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Brighton researchers' discovery may prolong cancer patients’ lives
By gdpawel at 2013-03-20 08:57
Brighton researchers' discovery may prolong cancer patients’ lives

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.”

5 comments | 2237 reads

by gdpawel on Wed, 2013-03-20 09:00
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.

Note: Dr. Weisenthal's functional cytometric profiling analyses have reported out positive for Xalkori (crizotinib), a Kinase inhibitor, killing tumor cells and killing endothelial cells, with absolutely brilliant responses, in some ALK translocation negative lung cancer patients.

by gdpawel on Wed, 2013-03-27 21:09
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.

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