Jean Zhao, PhD, is a senior author of the report.n
Scientists at Dana-Farber Cancer Institute report they have blocked
the development of prostate tumors in cancer-prone mice by knocking out a
molecular unit they described as a "powerhouse" that drives runaway
In an article that is being published as an advanced online
publication by the journal Nature, the researchers said the
growth-stimulating molecule called p110beta – part of a cellular
signaling network disrupted in several common cancers – is a promising
target for novel cancer therapies designed to shut it down. Lead
authors of the report are Shidong Jia, MD, PhD, Zhenning Liu, PhD, Sen
Zhang PhD, and Pixu Liu, MD, PhD.
The p110beta molecule and a counterpart, p110alpha, are "isoforms" –
slightly different forms – of an enzyme called PI(3)K that is an intense
focus of cancer research and drug development. PI(3)K is the linchpin
of a cell-signal pathway that responds to growth factor signals from
outside the cell.
When activated by growth factor receptors, PI(3)K turns on a cascade
of genes and proteins that drives cells to divide and grow. The
molecular accelerator is normally kept under control by a
tumor-suppressor protein, PTEN, which acts like a brake to curb excess
cell growth that could lead to cancer.
Slices of mouse prostate tissue show tumor (top left, irregular cells) in mice with a broken PTEN tumor suppressor protein but normal p110beta protein. pAKT cancer pathway is activated (lower left, brown area.) When p110beta was knocked out, pAKT pathway was silent (lower right) and prostate tissue was cancer-free (top right). Courtesy of Shidong Jia, Dana-Farber Cancer Institute.
Mutations that inactivate PTEN – in effect releasing the brake on
growth signals – are found in a significant proportion of prostate,
breast and brain tumors. The senior authors of the new report, Jean Zhao, PhD, and Thomas Roberts, PhD, previously showed that blocking
p110alpha protein inhibits cancerous growth induced by various
cancer-causing proteins, such as Her2 and EGFR. With that knowledge in
hand, the researchers, in collaboration with pharmaceutical companies,
are developing p110alpha blockers.
P110beta, by contrast, was thought to be a relatively insignificant
player in tumors. However, "the surprise in this paper is that p110beta
has been found to be a bigger player than p110alpha in tumors that
result from PTEN loss," noted Zhao. "Now the drug companies, which have
been focusing on p110alpha, will have to think about making p110beta
inhibitors as well."
Both forms of the p110 molecule have dual tasks: they are involved in
responding to insulin signals – a metabolic function – as well as
relaying growth signals from outside the cell. But the importance of
110beta had been vastly underestimated, the researchers said, for
reasons they don’t entirely understand.
"We knew that when cells are stimulated with growth factor signals,
the activity of p110alpha, but not p110beta, rises rapidly and sharply
in triggering excess cell growth," Zhao said. "We speculate that 110beta
may be providing a low-level but steady growth stimulus and when PTEN
is lost, it becomes an important source of cell proliferation signals."
The new findings stem from experiments in which the scientists
disabled the p110beta protein in mice as a way of exploring its normal
functions. In one of the experiments, the researchers "knocked out"
p110beta in mice that also lacked the PTEN tumor suppressor protein and
were therefore highly prone to prostate cancer. Mice that lacked PTEN
but had functioning p110beta proteins all developed early prostate
cancers by 12 weeks of age. In contrast, the "knockout" mice with no
p110beta function remained free of prostate cancer even though the PTEN
"brake" had been disabled.
The scientists concluded, as a result, that p110beta becomes a
"powerhouse" to drive cancerous cell growth when PTEN function is
In light of the new findings, there is likely to be great interest in
finding drugs or other tools to block the p110beta protein in cancers
where mutations in PTEN have unleashed the overactive growth signals,
said Zhao, who is also an assistant professor of surgery at Harvard
The task is made somewhat easier, said Roberts, by the fact that "we
know what the inhibitor should look like because of our work on
Roberts, who is also a professor of pathology at Harvard Medical
School, said that drugs designed to block the p110alpha form are on
their way to clinical testing, but he could not predict when p110beta
inhibitors might become available for clinical testing.
The research was supported by grants from the National Institutes of Health and the Department of Defense for Cancer Research.
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 Cancer