February 2, 2004

Obesity and atherosclerosis medications could cause increased risk

Vanderbilt-Ingram Cancer Center researchers have provided the first evidence that activation of a particular cellular receptor dramatically increases the development of precancerous polyps in the intestine.

Nashville, (Tenn) – Vanderbilt-Ingram Cancer Center researchers have
provided the first evidence that activation of a particular cellular
receptor dramatically increases the development of precancerous polyps
in the intestine.

The findings suggest a new strategy for preventing colorectal cancer by
blocking activation of this receptor. However, they also raise
caution about an increased risk of colorectal cancer among people who
take drugs that activate this receptor. Such drugs are currently in
clinical development to treat obesity and atherosclerosis.

The researchers report their findings this week in the online version
of the journal Nature Medicine. The paper is scheduled for publication
in the print edition next month.

The work was funded in part by the National Colorectal Cancer Research
Alliance (NCCRA), an initiative led by NBC’s Katie Couric, Lily
Tartikoff and the Entertainment Industry Foundation. Other support came
from the T.J. Martell Foundation for Leukemia, Cancer and AIDS Research
and the National Cancer Institute.

The group found that among mice with a specific genetic mutation – one
that is found among 80 percent of human patients with colorectal cancer
– the incidence of larger colon polyps increased fivefold with
treatment of a compound known to bind very specifically to the
peroxisome proliferator-activated receptor delta (PPAR-delta).

"This is extremely significant because it is these larger polyps that
are most likely to develop into intestinal cancer," said Raymond N.
DuBois, MD, PhD, Hortense B. Ingram Professor of Molecular Oncology, a
professor of Medicine, and associate director of cancer prevention,
control and population-based research at Vanderbilt-Ingram.

The team became interested in PPAR-delta’s potential role in colorectal
cancer development after the observation that the receptor is
overexpressed in most colorectal cancer tumors. As part of the lab’s
ongoing research into the enzyme cyclooxygenase-2 (COX-2) and its role
in colorectal cancer, the group noted that PPAR-delta is activated by a
COX-2 prostaglandin product.

Raju Gupta, a Vanderbilt medical student and member of the DuBois’
laboratory, reported these findings in the Proceedings of the National
Academy of Sciences in 2000. Dr. Bert Vogelstein and colleagues at
Johns Hopkins’s Sidney Kimmel Cancer Center reported similar findings a
year earlier in the journal Cell.

Evidence for a direct role for PPAR-delta in colorectal cancer has been
mixed; however, the Vanderbilt-Ingram scientists noted, those studies
did not test agonists (which activate receptors) that strongly bind to
PPAR-delta without similar attraction to two other forms of the
receptor, named PPAR-alpha and PPAR-gamma.

They selected a molecule for this work with high specificity for the
delta version of the receptor, known as GW501516. They tested this
ligand (a molecule that binds to a receptor) in mice with a known
mutation in the APC gene.

"APC mutations are found in all individuals with an inherited form of
colon cancer called familial adenomatous polyposis (FAP) and is seen in
80 percent of sporadic colorectal cancers, so the mutation is highly
relevant to colorectal cancer in humans," DuBois said.

In line with published data, the untreated mice developed an average of
30 polyps in the small intestine and an average 1.4 polyps in the
colon. Treatment with GW501516 led to a twofold increase in small
intestine polyps and no change in colon polyps.

Because polyp size is an independent risk factor for progression to
colorectal cancer, the scientists evaluated the data according to polyp
size. Interestingly, this is where the treatment’s effects were most
dramatic – the mice treated with the PPAR-delta agonist developed five
times more polyps larger than 2 mm. The polyps were examined under the
microscope, and the polyps from the treated ice were much larger and
showed more dysplasia (abnormal appearance) than those from the
untreated mice. Dysplasia is known to be a precursor of malignancy.

The researchers conducted cell culture studies to eliminate any effects
of GW501516 that were not related to PPAR-delta activation. They
treated wild-type cells and cells engineered to remove the PPAR-delta
gene. There was no change in cell proliferation; however,
treatment with GW501516 significantly suppressed apoptosis (programmed
cell death) in the wild-type cells but not in the cells lacking

"These results argue that PPAR-delta stimulates intestinal adenoma
development and size by activating antiapoptotic pathways in intestinal
epithelial cells," the researchers write. Because the cells avoid cell
death, they have a survival advantage, DuBois further explained,
suggesting that PPAR-delta may play a role in colorectal cancer not by
initiating polyp development but by accelerating their growth.

Additional research is needed, including verifying the results in APC
mutant mice which are engineered to eliminate the PPAR-delta receptor.
However, the researchers noted, "PPAR-delta may be an attractive target
for the development of small molecule antagonists as chemopreventive or
chemotherapeutic agents for colorectal cancer."

Because the APC mutation is present in all individuals with FAP, this
research suggests that patients with this inherited disorder should not
take PPAR-delta agonists for other indications. The researchers also
caution that because the mutation occurs in the vast majority of
sporadic colorectal tumors, individuals with pre-existing polyps who
take PPAR-delta agonists may also be at significantly increased risk
for colorectal cancer.

In addition to Gupta and DuBois, co-authors at Vanderbilt are Dinghzi
Wang, Sharada Katkuri (department of Medicine), Haibin Wang and
Sudhansu K. Dey (departments of Pediatrics and Cell & Developmental

Media contact: Cynthia Manley
Vanderbilt-Ingram Cancer Center
(615) 322-4747