Using human cell lines, the researchers showed that pancreatic cancer
growth can be arrested by chemically blocking a signaling pathway which
previously had been known to be active in human embryonic development.
Known as the Hedgehog pathway, this cascade of chemical steps allows
proteins to pass along a signal that ultimately leads to changes in
gene activity and has already been linked to several other types of
cancer.
The researchers also examined 26 human pancreatic cancer cell lines and
found Hedgehog activity in all of them. When the Hedgehog pathway was
blocked experimentally, the cancer was killed half of the time.
Cancer-causing mutations "downstream" from the Hedgehog pathway may
cause the other half of the cancers, the researchers think. The
scientists then transplanted pancreatic cancer cells into mice,
creating tumors. They injected the mice with an inhibitor of the
Hedgehog pathway, which resulted in a 50 to 60 percent reduction in
tumor size after seven days.
The experimental results - death of tumor cells both in the Petri dish
and in animals - suggest that this may one day hold promise as a
treatment avenue, the researchers say. Unfortunately, the inhibitor
used for these experiments is not a practical drug for clinical use,
they point out. But since abnormalities in Hedgehog expression have
already been linked to gliomas, basal cell carcinoma and very recently,
small cell lung cancer, university and commercial labs are screening
for more effective Hedgehog blockers. "If Hedgehog is involved in
pancreatic cancer, these other blockers might offer a bright prospect
in treating a disease that has eluded effective treatment up to now,"
Hebrok said.
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The data are being presented by a Genentech, Inc. researcher as part of
the "New Horizons in the Development of Targeted Therapies for the
Treatment of Cancer" Symposium. These data were generated as part of
Curis' ongoing collaboration with Genentech to develop systemically
administered Hedgehog small molecule antagonists for the potential
treatment of solid tumors.
For these studies, researchers used a primary tumor xenograft
model, whereby a human tumor is grown and expanded directly in
recipient mice. Treatment with a small molecule Hedgehog antagonist
inhibited the rate of tumor growth in mouse xenograft models initiated
from both a human small cell lung cancer and a human pancreatic cancer.
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Cancer Res. 2007 Mar 1;67(5):2187-96
In the context of pancreatic cancer, metastasis remains the most
critical determinant of resectability, and hence survival. The
objective of this study was to determine whether Hedgehog (Hh)
signaling plays a role in pancreatic cancer invasion and metastasis
because this is likely to have profound clinical implications. In an orthotopic xenograft model, cyclopamine profoundly inhibited
metastatic spread; only one of seven cyclopamine-treated mice developed
pulmonary micrometastases versus seven of seven mice with multiple
macrometastases in control animals. Combination of gemcitabine and
cyclopamine completely abrogated metastases while also significantly
reducing the size of "primary" tumors. Gli1 levels were up-regulated in
tissue samples of metastatic human pancreatic cancer samples compared
with matched primary tumors. Aldehyde dehydrogenase (ALDH)
overexpression is characteristic for both hematopoietic progenitors and
leukemic stem cells; cyclopamine preferentially reduced "ALDH-high"
cells by approximately 3-fold (P = 0.048). We confirm pharmacologic Hh
pathway inhibition as a valid therapeutic strategy for pancreatic
cancer and show for the first time its particular efficacy against
metastatic spread. By targeting specific cellular subpopulations likely
involved in tumor initiation at metastatic sites, Hh inhibitors may
provide a new paradigm for therapy of disseminated malignancies,
particularly when used in combination with conventional antimetabolites
that reduce "bulk" tumor size.