The Rockefeller University » Newswire

The Rockefeller University » Newswire

Just saw this on the newsletter that I subscribe to from the Life Raft Group-the organization that helps people with GIST and funds scientists and doctors for research. I was just telling a friend last night that even though I am NED (no evidence of disease)-there's a very strong possibility that those little nasty cells will overcome Gleevec-the drug I take-and begin to multiply. With this new discovery-scientists have pin pointed the protein in the GIST cancer cell that is the culprit-which means now they can develop a new drug that will target and eradicate that protein if Gleevec fails.
I have to say-this is what I've been praying for because I was never satisfied with the idea that it was only the KIT protein-I knew there had to be another one. Thank you Rockefeller University!
It is by far-the BEST Christmas present ever!


Posted: December 22, 2010

Scientists identify protein that drives survival of gastrointestinal tumors

For patients with gastrointestinal stromal tumors, or GISTs, the blockbuster
cancer drug Gleevec has been a reason to hope. Since the drug’s
introduction, survival rates have climbed dramatically and recurrence has
fallen by two-thirds. But there’s a downside: over time, many patients
develop resistance to the drug. Now, scientists at Rockefeller University
and Memorial Sloan-Kettering Cancer Center have identified a molecule that
acts as a survival factor for gastrointestinal tumors, a finding that may
lead to next-generation therapies that can pick up where Gleevec leaves off.

Gleevec was initially approved for fighting chronic myelogenous leukemia and
it targets the BCR-ABL fusion protein that causes that rare blood disease.
But Gleevec also inhibits the activated KIT receptor tyrosine kinase.
Scientists have known that mutations in the gene that codes for KIT are
responsible for development of GISTs, as well as other cancers such as
melanomas, which makes Gleevec a potent treatment for GISTs.

Ping Chi, a postdoctoral fellow in C. David Allis’ Laboratory of Chromatin
Biology and Epigenetics at Rockefeller and a clinical fellow at MSKCC, and
in collaboration with Yu Chen in Charles Sawyers’ group at MSKCC, searched
for GIST-specific genes to obtain better insight on the molecular events in
GIST development. She focused on a group of cells in the gastrointestinal
tract called interstitial cells of Cajal, or ICCs. GISTs arise from two
specific populations of ICCs, myenteric and intramuscular; it’s been known
that KIT is highly expressed in these two types of ICCs, and these cells
have been implicated as the cells that spur GIST formation.

By analyzing patient tumor samples stored at MSKCC, Chi and colleagues found
that a protein called ETV1 is expressed in all GISTs at significantly
greater levels than in any other type of tumor. Using RNA interference, in
which small RNAs are deployed to prevent gene expression, Chi and her
colleagues blocked ETV1 in GIST cell lines. The result was a decrease in
cell division and an increase in cell death, findings that indicated that
GISTs require ETV1 for growth and survival.

“We’ve shown that ETV1 is just as important as KIT in the development of
gastrointestinal stromal tumors,” says Chi. The findings have far-reaching
implications, she says.

“About five percent of GISTs are KIT negative by immunohistochemistry,” Chi
says. “Because all GISTs express ETV1, we now have a very good biomarker for
diagnosing GIST.”

Chi and her colleagues were also interested in determining if ETV1 is
required for normal growth of ICCs. They looked at the gastrointestinal
tracts of genetically modified mice lacking the gene for ETV1 and observed
significant loss of only myenteric and intramuscular ICCs, providing
evidence of ETV1’s role as a survival factor for the ICC-GISTs lineage.

The discovery by Chi and her colleagues also means that scientists now have
a new therapeutic target. In addition to the risk of developing resistance
to Gleevec, the drug must be given continuously because interrupting Gleevec
treatment can cause GISTs to rapidly regrow.

“Now that we know ETV1’s importance in GIST formation, we need to determine
how the ETV1-driven oncogenic transcriptome is regulated,” Chi says. “This
opens possibilities for stopping GIST development when targeting of KIT
fails.”

“This work represents a remarkable collaborative effort from both sides of
York Avenue wherein our combined strengths in signaling, mouse modeling,
transcriptional regulation and chromatin biology came together to tackle
complex mechanisms of cancer pathogenesis,” says Allis, who is Joy and Jack
Fishman Professor. “In addition to the gain-of-function KIT mutation, our
results clearly show that cellular context, likely determined by
transcription factor networks and chromatin landscape, also plays critical
roles in oncogenesis.”