Cetuximab is
a fairly effective drug for the treatment of colorectal, head and neck and lung cancers. This
monoclonal antibody is
directed against the EGFR (epidermal growth factor receptor)
membrane receptor, which is particularly involved in the control of cell survival and cell cycle progression.
Glioblastomas are the most common malignant brain tumors in adults. In approximately 60% of glioblastomas, biological analyses show
over-expression of EGFR, suggesting a potential therapeutic effect of cetuximab. However, clinical trials have
not demonstrated the efficacy of this immunotherapy in glioblastoma.
IS THIS LACK OF EFFICACY DUE TO THE LOW PASSAGE OF THE DRUG THROUGH THE BLOOD-BRAIN BARRIER?
In
a pilot preclinical study
conducted in mice using immunoPET, researchers from the
BioMaps laboratory (SHFJ), Baobab (NeuroSpin) and
SIMoS (DMTS) had demonstrated that
the combined use of focused ultrasound (FUS) and microbubbles to transiently "open" the blood-brain barrier induced a drastic increase in the transfer of zirconium-89 radiolabeled cetuximab from the blood to the brain (see the news item of October 6, 2020 "Permeabilizing the blood-brain barrier to deliver therapeutic antibodies to the brain? ").
In addition, data in the literature suggest that
FUS may also have the property of inducing activation of glial cells, i.e. an immune response in the central nervous system. When applied to the tumor, FUS
could create a cytotoxic environment within the tumor, which would contribute to its destruction.
NEW STUDY IN A MODEL OF GLIOBLASTOMA
In a new study that also takes advantage of immunoPET, SHFJ and NeuroSpin investigators compared pharmacokinetic and pharmacodynamic parameters of cetuximab with and without FUS in animal models of glioblastoma.
Their data confirm that, very rapidly after cetuximab injection, FUS significantly increase its delivery to areas of ultrasound exposure, particularly in the tumor. In contrast, FUS do not improve the long-term accumulation and retention of cetuximab in the tumor. Furthermore, no difference was observed in the efficacy of cetuximab treatment combined or not with FUS. The authors conclude that glial activation by FUS, if it occurs at all, is nevertheless too weak to have a toxic effect on glioblastoma.
This study shows once again the interest of immunoPET, a non-invasive medical imaging technique to guide the therapeutic choice according to the integrity of their blood-brain barrier for each patient.
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