[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.