Posted on: 04/16/2010

Targeted Agent Blocked Growth of Deadly Brain Cancer in Preclinical

The drug, now being tested in other cancers, provides new hope for
treatment of glioblastoma

Washington, DC - A drug already in clinical trials to treat a variety of
tumors shows a remarkable ability to shut down growth of glioblastoma in
both laboratory cells and in animals, say researchers from Georgetown
Lombardi Comprehensive Cancer Center and the University of California,
San Francisco (UCSF).

In their experiments, the agent put a brake on growth of laboratory cancer
cell lines, and no mice with glioblastoma in their brain died as a result of
their tumor while on therapy.They say their findings, reported in the April
15 issue of Cancer Research posted online today, provides hope that the
drug, PD-0332991, could offer a new treatment option for glioblastoma,
which is the most common as well as the deadliest form of brain cancer. A
clinical trial testing the therapy in patients with recurrent brain cancer is
under development.

"We have had just amazing results in these preclinical studies," says Todd
Waldman, MD, PhD, an associate professor of oncology at Lombardi. "We
are hopeful it will prove to be effective in brain cancer patients for which
there is little effective therapy."Waldman is the study's co-lead
investigator, along with C. David James, PhD, professor of neurological
surgery at UCSF. "What is especially encouraging about this agent is that
we found it can easily pass through the blood-brain barrier and access
glioblastoma, and that there is already a simple test available for screening
glioblastoma patients in advance to see whether or not they should be
responsive to this therapy," James says.Given the molecular data from a
recently published study by The Cancer Genome Atlas Research Network,
about 90 percent of glioblastoma patients have a molecular profile that
would make them candidates for the drug, the researchers say.The drug is
currently being tested in clinical trials for otherwise untreatable teratomas,
as well as multiple myeloma and breast cancer. It is designed to shut down
the activity of molecules, cyclin-dependent kinases 4 and 6 (cdk4/6), that
drive cell division. "In normal cells, these kinases are kept under exquisite
control by a gene known as p16," says Waldman. "But in glioblastoma, and
other cancers, p16 is frequently deleted, and these two kinases are
uncontrollably activated, which drives the cell to divide and form
cancer."The agent, however, does not work if the cancer is missing
expression of a tumor suppressor protein known as retinoblastoma (Rb)
because Rb is needed to control growth in these cells even if cdk4/6 are
inhibited. A test to determine if RB is present is already being used to
screen patients for use of PD-0332991 in the ongoing clinical trials.A
research team at Georgetown led by Waldman, conducted laboratory
studies on 21 different cell lines derived from the tumors of patients with
glioblastoma. They tested PD-0332991 at various concentrations to see if it
could stop growth of the cancer cells, and found it to be effective in all 16
cell lines with a functioning Rb gene, but it did not work in 5 cell lines
missing Rb. "The agent was very potent in stopping cancer growth, but it
was also quite clean in that it only seemed to inhibit the two molecules it
targeted, and no other," says Waldman. "Most drugs are dirtier than that -
they hit multiple unintended targets."What intrigues Waldman, he says, is
that no one has discovered what the "normal" function for cdk4/6 is. "Mice
lacking either cdk4 or cdk6 grow up to be relatively healthy, so it may be
that these kinases are really only important for cancer growth," Waldman
says. "That would be an exciting development, if true, but no one knows
yet."James led a team of scientists at UCSF that implanted three different
kinds of human glioblastoma directly into the brains of mice, and then they
treated them with PD-0332991. They discovered first that the agent
effectively reached intracranial tumors - "and it wasn't known beforehand
that it would, so this was very good news," says James - and that the cancer
did not grow as long as the mice continued on the drug, but that they
quickly died from the cancer when the agent was withdrawn.Because PD-
0332991 itself does not kill cancer cells - just arrests their growth - the
researchers then combined the agent with radiation and found that
outcomes were superior to use of PD-0332991 alone. They further
successfully tested the agent in mice in which glioblastoma had come back
after treatment with temozolomide, a chemotherapy that is the standard-of-
care for many patients."We don't know how well this agent will perform in
patients with glioblastoma, but in the mice we studied, we saw very
impressive, durable effect that was sustained as long as therapy was
administered," says James.The study was funded in part by grants from the
National Institutes of Health and the American Cancer Society. Pfizer
Global Research and Development supplied PD-0332991, and a researcher
from that company also participated in the study. The authors disclose no
potential conflicts of interest.


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