0-TESTO COMPLETO.pdf - Fondazione Santa Lucia

RF07.77 – Novel molecular targets for the treatment of brain tumors
Most of the research in the mGlu field has been “ synaptically oriented ” and
mGlu receptor subtypes are currently tagged as potential drug targets for the
most common neurological and psychiatric disorders. These receptors are also
expressed and functional outside the CNS, and are found in cells that do not
receive any glutamatergic innervation. The presence of mGlu receptors in
peripheral cells has stimulated their identification and characterization in different
types of stem/progenitor cells. Mouse embryonic stem cells express mGlu5
receptors, which support the self-renewal of these cells [Cappuccio et al. 2005;
Spinsanti et al. 2006]. Differentiation of embryonic stem cells into cells of the
three germ layers is associated with a progressive substitution of mGlu5 receptors
with mGlu4 receptors [Cappuccio et al. 2006].
It is particularly relevant to this proposal that neural stem cells also express
mGlu receptors, such as mGlu3 and mGlu5 receptors which supports proliferation
and survival of cultured neural stem cells [Di Giorgi Gerevini et al. 2005; Baskys et
al. 2005; Brazel et al. 2005]. Interestingly, the differentiation process of cultured
stem cells isolated from the subventricular zone (the putative cells of origin of
glioma stem cells) is critically influenced by the activation of mGlu3 receptors
[Ciceroni et al. 2006]. The potential relevanee of these findings for the treatment of
brain tumors is supponed by the evidence that in cell cultures prepared from bioptic
specimens of human malignant gliomas pharmacological blockade of mGlu3
receptors reduces cell proliferation and inhibits the activation of the MAPK and
the PI-3-K pathways [D’Onofrio et al. 2003]. In addition, systemic injection of the
mGlu2/3 receptor antagonist, LY341495, in mice implanted with glioma cells into
the brain parenchima reversibly inhibits tumor growth [Arcella et al. 2006].
What the project adds to the information already available
The identification of the role played by mGlu3 receptors, the glutamate
transporter GLAST, putative guanosine receptors, and muscarinic cholinergic
receptors will gain new insights into the biology of glioma stem cells and will
be a necessary step in the characterization and validation of new drugs treatments
of malignant gliomas. The characterization of the role played by Numb
in the regulation of medulloblastoma-initiating cells represents and important
follow-up of recent findings obtained by Unit 7 and may lead to the identification
of novel molecularly targeted treatments of medulloblastomas. Finally,
the study of caspase-8 phosphorylation may lead to the identification of a new
diagnostic and prognostic marker of brain tumors along the intracellular
pathway that mediates the execution of apoptotic cell death.
DETAILED DESCRIPTION OF THE PROJECT’S MAIN
AND SECONDARY OBJECTIVE(S)
Malignant gliomas are the 3rd cause of cancer-related death with a media
survival time of 12-14 months. The high resistance of these tumors to both
radiotherapy and chemiotherapy reflects the intrinsic features of a minor
population of putative glioma-initiating cells (glioma stem cells) that are ultimately
responsible for tumor growth and recurrence after surgery. Tumorinitiating
cells have also been isolated from medulloblastomas, the most fre-
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