Brighton researchers' discovery may prolong cancer patients

[gdpawel]

Cancer patients around the world could have their lives extended thanks to a discovery made by Sussex scientists.

Researchers at the University of Sussex, who have been working with the Institute of Cancer Research, have found that a cutting-edge cancer drug may be able to keep patients alive for longer than they live now.

The discovery by the researchers, who looked at exactly how the drugs attack tumours, has been hailed as “unexpected and exciting.”

The drugs, known as kinase inhibitors, are a new type of treatment, with 25 currently in use on a variety of cancers.

Another 400 are under development.

Around 5,000 to 10,000 patients receive the drugs in the UK each year, with that number set to grow as more of the drugs are approved for use.

Kinase inhibitors work across types of breast, skin, lung and kidney cancer, but often only extend life by around three to six months.
Researchers believe they can unlock the true potential of the drugs by changing the way they are used – after uncovering a hidden way that they work.

Keeping cancer at bay

The researchers now plan to conduct clinical trials using kinase inhibitors at higher doses, but with rest periods to take advantage of the new mechanism – and believe the new method has the potential to keep cancers at bay for much longer.

Laurence Pearl, a professor of structural biology in the Medical Research Council Genome Damage and Stability Centre at the University of Sussex, said: “Basically, the drugs at the moment are used to slow the progress of the cancer, but from what we have discovered, they can also be used in another way that may |actually damage the cancer cells instead.

“It seems these drugs work in a different way than people realised and they may be able to do a lot more than we realised.

Effective drugs

“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.”

Study co-author Professor Paul Workman, the deputy chief executive of the Institute of Cancer Research, said: “We already knew these drugs were very effective, but we now think they could be even better.

“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.”

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

Protein Kinase Inhibitors in Cancer Treatment: Mixing and Matching?

http://www.medscape.com/viewarticle/471462

[gdpawel]

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.

Protein Kinases

Signal transduction is defined as any biochemical communication from one part of the cell to another. It is essential for normal functioning of the cell and is highly regulated. The process begins with a specific protein called a receptor that is bound in the cell surface membrane. The portion of the receptor that faces the exterior of the cell contains a ligand or site that can bind to a signaling molecule. This binding results in the activation of the receptor. The interior portion of the receptor is either a functional enzyme, or can combine with and activate an enzyme.

Receptors for most growth factors are enzymes called tyrosine kinases. Signal transduction can be described as a cascade or reactions, in which a chemical change in one molecule leads to change in another molecule (mostly proteins). The signaling process begins when the enzyme receives a phosphate group from ATP, an energy generating molecule present in the cell. The phosphate group is then transferred to a series of protein kinase molecules in turn. The process continues until an activated molecule enters the nucleus, where it results in the activation of genes responsible for functioning of the cell cycle and cell division.

The cancer state is typically characterized by a signaling process that is unregulated and in a continuous state of activation. This may be due to the action of oncogenes, or genes that code for abnormal proteins that are themselves kinase enzymes or otherwise activate the signaling process. Gene mutations of cancer could also alter the receptor molecule in a manner that it remains active without regulation. The signal transduction pathways are very complex and still not completely understood. All proteins in the pathways are potential candidates for inhibition.

Epidermal growth factor receptors (EGFR) are typical enzyme-linked receptors, with an exterior ligand that binds with a signaling molecule, and an internal tyrosine kinase enzyme site. Drugs are developed to inhibit expression at either of these sites. Iressa binds to the external ligand, and has shown activity against non-small-cell lung cancer, adenocarcinoma and breast cancer. In the case of breast cancer, Iressa inhibits an overactive HER/neu tyrosine kinase. The monoclonal antibody, Erbitux, also binds to and inhibits the external ligand of EGFR. This antibody shows promise for use in patients with head a neck cancer who have developed resistance to chemotherapy.

Since unregulated signal transduction is a primary characteristic of many types of cancers, researchers are very active in the pursuit of inhibitors that can control the process. These drugs promise to become an essential part of the physician's armament against cancer, particularly those cancers that have developed resistance to other forms of treatment.

However, setbacks with Gleevec and Iressa, that specifically target protein kinases, reflect a lack of validated biomarkers. The next classes of signal transduction inhibitors, the vascular endothelial growth factor receptor (VEGFR) also lack validated biomarkers.

What is needed is to test the concept of targeted cancer drugs with biomarkers as pharmacodynamic endpoints, and with the ability to measure multiple parameters in cellular screens now in hand using flow cytometry.

The importance of mechanistic work around targets as a starting point for drug development should be downplayed in favor of a systems biology (cell function analysis) approach were compounds are first screened in cell-based assays, with mechanistic understanding of the target coming only after validation of its impact on the biology.

Gleevec turned out to be one of the first examples of a multi-targeted kinase inhibitor. The lessons learned from the Gleevec experience are that mutant kinase targets are a smoking gun for kinase dependency, resistance reveals tumor heterogeneity, and the conformation of the kinase (active or inactive) may be important when choosing drug leads to take into the clinic. In such molecules, different portions bind to different sites on kinases. Given the heterogeneity of tumors among people with cancer (and even in the same person over time), multiple drugs give clinicians an opportunity to vary dosing in proportion to the specific person's tumor expression profile and the pathways activated in that individual.

The fundamental role of kinases in cancer biology and the success of pioneering therapeutics have prompted intensive efforts to develop kinase inhibitors. However, many of these drugs cry out for validated clinical biomarkers to help set dosage and select people likely to respond.

[gdpawel]

The success of the original kinase inhibitors had raised hope that drugs that target key kinases underlying other cancers, such as members of the human epidermal growth factor receptor (HER) family, might be similarly efficacious. However, several small-molecule inhibitors of HER family kinases have shown limited efficacy in HER2-driven breast cancers, despite effective inhibition of kinase activity. An article in Nature, 7 Jan 2007, scientists had provided an explanation for this phenomenon: failure to completely inhibit the kinase activity of HER2 allows oncogenic signaling through the kinase-inactive family member HER3 to continue.

Signaling in the HER family, which consists of epidermal growth factor receptor (EGFR), HER2, HER3 and HER4, involves receptor dimerization and transphosphorylation, which leads to the activation of various pathways, including the potentially oncogenic phosphatidyl-inositol 3-kinase (PI3K)/Akt pathway. While these agents are effective at inhibiting EGFR and HER2 phosphorylation in patients' tissues and tumors, Akt activity is not inhibited as might be anticipated in many patients, which could explain the limited clinical activity of the drugs.

Patients with HER2-positive breast cancer being treated with anti-HER2 therapy may be able to prevent or delay resistance to the therapy with the addition of a PI3K kinase inhibitor to their treatment regimens. Dual simultaneous inhibition of both HER2 and PI3K may prolong the use of anti-HER2 therapies in women with breast cancer. Designing 'targeted' anticancer drugs begins with identifying the genes or proteins that are specific to the development of cancer and testing whether blocking those genes or proteins gets rid of the cancer. Genetic (molecular) tests are instrumental in accomplishing this task.

However, understanding 'targeted' treatments begins with understanding the cancer cell. Every tissue and organ in the body is made of cells. In order for cells to grow, divide, or die, they send and receive chemical messages. These messages are transmitted along specific 'pathways' that involve various genes and proteins in a cell.

Genetic-based testing examines a single process within the cell or a relatively small number of process. The aim is to tell if there is a theoretical predispostion to drug response. Phenotype analysis not only examines for the presence of genes and proteins but also for their 'functionality' (their interaction with other genes, proteins, and processes occurring within the cell, and for their response to 'targeted' drugs).

Genetic-based testing involves the use of dead, formaldehyde preserved cells that are never exposed to 'targeted' drugs. Genetic-based tests cannot tells us anything about uptake of a certain drug into the cell or if the drug will be excluded before it can act or what changes will take place within the cell if the drug successfully enters the cell.

Genetic-based tests cannot discriminate among the activities of different drugs within the same class. Instead, it assumes that all drugs within a class will produce precisely the same effect, even though from clinical experience, this is not the case. Nor can Genetic-based tests tell us anything about drug combinations.

Phenotype analysis (functional profiling) looks at 'fresh' living cancer cells. It assesses the net result of all cellular processes, including interactions, occurring in real time when cancer cells actually are exposed to specific anti-cancer drugs. It can discriminate differing anti-tumor effects of different drugs within the same class. It can also identify synergies in drug combinations.

When considering a 'targeted' cancer drug which is believed to act only upon cancer cells that have a specific genetic defect, it is useful to know if a patient's cancer cells do or do not have precisely that defect. Although presence of a 'targeted' defect does not necessarily mean that a drug will be effective, absence of the targeted defect may rule out use of the drug.

As you can see, just selecting the right test to perform in the right situation is a very important step on the road to personalizing cancer therapy. Sometimes a drug will inhibit the 'target' but not stop the growth of cancer. Not all genes and proteins have a critical role in the survival and growth of cancer cells.

The are many pathways to altered cellular (forest) function, hence all the different 'trees' which correlate in different situations. Improvement can be made by measuring what happens at the end of all processes (the effects on the forest), rather than the status of the individual trees (pathways/mechanisms). You still need to measure the net effect of all processes, not just the individual molecular (gene/protein) targets.

You can see why laboratory oncologists like Drs. Nagourney and Weisenthal have been interested in this. Nagourney will be presenting some information about the comparisons of various kinases.

Robert A. Nagourney, Paula J. Bernard, Eric Federico, Sophie Nguyen, Steven S. Evans.

Presentation Abstract Number: 3525

Presentation Title: Functional analysis of epidermal growth factor receptor tyrosine kinase inhibitors: A comparison of Afatanib, Lapatinib, and Gefitinib in human tumor primary cultures.

[gdpawel]

Robert A. Nagourney, M.D.

The American Association for Cancer Research (AACR) meeting held April 6 – 10 in Washington DC, provided a scientific perspective on oncologic developments. As opposed to the more clinical American Society of Clinical Oncology (ASCO), basic scientists attend this meeting, a large percentage of who are PhDs. The conference affords these investigators the opportunity to discuss their basic research and to present methodology workshops. The meeting also provides an early overview of the general direction that cancer research will be taking over the coming years, while ASCO reports what we’ve recently done, AACR reports what we will be doing.

There were several overarching themes at this year’s meeting, the most prominent of these being the remarkable strides in immunologic therapy. Numerous investigators reported novel developments in the field. Where the immune system used to present as an insurmountable barrier of complexity, today we have dissected specific response elements and immune suppressive pathways that offer unique opportunities for therapy. Immunologic therapeutics are now specializing into sub-domains.

One productive area reflects de-repression. The most mature example being ipilimumab, the monoclonal directed against CTLA-4. This broadly expressed T-cell repressor molecule can be de-repressed resulting in significant anti-tumor activity, but with moderate to severe toxicity. The inhibition of PDL-1 is more selective and therefore less toxic, it has provided responses in melanoma, NSCLC and other diseases.

Earlier stage research is also focusing on tryptophan metabolism and the role of indoleamine 2, 3-dioxygenase. Manipulations of dendritic cells, altering prostaglandin TGF beta, IL-10, IL-6 and the STAT3 signaling pathway are also areas of active investigation. Additional studies included transferred receptors, like the CD19-related chimeric antigen receptor work and the targeting of co-stimulatory molecules like CD28.

Among the most striking observations in this field is the role of the human immune system and the tumor microenvironment in tumor promotion. Immunologists are rapidly learning that cancer is much more than just cancer cells.

The second broad concept that occurred repeatedly was the growing recognition of cancer as an organismal disease. When we realize that circulating tumor cells can be identified in the blood stream and bone marrow of virtually all cancer patients, even in many of those with putative in-situ disease, it becomes evident that invasive malignancies occur as the intersection of a primed cell and a receptive microenvironment. In light of our laboratory’s long held belief in the concept of native state microspheroids as predictive models, this theme was highly appealing.

The developing principle that most closely approximated our work was captured in a special symposium organized by Charles Sawyer, president-elect of AACR. The topic of this well-attended session was the “N of 1.” That is, every patient is his or her own clinical trial. Nothing could be closer to our own work. During this session, two new directions for cancer research were described. The first, described as the “P2G,” was characterized by “exceptional responses.” The developing program through the NCI will collect tissue samples from patients who have had especially good responses from therapy and attempt to drill down on the mechanism of response. This exemplifies the phenotype to genotype (P2G). The second concept was the “G2P.” This reflects genomic screening, leading to the identification of lead targets followed by the administration of treatments. This “genotype to phenotype” approach is the one more closely aligned with investigations being conducted today at major centers here and abroad.

It is the exceptional response (phenotype to genotype) approach that most resonated. After all we have pioneered the field of phenotypic analysis. To wit, the use of human tissues in primary culture can offer the opportunity to explore literally dozens of exceptional responses in every patient’s tissues. A hit could provide insights for mechanistic discovery. It is my hope that this P2G paradigm will take hold – I see it as the most productive direction.

[Jackie07]

Looks like individualized medicine is finally coming! So happy for the new drug ...

J Hum Genet. 2013 May 16. doi: 10.1038/jhg.2013.42. [Epub ahead of print]
Use of pharmacogenetics for predicting cancer prognosis and treatment exposure, response and toxicity.
Hertz DL, McLeod HL.
Source

1] UNC Institute for Pharmacogenomics and Individualized Therapy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA [2] Department of Clinical, Social and Administrative Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI, USA.
Abstract

Cancer treatment is complicated because of a multitude of treatment options and little patient-specific information to help clinicians choose appropriate therapy. There are two genomes relevant in cancer treatment: the tumor (somatic) and the patient (germline). Together, these two genomes dictate treatment outcome through four processes: the somatic genome primarily determines tumor prognosis and response while the germline genome modulates treatment exposure and toxicity. In this review, we describe the influence of these genomes on treatment outcomes by highlighting examples of genetic variation that are predictors of each of these four factors, prognosis, response, toxicity and exposure, and discuss the translation and clinical implementation of each. Use of pre-treatment pharmacogenetic testing will someday enable clinicians to make individualized therapy decisions about aggressiveness, drug selection and dose, improving treatment outcomes for cancer patients.Journal of Human Genetics advance online publication, 16 May 2013; doi:10.1038/jhg.2013.42.

[gdpawel]

When it comes to anticancer drugs, not all patients respond alike. Some of the variation among patients in both response and toxicity associated with anticancer therapy is due to a patient's genetic makeup.

A new review provides an overview on the progress made in studies of pharmacogenetics and pharmacogenomics, which have successfully identified genetic variants that contribute to this variation in susceptibility to chemotherapy.

The authors say technological advances make it feasible to evaluate the human genome in a relatively inexpensive and efficient manner, but that extensive research and education are urgently needed to improve the translation of pharmacogenetic concepts from bench to bedside (CA Cancer J Clin 2009;59:42-55).

The basic definition of pharmacogenetics is the use of genetic information to help in the therapeutic treatment of a disease. Pharmacogenomics, on the other hand, can be defined as the study of how a person's genetic makeup determines response to a drug.

The terms pharmacogenomics and pharmacogenetics are often used interchangeably to describe a field of research focused on how genes affect individual responses to medicines. Whether a medicine works well for you—or whether it causes serious side effects—depends, to a certain extent, on your genes.

Just as genes contribute to whether you will be tall or short, black-haired or blond, your genes also determine how you will respond to medicines. Genes are like recipes—they carry instructions for making protein molecules. As medicines travel through your body, they interact with thousands of proteins. Small differences in the composition or quantities of these molecules can affect how medicines do their jobs.

These differences can be due to diet, level of activity, or the medicines a person takes, but they can also be due to differences in genes. By understanding the genetic basis of drug responses, scientists hope to enable doctors to prescribe the drugs and doses best suited for each individual. The right drug—for cancer.

Pharmacogenetics is used in targeted therapy for cancer to identify the best drug regimen for a particular tumor. Even tumors of the same type (such as lung, breast, or liver) vary at the genetic level. Cancer is fundamentally a genetic disease, but most of the genetic differences between cancer cells and normal cells are not inherited—they accumulate as the cancer develops. Analyzing specific genes in a patient’s tumor helps doctors identify the drug combination to which the tumor will most likely respond.

For example, the breast cancer drug Herceptin is only effective when the tumor cells have accumulated extra copies of the HER2 gene and have high levels of the protein this gene encodes on their surfaces. Cancer biopsy samples are also often subjected to genetic tests. The results can help guide therapy and predict the likelihood of recurrence.

A challenge facing pharmacogenetics is the number and complexity of interactions a drug has with biological molecules in the body. Variations in many different molecules may influence how someone responds to a medicine. Teasing out the genetic patterns associated with particular drug responses could involve some intricate and time-consuming scientific detective work.

Several new "targeted" drugs have been introduced during the last few years. Most of them have been developed for use in solid tumors but some have also emerged for hematological maligancies. These new "targeted" drugs mostly need to be combined with active chemotherapy to provide any benefit and the need for predictive tests for individualized therapy selection has increased.

Unfortunately, the introduction of these new drugs has not been accompanied by specific predictive tests allowing for a rational and economical use of the drugs. Drugmakers had said that pharmacogenetics will not change the landscape for the bulk of pharmaceuticals for several years. Pharmacogenetics is not going to transform the market any time soon.

There are a number of laboratory tests that are better able to predict the ability of targeted drugs, to produce positive clinical responders (outcomes). Given the technical and conceptual advantages of Oncologic In Vitro Chemoresponse Assays, together with their performance and the modest efficacy of therapy prediction based on analysis of genome expression, there is reason for a renewal in the interest for Oncologic In Vitro Chemoresponse Assays for optimized use of medical treatment of malignant disease.

Over the past few years, gene expression profiling has been suggested as the best or only way of determining ex vivo drug sensitivity. However, the clinical application of these DNA content assays have been shown to correlate only with response and not survival. And due to almost all patients being treated with combination chemotherapy, this methodology cannot even be calibrated without the use of Oncologic In Vitro Chemoresponse Assays. These assays can actually integrate all the gene expression into one convenient test result.

In obtaining information from gene mutations (DNA content assays) and/or gene expression (RNA content) it must be realized that DNA structure is only important insofar as it predicts for RNA content, which is only important insofar as it predicts for protein content, which is only important insofar as it predicts for protein function, which is important only insofar as it predicts for cell response, which is only important insofar as it predicts for tumor response and function. In other words, it correlates only with response and not survival, in entirely retrospective (not prospective) studies.

Patients, physicians, insurance carriers, and the FDA are all calling for predictive tests that allow for rational and cost-effective use of these drugs. You will find it with Oncologic In Vitro Chemoresponse Assays, testing for drug activity against a tumor. What a cancer patient would like ideally, is an active drug, one that will be beneficial the first time around.

By testing the tumor cells of a cancer patient and testing the patient toxicity tolerance, the oncologist can select drugs that have a higher probability of being effective for an individual patient rather than selecting drugs based on the average responses of many patients in large clinical trials.

Literature Citation:

Weisenthal, L.M. Functional profiling with cell culture-based assays for kinase and anti-angiogenic agents Eur J Clin Invest 37 (suppl. 1):60, 2007

Nagourney, R.A. Functional Profiling of Human Tumors in Primary Culture: A Platform for Drug Discovery and Therapy Selection (AACR: Apr 2008-AB-1546)