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Insulin-like Growth Factor Pathway Inhibitors

The Insulin-like Growth Factor (IGF) family and associated receptors are being investigated for relevance to gastrointestinal stromal tumor (GIST).  Pediatric GISTs and other wild-type GISTs (GISTs with no mutations in the genes for KIT or PDGFRA) are most likely to involve IGF signalling. 

The Insulin-like Growth Factor (IGF) pathway is a fundamental mechanism of cell growth and survival. Activation of this pathway by the binding of the growth factor IGF-1 to the receptor IGF-1R triggers a complex signaling cascade that stimulates cell growth, proliferation, and differentiation, and drives survival.

IGF-1R is a receptor with high affinity for IGF-1 and -2 that has been shown to stimulate cell growth, survival, differentiation, and proliferation by mediating activation of complex signaling pathways.   Among the main downstream pathways involved in IGF-1R signaling, PI3K-Akt-mTOR and Raf-MEK-MAPK are thought to be important.

Previous research on cancer cells suggests that signaling through IGF-1R regulates processes of cancer initiation, progression and sometimes, resistance to therapy. Tumor cells appear to rely on the IGF-1R signaling pathway as a pro-survival and anti-apoptotic mechanism. It is hoped that selective IGF-1R inhibition will result in apoptosis of tumor cells, inhibition of tumor formation, and inhibition of tumor.

In early 2008 and later at ASCO, Dr. Andrew K. Godwin and his laboratory associates announced results from their research that IGF-1R is amplified and the protein is over-expressed in wildtype and pediatric GISTs. These results demonstrate that the "aberrant expression of IGF-1R may be associated with oncogenesis in (this) subset of GISTs that lack c-KIT or PDGFRα mutations and suggest an alternative or complementary therapeutic regimen in the clinical management of GIST, especially in tumors that respond less favorably to imatinib-based therapy."

For summaries about the insulin-like growth factor (IGF) signaling family in gastrointestinal stromal tumor (GIST cancer), please link to these pages on our site:

Current Clinical Trials of IGF Family Inhibitors

Several drugs aimed at inhibiting IGF family targets are in clinical trials at present, and more drugs are expected to enter trials soon.  Although many of these trials are intended for other types of cancer (not GIST), patients with GIST appear to be eligible for trials of the following drugs. 

Click the links below to learn about each drug. 

BIIB022

AMG 479

MK0646

Figitumumab (CP-751,871)   

R1507

OSI-906 

XL228

Cixutumumab (IMC-A12)

MEDI-573

 



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