Sutent, One of the New 'Targeted' Drugs

The new "smart" drugs are a really exciting element of cancer medicine. One of the new molecularly-targeted cancer drugs is Sutent. It is a "multi-targeted kinase inhibitor." A drug that inhibits several proteins involved in triggering replication in cancer cells. Basically, inhibits various kinases, a type of enzyme that transfers phosphate groups from high-energy donor molecules to specific target molecules.

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?

Sutent is conveniently pigmented. Brilliant yellow. Easy to see which cells have taken it up. 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. But you wouldn't pick this up with an assay which only measured the kinases themselves. The new EGFRx (TM) Assay measures the net effect of everthing which goes on (Whole Cell Profiling). Are the cells ultimately killed, or aren't they?

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.

Whole cell 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 (TM) 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.