From an Email I received this morning:
CAMBRIDGE, Mass., Apr 16, 2008 (BUSINESS WIRE) -- Sirtris Pharmaceuticals, Inc.
(NASDAQ: SIRT), a biopharmaceutical company focused on discovering and
developing small molecule drugs to treat diseases of aging, announced that a
research team led by the company's two Scientific Advisory Board co-chairs has
demonstrated that overexpression of the SIRT1 enzyme can suppress tumor
formation and growth in a preclinical mouse model of colon cancer, providing the
first in-vivo data that SIRT1 can suppress tumor cell development. The paper,
titled SIRT1 Deacetylase Suppresses Intestinal Tumorigenesis and Colon Cancer
Growth, appears in today's issue of the scientific journal PLoS One.
"Research data suggest that calorie restriction (CR), which is known to cause
SIRT1 expression, has a tumor suppressive effect in mammals," says paper
co-author David Sinclair, PhD, Sirtris Scientific Advisory Board Co-Chair and
Associate Professor of Pathology at Harvard Medical School. "In this study, we
proposed that the SIRT1 enzyme is responsible for many of the effects of CR,
including tumor suppression. This study clearly shows that SIRT1 can suppress
tumor development and may mediate the effect of CR. Sirtris plans to initiate a
cancer trial in humans in the second-half of this year."
"Additional studies are underway to determine other cancer models where SIRT1
overexpression may suppress tumor development," says paper co-author Leonard P.
Guarente, PhD, Sirtris Scientific Advisory Board Co-Chair and the Novartis
Professor of Biology at the Massachusetts Institute of Technology.
The research team tested a strain of mice that physiologically mimics the early
events of human colon cancer. A mutation in the strain allows the protein
B-catenin to localize in the nucleus of cells and initiate a pathway that drives
unchecked cell proliferation. Activation of the B-catenin pathway has been found
in 90 percent of colorectal cancers, and is also activated in other cancers,
including prostate, breast, ovarian and melanoma.
The team chose this particular strain of mice because previous research showed
that calorie restriction in this strain could slow tumor development.
They bred the B-catenin colon cancer mice with mice that overexpress the SIRT1
enzyme in the gut. At four months of age, the SIRT1 overexpressing mice had a
three- to four-fold reduction in the number and size of adenomas. Adenomas are
benign growths, but over time may progress to become malignant. The research
team also found that the adenomas found in SIRT1 overexpressing mice had a
significant reduction in Ki-67, a protein expressed in proliferating cells, used
as a marker for tumor growth.
At 16 weeks of age, the study's control mice--those that did not overexpress
SIRT1--began to show signs of weight loss, fatigue, loss of appetite, weakness
and anemia, which occurs when the level of healthy red blood cells in the body
becomes too low. The SIRT1 overexpressing mice did not display such overt signs
of sickness.
The research team then demonstrated that the reduction in tumor development was
caused by the ability of SIRT1 overexpressing mice to suppress B-catenin. Using
human colon cancer cell lines whose growth is driven by active B-catenin, the
team was able to greatly reduce cancer cell proliferation with increased SIRT1
expression. In another cell line, the researchers were able to show that SIRT1
promoted the deacetylation and inactivation of B-catenin.
B-catenin, when found in large amounts in the nucleus of tumor cells, is
associated clinically with poor patient prognosis. The team examined 81 human
colon cancer tissue samples to determine the relationship between SIRT1 and
B-catenin expression. There was a significant inverse relationship between the
level of SIRT1 expression and the levels of B-catenin in the nucleus of these
cancer cells.
"This research suggests that SIRT1 activation is a potential therapeutic avenue
for certain cancers," says Sirtris Pharmaceuticals Chief Executive Officer and
Vice Chair, Christoph Westphal, MD, PhD. "Our recently announced research effort
with the National Cancer Institute to test our SIRT1 activators in multiple
cancer models, as well as ongoing work by these investigators, will help guide
our programs."
