital role in the stability of proteins.

Professor Paul Workman FMedSci, Deputy Chief Executive of The Institute of Cancer Research (ICR), and team demonstrated that by depriving this chaperone system, the cancer-causing kinases stopped the cancer cells from growing and dividing.

Prof. Workman says the team now plans to carry out clinical trials using kinase inhibitors at high doses, but with rest periods "to take advantage of the new mechanisms". He believes this new method could keep cancer from progressing for much longer.

Prof. Workman said: "We already knew these drugs were very effective, but we now think they could be even better. We found that several clinically used kinase inhibitors could not only disable cancer-causing kinases but also cause their destruction. It's an unexpected and exciting discovery, with major implications for how to dose these drugs to help patients live for longer.

We hope to launch a clinical trial in the next year to test the benefits of delivering kinase inhibitors in a way that should maximise their impact in destroying their targets. There is more work to do to prove the benefit to patients, but these drugs are already approved so there are fewer regulatory burdens than usual to overcome to test our new idea."

Study co-author Professor Laurence Pearl FRS, explained that their discovery could have a major impact on target cancer treatments. Kinase inhibitors are becoming important medications in modern cancer therapy.

This latest study has demonstrated another hidden power kinase inhibitors have to destroy the kinases that promote cancer growth - a power that has not yet been exploited clinically. Prof. Pearl said "It shows how important it is to understand the basic biology of how cancer drugs work. We have more work to do to understand this mechanism fully, but we are optimistic that our discovery will help many patients live for longer."

Cancer Research UK Senior Science Information Manager, Dr. Julie Sharp, said "Cancer Research UK scientists have helped to develop and test a number of kinase inhibitors. Having a better understanding of how these drugs work means that researchers can now try and fine tune their use to make them even more effective and improve survival for cancer patients."

Dr Michael Dunn, Head of Molecular and Physiological Sciences at the Wellcome Trust, said that this latest discovery has demonstrated the importance of using biology in the quest to understand how cancer medications work. He added that this "very surprising and interesting result" may well lead to more effective therapies in the future.

Reference: ”ATP-competitive inhibitors block protein kinase recruitment to the Hsp90-Cdc37 system” Sigrun Polier, Rahul S Samant, Paul A Clarke, Paul Workman, Chrisostomos Prodromou & Laurence H Pearl Nature Chemical Biology (2013) doi:10.1038/nchembio.1212. Published online 17 March 2013

Citation: Christian Nordqvist. "Kinase Inhibitors Could Keep Cancer Patients Alive For Much Longer." Medical News Today. MediLexicon, Intl., 18 Mar. 2013

http://www.nature.com/nchembio/journ...mbio.1212.html

According to laboratory oncologist Dr. Larry M. Weisenthal, high dose pulse Kinase inhibitors can be effective for central nervous system (CNS) disease, so long as resistance has not developed.

Laboratories like Rational Therapeutics and Weisenthal Cancer Group have been testing erlotinib (Tarceva), lapatinib (Tykerb), sorafenib (Nexavar) and vemurafenib (Zelboraf) - the 'nib' drugs, along with about eight other kinase inhibitors, in actual human tumor primary culture micro-spheroids (microclusters), in various cancers.

This is exactly the area they are interested in. Specifically re-examine the role of all of these compounds in a wide variety of disease. They have often recommend higher dose, pulse/intermittent therapy, in combination with other agents. In addition, they have been successfully increasing the dose of erlotinib (Tarceva) to recapture patients.

These drugs are not identical, however. Some work in some tumors, while others do not -- yet in other tumors, the drugs which didn't work do work and vice versa. You'd think that if they all had the identical mechanism of action that they'd all work or they'd all not work; but that's not the way it goes.

It may have something to do with entry into the cell; efflux out of the cells; inactivation, or whatever. It does show that there's much more to the action of a drug than simply the presence of a "target" molecule.