Researchers reposition existing prazosin drug to combat
glioblastoma
Treatments available for
glioblastoma—malignant brain tumors—have little effect. An international
collaboration led by the Laboratoire Neurosciences Paris-Seine (CNRS/
INSERM/UPMC) tested active ingredients from existing medications and eventually
identified one compound of interest, prazosin, on these tumors. Not only did it
seem to be effective in this type of cancer, but it also acted on a signaling
pathway that is common with other cancers. These promising findings are
available online (advance publication) in EMBO Molecular Medicine.
Turning old into new is what
recycling is all about—and what is being attempted by an international
collaboration of research scientists coordinated by Marie-Pierre Junier and
Hervé Chneiweiss at the Laboratoire Neurosciences Paris-Seine (Paris). The
researchers chose to study the most common malignant tumors that develop from
brain cells, glioblastomas, which represent the fourth most frequent cause of
cancer deaths among adults and the second in children. This is due to the
inefficacy of current treatments. Indeed, a glioblastoma can resist treatment
and reawaken from a very small number of tumor cells called
glioblastoma-initiating cells (GIC). It is these cells—whose characteristics
and properties resemble those of stem cells—that were targeted in the study.
Rather than trying to discover
new compounds, the team opted for repositioning existing drugs. In other words,
they tested a collection of substances used for so long to treat other
conditions that their patents have now fallen into the public domain. This
method makes it possible to develop new active ingredients cheaply and very
rapidly. Twelve hundred compounds were thus tested on normal human neural stem
cells and on glioblastoma-initiating cells from different aggressive tumors.
Twelve of these compounds showed a toxic effect on GIC—and none on the normal
neural stem cells. The most effective was prazosin. Tested in mice carrying
glioblastoma-initiating cells, prazosin significantly reduced the size of
tumors and prolonged survival of the mice by more than 50%.
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This compound, which has been
used for many years to treat hypertension, is an alpha-adrenergic receptor
antagonist. The researchers nonetheless made a surprising finding:
glioblastoma-initiating cells are devoid of these receptors. The compound
therefore acts via an "off-target" mechanism, or in other words
through another pathway than standard interaction. The scientists thus
identified an intracellular signaling molecule, PKCδ, which is over-expressed
in GIC when compared with normal neural stem cells. In the presence of
prazosin, it is only cleaved in GIC, which leads to their death.
Clinical trials will be initiated
this year to confirm these findings. If they are conclusive, the compound could
rapidly be introduced to complement existing therapies and improve the
management of patients with brain cancer. Already, the scientists have
discovered that other cancer cells display altered PKCδ signaling, including
those in colorectal, pancreatic and liver cancer. Understanding the mechanism
of action of prazosin may therefore pave the way for the development of new
potential treatments for other cancers.
Source:
CNRS (Délégation Paris
Michel-Ange)
