Sutent (sunitinib) is an inhibitor of multiple protein kinases, platelet-derived growth factor (PDGFR), vascular endothelial growth factor receptors (VEGFR), stem cell factor receptor (KIT), FMS-like tyrosine kinase (Flt3), colony stimulating factor (CSF-1R), and the neurotrophic factor receptor (RET). Because these proteins are involved in both tumor proliferation and angiogenesis, Sutent has both anti-tumor as well as anti-angiogenic properties. In addition, because Sutent inhibits multiple kinases, it possesses activity against multiple types of tumors.

Sutent can be used as a second-line drug for tumors that are non-responsive to Gleevec. The proto-oncogene KIT, a tyrosine kinase that is inhibited by Gleevec, is overexpressed in a majority of GISTs. Some patients have suffered relapses due to acquired point mutations in KIT, which prevents Gleevec from binding to the protein. Similar mutations have been characterized in EGFR from Iressa-resistant lung cancer patients.

The largest group of kinases are Protein kinases, which act on and modify the activity of specific proteins. So people will try and get some sort of gene-based test to measure the expression-mutation of these kinases. But something more elemental is going on. Does the drug even enter the cell? Once entered, does it immediately get metabolized or pumped out, or does it accumulate?

The new EGFRx ™ Anti-Tyrosine Kinase Profile Assay measures the net effect of everthing which goes on (Functional Profiling). Are the cells ultimately killed, or aren’t they? In photomicrographs (two magnifications), it is fairly easy to see that some clones of tumor cells don’t accumulate the drug. These cells won't get killed by it. Sutent is conveniently pigmented, brilliant yellow. It is easy to see which cells have taken it up. But you wouldn’t pick this up with an assay which only measured the kinases themselves.

Normal chemotherapy kills both cancer cells and healthy normal cells (mainly rapidly-dividing cells). Oncologists try to minimize damage to normal cells and to enhance the cell-killing effect on cancer cells. Too often, this delicate balance is not achieved.

Targeted therapy drugs interfere with specific molecules (receptors and enzymes inside and outside a cancer cell). By focusing on these molecular and cellular changes, targeted cancer drugs go after the “target” in these cells, rather than just all cells. Because of this, “targeted” drugs may be more effective than current treatments, and may be less harmful to normal cells.

Functional profiling can discriminate between the activity of different “targeted” drugs and identify situations in which it is advantageous to combine the “targeted” drugs with other types of cancer drugs. Because these new “smart” drugs will work for “some” but not “all” cancer patients who receive them, whole cell profiling can accurately identify patients who would benefit from treatment with molecularly-targeted anti-cancer therapies.

Not only is this an important predictive test that is available, but it is also a unique tool that can help to identify newer and better drugs, evaluate promising drug combinations, and serve as a “gold standard” correlative model with which to develop new DNA, RNA, and protein-based tests that better predict for drug activity.

This kind of technique exists, and might be very valuable, especially when active chemoagents are limited in a particular disease; it makes more sense than ever to test the tumor first. Afterall, cutting-edge techniques can often provide superior results over tried-and-true methods that have been around for many years.

The EGFRx ™ Anti-Tyrosine Kinase Profile Assay is the only assay that involves direct “visualization” of the cancer cells at endpoint. This allows for accurate assessment of drug activity, discriminates tumor from non-tumor cells, and provides a permanent archival record, which improves quality, serves as control, and assesses dose response in vitro.

http://weisenthalcancer.com/index.htm *** Edited 1/19/2008 7:18:05 AM UTC by gdpawel***

In the last few years, 'targeted' therapies are becoming a component of treatment. 'Targeted' therapy is designed to block a specific gene or protein that has a critical role in the survival, growth, invasion, or metatasis of a specific cancer cell. It takes advantage of the biologic differences between cancer cells and healthy cells by 'targeting' faulty genes or proteins that contribute to the growth and development of cancer.

In other words, 'targeted' treatments fight cancer by correcting or modifying defective 'pathways' in a cancer cell. In healthy cells, each 'pathway' is tightly controlled. For instance, healthy cells are allowed to divide into new cells, and damaged cells are destroyed. However, in cancerous cells, certain points in the 'pathway' become disrupted, usually through a genetic mutation (change in form).

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 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. Cell-based testing 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 testing involves the use of dead, formaldehyde preserved cells that are never exposed to 'targeted' drugs. Genetic 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 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 tests tell us anything about drug combinations.

Cell-based testing 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.'