gpawelski
04-02-2008, 10:55 PM
Gleevec is a small molecule enzyme inhibitor (blocks enzymes inside the cancer cell) of tyrosine kinase, a key intermediary in the EGF cascade pathway. EGF-targeted drugs are poorly-predicted by measuring the target EGFR, but can be well-predicted by measuring the effect of the drug on the function of "live" cells.
This therapy targets signaling pathways involved in the pathogenesis of different tumors. Gleevec is by far the most successful "targeted" drug and is vastly superior to other drugs in the treatment of CML. Non-solid cancers are intrinsically "sensitive" to most any anticancer drug.
Besides CML, a rare type of solid abdominal cancer called gastrointestinal stromal tumor (GIST) is commonly assoicated with mutations in a gene called "kit." The oncogene produces a protein called "kit" that like the Bcr-Abl protein in CML, is inhibited by Gleevec. Gleevec shrinks many GIST tumors in patients that it is working. It has demonstrated significant clinical utility in the treatment of GIST.
The c-kit protein (CD117) is a member of the type III receptor tyrosine kinase family. Several tumors express c-kit, a growth factor receptor with tyrosine kinase activity. Clinical trials have shown the efficacy of Gleevec in c-kit positive tumors. However, there is no correlation between c-kit status and clinical efficacy of Gleevec in either small cell carcinoma or prostate carcinoma.
Gleevec is a bust for both small cell carcinoma and prostate carcinoma. It is very toxic when given to prostate cancer patients and there is no clinical efficacy of its use.
C-kit (KIT) is a protein that indicates GIST (Gastrointestinal Stromal Tumors). The proto-oncogene c-kit and platelet-derived growth factor receptors (PDGFR) are tyrosine kinase proteins that are inhibited by Gleevec in c-kit (CD117) positive GIST. It is overexpressed in a majority of GISTs. Since Gleevec works for some patients with GIST, they think Gleevec will work against prostate cancer.
The c-kit protein may be expressed in prostate cancer and in small cell lung cancer. However, lots of other tumors can express c-kit by immunohistochemistry (IHC), which is an utterly worthless test in this situation. But this expression is only correlated with response to Gleevec in GIST rumors. It is meaningless in other tumors, which is why patients don't routinely test for c-kit in diseases where Gleevec is known to have lousy activity (e.g. prostate cancer, small cell undifferentiated cancer). Gleevec will kill virtually anything if used at a sufficiently high concentration.
There is clinical trial literature in both prostate cancer and in small cell lung cancer with Gleevec. It basically doesn't work very well and the c-kit (CD117) status doesn't correlate one bit with response. There are lots of tumors which are c-kit positive which don't respond to Gleevec. Just like there are lots of tumors which are estrogen receptor positive which don't respond to tamoxifen (e.g. melanoma). And lots of tumors Her2/neu positive which don't respond to Herceptin.
Cancer Biol Ther. 2005 Nov;4(11):1270-4. Epub 2005 Nov 18.
BJU Int. 2006 Oct;98(4):763-9.
This therapy targets signaling pathways involved in the pathogenesis of different tumors. Gleevec is by far the most successful "targeted" drug and is vastly superior to other drugs in the treatment of CML. Non-solid cancers are intrinsically "sensitive" to most any anticancer drug.
Besides CML, a rare type of solid abdominal cancer called gastrointestinal stromal tumor (GIST) is commonly assoicated with mutations in a gene called "kit." The oncogene produces a protein called "kit" that like the Bcr-Abl protein in CML, is inhibited by Gleevec. Gleevec shrinks many GIST tumors in patients that it is working. It has demonstrated significant clinical utility in the treatment of GIST.
The c-kit protein (CD117) is a member of the type III receptor tyrosine kinase family. Several tumors express c-kit, a growth factor receptor with tyrosine kinase activity. Clinical trials have shown the efficacy of Gleevec in c-kit positive tumors. However, there is no correlation between c-kit status and clinical efficacy of Gleevec in either small cell carcinoma or prostate carcinoma.
Gleevec is a bust for both small cell carcinoma and prostate carcinoma. It is very toxic when given to prostate cancer patients and there is no clinical efficacy of its use.
C-kit (KIT) is a protein that indicates GIST (Gastrointestinal Stromal Tumors). The proto-oncogene c-kit and platelet-derived growth factor receptors (PDGFR) are tyrosine kinase proteins that are inhibited by Gleevec in c-kit (CD117) positive GIST. It is overexpressed in a majority of GISTs. Since Gleevec works for some patients with GIST, they think Gleevec will work against prostate cancer.
The c-kit protein may be expressed in prostate cancer and in small cell lung cancer. However, lots of other tumors can express c-kit by immunohistochemistry (IHC), which is an utterly worthless test in this situation. But this expression is only correlated with response to Gleevec in GIST rumors. It is meaningless in other tumors, which is why patients don't routinely test for c-kit in diseases where Gleevec is known to have lousy activity (e.g. prostate cancer, small cell undifferentiated cancer). Gleevec will kill virtually anything if used at a sufficiently high concentration.
There is clinical trial literature in both prostate cancer and in small cell lung cancer with Gleevec. It basically doesn't work very well and the c-kit (CD117) status doesn't correlate one bit with response. There are lots of tumors which are c-kit positive which don't respond to Gleevec. Just like there are lots of tumors which are estrogen receptor positive which don't respond to tamoxifen (e.g. melanoma). And lots of tumors Her2/neu positive which don't respond to Herceptin.
Cancer Biol Ther. 2005 Nov;4(11):1270-4. Epub 2005 Nov 18.
BJU Int. 2006 Oct;98(4):763-9.