Bruce Spiegelman, PhD
A widely used diabetes drug dramatically boosted the potency of
platinum-based cancer drugs when administered together to a variety of
cancer cell lines and to mice with tumors, scientists from Dana-Farber
Cancer Institute report.
Combining a platinum chemotherapy agent and the diabetes drug
rosiglitazone halted or shrank mouse tumors as much as three times more
effectively than either of the drugs given alone, according to the
article in the May issue of Cancer Cell.
If pairing the drugs has the same synergistic effect in humans, the
researchers say, it could improve control of ovarian, lung and other
cancers routinely treated with platinum-based chemotherapy, to which
tumors eventually become resistant. Moreover, the experiments suggest
the combination might extend the use of platinum drugs to other cancers
where they haven't previously been shown to be effective.
"There's still a huge gulf between these experiments and human
cancers," said Bruce Spiegelman, PhD, senior author of the report. "But
it's worked in every animal model of cancer we've looked at, and I think
there's a fair chance it will help people."
Dana-Farber researchers are already drawing up plans for initial clinical trials, which could begin sometime this year.
"We really see a way forward here to improve the chemotherapy's
effectiveness for multiple forms of cancer," said George Demetri, MD, a
Dana-Farber researcher who is preparing a proposal for a pilot study of
rosizitaglone and platinum chemotherapy drugs in lung and ovarian cancer
If a pilot study shows promising activity, the combination would need
to be compared with standard chemotherapy in larger phase 2 and phase 3
trials involving many hundreds of patients.
Rosizitaglone, sold under the name Avandia, enhances insulin
receptors' sensitivity in diabetics whose pancreas secretes too little
insulin. It was approved in 1999 for use by patients with type 2
diabetes to help control blood sugar levels. An estimated 5 million
people in the U.S. take Avandia or a similar drug, piozitaglone, which
is sold as Actos.
Both drugs work by activating PPAR-gamma, a transcription factor that
functions as a master regulator of fat development in the body, a
function discovered in the Spiegelman lab in 1994. Spiegelman and others
observed that certain PPAR-gamma-activating compounds, called
PPAR-gamma ligands, caused cancer cells to stop growing and become more
mature, or differentiated. Therefore, Spiegelman and others felt it was a
logical step to try PPAR-gamma ligands as cancer treatment, but several
small clinical trials found rosiglitazone alone was ineffective against
several cancer types.
Despite this setback, and because rosizitaglone was well-tolerated by
patients compared to standard cancer drugs, Dana-Farber researchers
believed it was worthwhile to try it and similar PPAR-gamma ligands in a
different context, said Geoffrey Girnun, PhD, a researcher in
Spiegelman's laboratory and lead author of the Cancer Cell
report. "After discussing it with other Dana-Farber researchers, we
decided to try these agents in combination with platinum-based drugs,
and in several different cell lines, we saw positive results," said
In addition to rosizitaglone, the scientists tested pioglitazone and
an experimental compound made by Glaxo Smith Kline, combining each of
them with cisplatin, carboplatin and oxalyplatin — all commonly used
chemotherapy drugs that destroy cancer cells by damaging their DNA.
When non small-cell lung cancer cell lines were treated with
rosizitaglone alone, there was no effect on growth. Carboplatin alone
reduced growth of the cancer cells by about 60 percent. But when both
drugs were administered, cell growth was reduced by 80 percent. The
drugs were also tested individually and together on ovarian cancer cell
lines that normally are resistant to chemotherapy — and proved capable
of reducing growth of the cancer cells by 90 percent. Even when applied
to colon cancer cells, a type of cancer not usually treated with
platinum drugs, rosiglitazone and carboplatin lowered the growth rate by
70 percent. (Rosizitaglone did not show the same positive effect when
paired with oxalyplatin.)
The drug combination also had striking growth-suppressing results
when given to mice with human lung and ovarian tumors implanted under
their skin and in mice that had received a chemical that causes them to
develop colon cancer, explained Spiegelman, who is also a professor of
cell biology at Harvard Medical School.
The experiments showed that the PPAR-gamma ligands suppressed the
activity of metallothioneine genes, which are believed to trigger the
development of cancer cells' resistance to platinum chemotherapy.
"Our finding that PPAR-gamma activation dramatically increases the
efficacy of carboplatin, potentially causing tumor stasis or even tumor
shrinkage could represent a significant advance in chemotherapy," the
The work was supported by the National Institutes of Health and the Madeline Franchi Ovarian Cancer Award.
Dana-Farber Cancer Institute (www.dana-farber.org)
is a principal teaching affiliate of the Harvard Medical School and is
among the leading cancer research and care centers in the United States.
It is a founding member of the Dana-Farber/Harvard Cancer Center
(DF/HCC), designated a comprehensive cancer center by the National