Cancer Drug Gleevec® Decreases Recurrence in Primary Gastrointestinal Stromal Tumor (GIST) Patients
April 18, 2007 by Gloria Gamat
Filed under Diseases & Conditions
Primary gastrointestinal stromal tumor (GIST) is a type of tumor often found in the stomach or small intestine.
Preliminary data of a large, randomized, placebo-controlled clinical trial which tested imatinib mesylate (Gleevec ®) in patients with primary gastrointestinal stromal tumor (GIST) following complete removal of their tumor were found to be significantly less likely to have a recurrence of their cancer compared to the placebo group.
According to Elias A. Zerhouni, M.D., NIH Director:
“The standard treatment for primary GIST is complete surgical removal of the tumor without additional therapy. It is excellent news that addition of this well-tolerated cancer pill to the treatment regimen can have such a positive impact on decreasing the risk of recurrence.”
A product of Novartis Pharmaceuticals Corporation, Gleevec® belongs to a class of agents that block cellular communication to prevent tumor growth.
Gleevec®was USFDA-approved in 2002 for the treatment of unresectable or metastatic GIST.
The said clinical trial was sponsored by the National Cancer Institute (NCI) and conducted by a network of researchers led by the American College of Surgeons Oncology Group (ACOSOG).
Find more details from the full report.
Will Gleevec always work?
Cell culture assay results of fresh tumor specimens with Sutent (a new multi-targeted kinase inhibitor approved for use as a second-line drug for tumors that are non-responsive to Gleevec) have shown tumor cell clusters treated with this drug sometimes take up copious amounts and sometimes have taken up little or none. This drug inhibits several proteins involved in triggering replication in cancer cells. With the new EGFRx Assay, it is possible to see which cells have taken it up and which haven’t.
Drug resistance/drug response is multifactorial. It matters not that a particular intracellular molecular target is present, if the drug can’t even get into the cell to interact with that target or if it gets in but is metabolized or actively extruded out of the cell (a common mechanism of drug resistance). What is measured with the EGFRx Assay is the net result of everything.
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 patient.
It is not known why Gleevec (and most other drugs) either works or doesn’t work. The advantage of the EGFRx Assay is that there is a good idea of what will happen. The disadvantage is that it is not known why the drug worked or why it didn’t work, only that it worked. The EGFRx Assay uses a combination of the morphologic endpoint (DISC) and one or more of the metabolic endpoints (MTT, ATP, resazurin) to test the targeted molecular drugs.
The kinases 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 kniases. 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?
Some clones of tumor cells don’t accumulate these drugs. 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 Assay measures the net effect of everything which goes on (Whole Cell Profiling). Are the cells ultimately killed, or aren’t they?
Source: Cell Function Analysis