Biomedical Engineering Reference
In-Depth Information
behave very indolently while larger mitotically active GISTs may
act more aggressively. In the latter scenario, they may metastasize,
usually to the abdominal cavity and liver and can even be fatal.
GISTs are a great example of how science can impact outcomes in
cancer patients. The discovery by Hirota in 1998 that GIST contained
mutations in
was a breakthrough for advancing the biology
and treatment of GIST [4]. From a molecular perspective, these
tumors are characterized by activating mutations, primarily in the
genes for tyrosine kinase receptors (TKRs): most often in
c-KIT
[5],
the normal cellular homologue of the viral oncoprotein v-Kit (v-Kit,
Hardy Zuckerman 4 feline sarcoma viral oncogene homologue) [6, 7]
and less commonly in platelet derived growth factor receptor alpha
(
KIT
PDGFRA
) [8]. These mutations account for the vast majority of
GISTs:
KIT
mutations are present in approximately 80% of GISTs and
PDGFRA
mutations in roughly 7% of the tumors [4, 8-16]. A recent
protein kinase that been added to this list is BRAF (also known as
v-Raf murine sarcoma viral oncogene homolog B1). Mutations in this
gene, encoding for a serine-threonine kinase, have been identified in
4-13% of GISTs that lack the aforementioned mutations [17-20].
GISTs are believed to arise from the Interstitial Cells of Cajal
(ICC) [21], the pacemaker cells of the gastrointestinal tract, which
are located around the myenteric plexus in the muscularis propria
of the GI wall or from interstitial mesenchymal precursor stem cells
[22] that also have the potential of giving rise to cells in the omentum
and peritoneal surfaces. This similarity between GISTs and ICCs is
further borne out by the expression of the KIT protein (also called
CD117) in non-neoplastic ICC and most GISTs. ICC also require the
KIT kinase and its ligand stem cell factor (SCF) for their development
[4, 22-26].
GISTs are generally chemotherapy-resistant compared with
mesenchymal tumors outside the GI tract [27]. The identification of
fundamental hallmark of the biology of GIST resulted in the rapid
transformation of this treatment paradigm. Small molecule tyrosine
kinase inhibitors have been developed and found to be effective in the
treatment of GIST resulting in dramatic improvement in the outcome
of patients with this disease. The median survival of patients with
advanced GIST on chemotherapy is about 15 months compared with
58 months on imatinib mesylate (also known as Gleevec™) [28], an
oral 2-phenylaminopyrimidine derivative that works as a selective
