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ASCO: Missing Mutations Hold Clue to Imatinib (Gleevec) GIST Resistance

By Michael Smith, North American Correspondent, MedPage Today
Published: May 16, 2008
Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of Medicine, Harvard Medical School, Boston.

PHILADELPHIA, May 16 -- Some imatinib (Gleevec)-resistant patients with gastrointestinal stromal tumors (GIST) don't respond because they are missing the mutations in two genes that are usually integral to the disease.

Niektorzy pacjenci chorujacy na GIST nie reaguja na leczenie imatinibem (Gleevec) poniewaz nie posiadaja mutacji w dwoch genach bedacych zazwyczaj integralnym elementem choroby.

Instead of mutations in c-KIT or PDGFRα, found researchers here, the GIST patients have extra copies of a gene for insulin-like growth factor 1 receptor (IGF-1R) and markedly higher expression of the protein created by the gene.

Zamiast mutacji w c-KIT lub PDGFRa pacjenci z GIST maja dodatkowe kopie genu receptora IGF-1R i wyraznie wieksza ekspresje bialka kodowanego przez ten gen.

The same also appears to be true in many cases of pediatric GIST, which are also resistant to imatinib, reported Andrew Godwin, Ph.D., of the Fox Chase Cancer Center and colleagues.

In laboratory studies, Dr. Godwin said, blocking the gene's expression led to the death of tumor cells, suggesting that such an approach might have therapeutic value.

"Our real excitement," Dr. Godwin said, "is that we think this might be the oncogenic driving force" behind wild-type GIST.

Some compounds aimed at blocking the gene are already in early clinical studies in other types of cancer and Dr. Godwin and colleagues are hoping to leap on that bandwagon.

"We're talking to companies right now about possible clinical trials," Dr. Godwin said.

The research results are to be presented orally at the American Society of Clinical Oncology meeting from May 30 through June 3 in Chicago. A full paper is slated to appear in the June 1 issue of the Proceedings of the National Academy of Sciences.

Most patients with GIST have mutations in either c-KIT or PDGFRα that cause the genes to be more active, mutations that are blocked by imatinib. But between 10% and 15% of patients don't have such mutations and their tumors are resistant to the drug, Dr. Godwin said.
Wiekszosc pacjentow z GIST posiada mutacje w C-KIT lub PDGFRa. Gleevec blokuje te mutacje. 10 do 15 % pacjentow mutacji tych nie posiada i ich guzy sa odporne na dzialanie Gleevec'u.

Instead, they have from three to five extra copies of the IGF-1R gene, compared with standard GISTs that have c-KIT or PDGFRα mutations. The difference was statistically significant at P=0.0163, the researchers found.
Zamiast tego pacjenci Ci maja 3 do 5 dodatkowych kopii genu IGF-1R.

On the other hand, expression of the IGF-1R protein is about 50 times higher in wild-type than in mutated GIST, a difference that was significant at P=0.000002.

The extra gene copies are not enough to cause the additional protein expression[/b], Dr. Godwin said, and he and colleagues are now trying to figure out else is going on.
Niemniej jednak te ekstra kopie genu nie sa wystarczajace by spowodowac dodatkowa ekspresje bialka.

The researchers tested an inhibitor of the gene -- a compound dubbed NVP-AEW541 and made by Novartis, as is imatinib -- and found that, both alone and in combination with imatinib, it induced a "strong cytotoxic response."
Badacze przetestowali inhibitor genu nazwany NVP-AEW541 (wyprodukowany, podobnie jak Gleveec, przez firme Novartis) i stwierdzili, ze zarowno dzialanie samego inhibitora jak i w polaczeniu z imatinibem powodowalo silna reakcje cytotoksyczna.

The findings might usher in an age of "personalized medicine" for GIST, which is now treated with imatinib in a one-size-fits-all fashion. Other inhibitors of c-KIT and PDGFRα are also available, but are usually reserved for second-line therapy.

But Dr. Godwin said his institution, which already tests GISTs for c-KIT and PDGFRα mutations, will soon be able to test for the copy number changes in IGF-1R, although no therapy is approved for those patients.

Robert Benjamin, M.D., of the University of Texas M.D. Anderson Cancer Center in Houston, who was not involved with the New York research, called the report exciting. "It opens the distinct possibility that inhibiting the IGF pathway may be a new approach to therapy for these patients," he commented.

The study was supported by the NIH and the GIST Cancer Research Fund. The researchers reported financial links with Novartis, Pfizer, MedImmune, Human Genome Sciences, Johnson & Johnson, Transgenomic Inc., and MolecularMD.

Primary source: Journal of Clinical Oncology
Source reference:
Godwin AK, et al "Insulin-like growth factor 1 receptor (IGF-1R): A potential therapeutic target for gastrointestinal stromal tumors (GIST)" J Clin Oncol 26: 2008 (May 20 suppl; abstr 10507).

http://www.medpagetoday.c...erage/ASCO/9492

Tutaj jest lista aktywnych badan klinicznych dot odpornego na Gleevec /Sutent GIST
(stan na 8/05/2010). Niestety zaden polski osrodek na niej nie figuruje :-(

Clinical Trials for Gleevec/Sutent-resistant GIST
http://www.liferaftgroup.org/treat_trials.html

Inna lista - jw
http://gisttrials.fmgatew...ternational.pdf

Insulin-like growth factor 1 receptor is a potential therapeutic target for gastrointestinal stromal tumors
Chi Tarn*,†, Lori Rink*,†, Erin Merkel*, Douglas Flieder‡, Harsh Pathak*,Daphne Koumbi§, Joseph R. Testa§, Burton Eisenberg,Margaret von Mehren*, and Andrew K. Godwin*,‖

In conclusion, we have shown that IGF1R is amplified and overexpressed in the majority of GISTs that lack c-KIT or PDGFRα mutations. More importantly, we have shown that imatinib-sensitive and -resistant GIST cells respond equally well to a small molecular inhibitor of IGF1R, suggesting an alternative and/or complementary therapeutic regimen in the clinical management of GIST, especially in tumors that respond less favorably to imatinib-based therapy, including pediatric cases. These findings are particularly exciting given the number of agents targeting IGF1R that are currently being tested in clinical trials. It is feasible in the near future to initiate clinical trials by using IGF1R-targeted therapies for imatinib-refractory GIST patients, initially focusing on adult and pediatric GIST patients lacking c-KIT or PDGFRα mutations and expanding possibly to all GIST patients.
http://www.pnas.org/content/105/24/8387.full