Ronald A. DePinho, MD
Researchers at Dana-Farber Cancer Institute have shown that several,
rather than just one, cell-growth switches are simultaneously overactive
in many brain tumors and other solid tumors, explaining why treatment
with just a single "targeted" switch-blocking drug often yields
disappointing results. The laboratory finding argues for quickly moving
to clinical trials that combine three or more such targeted drugs for
such cancers to shut down all the malfunctioning growth switches,
according to the team led by Ronald DePinho, MD, director of the Center
for Applied Cancer Science at the Dana-Farber. Their report is being
posted online on Sept. 13 by the journal Science and will appear in a forthcoming print issue.
The switches are formed by molecules called receptor tyrosine kinases
(RTKs) that often are mutated and hyperactive in cancer cells. Since a
number of kinase-blocking drugs are already available — Gleevec and
Tarceva are two of the best-known — the researchers said clinical trials
of combinations of the compounds should be planned quickly.
"This is a transformative finding that will motivate clinicians and
our pharmaceutical colleagues to design clinical trials with regimens
using several inhibitors," said DePinho. He noted that in the laboratory
study using cancer cell lines and fresh specimens of brain tumors,
three or more kinase inhibitors were needed to quell the abnormal
The study focused on glioblastoma multiforme (GBM), an aggressive
brain tumor that is nearly always fatal. The scientists also found
similar patterns of multiply activated RTKs in other common cancers of
the pancreas and lung. Jayne Stommel, PhD, lead author of the report
and a post-doctoral fellow in the DePinho lab, undertook a survey of
molecular RTK "signaling pathways" in GBM cells to find the sources of
RTKs are located on the surface of both normal and cancerous cells
and receive signals from the cells' environment. Many of the signals are
chemical "growth factors" directing the cell to divide and grow.
Signals received by the RTKs are transmitted to the cell's nucleus via a
pathway called PI3K, which often behaves abnormally in cancer cells.
At least 54 RTKs have been identified, and some, such as epidermal
growth factor receptor (EGFR) have been implicated in glioblastomas.
However, drugs that block EGFR have had limited success in delaying the
progression of these and other virulent tumors. "Typically one elicits a
positive initial response, but rarely durable cures," said DePinho, who
is also a professor of medicine at Harvard Medical School. "Overall,
the record of receptor tyrosine kinases inhibitors in these brain tumors
has been somewhat disappointing."
Perhaps the problem was that other kinase pathways were also sending
abnormal growth signals, acting as a redundant or backup source of
growth simulation. "No one had looked to see how many receptor tyrosine
kinases are activated at the same time in these cells," said Stommel.
The researchers tested 20 glioblastoma cell lines using an antibody
array technique that measured the activation of 45 different RTKs at one
time. In 19 of the 20 cell lines, three or more RTKs were activated at
the same time, sending abnormal growth signals in triplicate to the
nucleus. Moving from cell lines to fresh cells, the researchers saw the
same multiple-RTK activity when they studied tumor samples from newly
The kinase inhibitor imatinib (Gleevec) had little effect on the
errant signaling pathways when applied to the brain tumor cells. But
when imatinib was given in combination with two other kinase inhibitors,
erlotinib (Tarceva) and SU11274, traffic in the PI3K signaling pathway
was eliminated, and the cancer cells died.
The study's findings "provide a rational explanation for the feeble
clinical responses" when RTK inhibitors are given singly to patients
with solid tumors, the investigators wrote, and suggest that combination
therapy should yield better results.
In addition, patients' tumors can be "profiled" to identify which
among the many RTK "switches" are activated, so that tailored therapy
with the appropriate combination of inhibitors can be prescribed.
"This study provides proof of concept for the eventual implementation
of a 'personalized' therapeutic paradigm in human cancer," the
The paper's other authors included James Bradner, MD, Keith Ligon,
MD, PhD, and Lynda Chin, MD, at Dana-Farber, and Cameron Brennan, MD, at
Memorial Sloan-Kettering Cancer Center.
The research was funded in part by the National Institutes of Health,
the American Brain Tumor Association, The Claudia Adams Barr
Foundation, the Chris Elliott Fund, and the Goldhirsh Foundation.
The Center for Applied Cancer Science is a fully integrated drug
development program established at Dana-Farber to provide scientists
across the full range of cancer research with a system for discovering
and developing the next generation of targeted therapies and getting
them into a clinical setting. Dana-Farber Cancer Institute (www.dana-farber.org)
which 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