published in Neuro Oncology, researchers from IISc and NIMHANShave
unraveled pathways and proteins involved in Glioblastoma (GBM) - the
most common form of brain cancer and also the deadliest.
tumors, although rare are devastating. Patients are known to have
very short survival rates (median
survival rate is 15 months)
and the economic burden on the families is highest when compared with
other cancers. Known for its aggressiveness, GBM mostly occurs in the
cerebral hemispheres but can be found anywhere in the brain or spinal
cord. It is not known to spread elsewhere in the body. Treatment
include surgical excision of the tumor followed by aggressive
radiation and chemotherapy. Complete excision of the tumor is
difficult and rates
of the disease are high.
The present study, spearheaded by Paturu Kondaiah of IISc, has shown how
Insulin-like growth factor binding protein-2 (IGFBP-2) affects tumor
progression in GBM. Working on a type of brain tumour considered
almost incurable was challenging for the research team, especially
since existing knowledge about IGFBP-2 is insufficient to develop an
effective treatment modality.
is one of six proteins,
which bind Insulin-like growth factors (IGFs) I and II. IGFs are
secreted by the liver in response to growth hormone. The IGF‘signaling
controls cell proliferation and inhibition of apoptosis in normal as
well as in cancer cells. The research team found that IGFBP-2
regulates the protein β-catenin and inhibits expression of the
glycogen synthase kinase-3β (GSK-3β)
gene, causing malignant cell proliferation and tumour progression.
down IGFBP-2 in certain cell lines causes a decrease in β-catenin
levels. Similarly, in other cell lines, overexpressing IGFBP-2 showed
an increase in intracellular β-catenin levels. However, this trend
does not show up in β-catenin RNA levels. This tells us that IGFBP-2
stabilises intracellular levels of β-catenin and does not allow it
to be degraded. GSK-3β, a multifunctional enzyme, is known to
protect GBM cells from apoptosis by promoting cell survival and
proliferation. It is active in IGFBP-2 knockdowns and inactive in
cell lines over-expressing IGFBP-2. The authors found that GSK-3β
inactivation could be one of the mechanisms by which IGFBP-2
stabilizes β-catenin levels.
importantly, the researchers identified the component of IGFBP-2 that
might be responsible for the aggressiveness GBM is known for. Shilpa
Patil, lead author of the study says, “We wanted to dissect out the
functions of N and C terminal domains of IGFBP-2. These N and C
terminal fragments have been detected in the cerebrospinal fluid and
serum of GBM patients. We wanted to know if any of the domains
individually have a major pro-tumorigenic function and if so, could
it be targeted for therapeutic relevance.” They found that the
C-terminal domain, containing the vital RGD domain, alone could
activate β-catenin signaling and progression of in
growth. Compared to the full-length protein or the N-terminal domain,
this component caused faster tumour growth in mice, thus establishing
itself as a potential drug target.
study not only gives the proof of principle but also a preliminary
therapeutic approach towards GBM. We believe, it opens up avenues to develop important therapeutic strategies against
GBM,” says Priyanka Gokulnath from IISc, a co-author of the paper.
the results of this study be extrapolated to other aggressive cancers? IGFBP-2 has been proposed as a therapeutic target even for
cancers of breast, prostate, and ovary. Possibly, inhibiting IGFBP-2
could be one of the important strategies against these cancers too.
a follow-up to this study, the research team aims to generate a more
effective inhibitor of IGFBP-2 with superior binding affinity and
specificity. This may well be the shot in the arm for most scientists
worldwide working on treatment options for Glioblastoma.