Excess amounts of a protein called IGF-1R in patients with
gastrointestinal stromal tumours (GISTs) could indicate that the patient may become less responsive to the drug imatinib mesylate (Gleevec), the gold standard treatment after surgery.
Preliminary studies have shown
that GIST cells, especially Gleevec-resistant cells, may respond well
to agents in development for treatment-resistant breast cancer, which is marked by excessive production of the IGF-1R
protein. IGF-1R could potentially serve as a marker to identify this subset of
GIST patients before therapy begins, when alternative treatments would
be most effective.
Researchers at Fox Chase Cancer Center are presenting their findings at the 2008 Annual Meeting of the American Society of Clinical
Oncology later this month.
percentage of adult gastrointestinal stromal tumours and most
pediatric cases, are often less responsive to Gleevec. They found that tumours in many of these cases coincide with an
overabundance of the IGF-1R protein.
GISTs develop through a mutation in the genes c-KIT or PDGFRα, both of
which are targets of Gleevec. GISTs without those mutations, known as
“wild type,” as well as pediatric GISTs, often do not respond as well to
treatment with Gleevec.
The Fox Chase researchers found that,
when compared to mutant GISTs, the DNA of wild type and pediatric types
exhibited more copies of the IGF1R gene. These tumours also produced
many more copies of the IGF-1R protein, which serves to promote cell
survival, proliferation and growth in normal cells. In tumours, an
excess of IGF-1R allows cancer cells to grow out of control, breaking
the normal control mechanisms that are an inherent part of cell
function. In the laboratory, the researchers found that drugs that
decrease IGF-1R activity induced the death of tumour cells. These studies are the first to reveal the development of wild type GISTs could be related to abnormal
expression of IGF-1R.
The next logical step is to test the concept in clinical trials in the appropriate populations. The good news for small number of patients who become rsistant to Gleevec is that there is hope on the horizon given the number of IGF-1R compounds being tested in the clinic for several different cancer types.