Grade II gliomas are slowly growing primary brain tumors that affect mostly young patients. Cytotoxic therapies (radiotherapy and/or chemotherapy) are used initially only for patients having a bad prognosis. These therapies are planned following the “maximum dose in minimum time” principle, i. e. the same schedule used for high-grade brain tumors in spite of their very different behavior. These tumors transform after a variable time into high-grade gliomas, which significantly decreases the patient’s life expectancy. In this paper we study mathematical models describing the growth of grade II gliomas in response to radiotherapy. We find that protracted metronomic fractionations, i.e. therapeutical schedules enlarging the time interval between low-dose radiotherapy fractions, may lead to a better tumor control without an increase in toxicity. Other non-standard fractionations such as protracted or hypoprotracted schemes may also be beneficial. The potential survival improvement depends on the tumor’s proliferation rate and can be even of the order of years. A conservative metronomic scheme, still being a suboptimal treatment, delays the time to malignant progression by at least one year when compared to the standard scheme.
The original version of this article, published on 15 October 2018, unfortunately contained a mistake. The following correction has therefore been made in the original: The name of Mariano Amo-Salas and the affiliation of Ismael Herruzo were presented incorrectly. The corrected author list is given above; the corrected affiliations are given below. The original article has been corrected.
Abstracts iii12NEURO-ONCOLOGY • MAY 2017 that promotes proliferation and migration and inhibits apoptosis and differentiation. There is mounting evidence that YAP is important in many solid malignancies, however its role in GBM is poorly understood. METHODS: Mutation, copy number, gene expression and clinical data from the Cancer Genome Atlas glioma datasets were downloaded analysed in R. For in vitro experiments, two YAP specific lentiviral, doxycycline inducible shRNA vectors were utilised, as was a scramble control. YAP knockdown models were generated in two established GBM cell lines and two patient derived gliomasphere lines with variable baseline YAP expression. Knockdown was confirmed using Western blot and qPCR. Functional domains assayed included proliferation, migration and colony formation. Signalling network activation will be assessed by RNA-Seq. Luciferase expressing human glioblastoma cells were stereotactically implanted into the right frontal lobe of five week old Balb/c nu/nu mice. Once tumours were detectible, YAP was knocked down by feeding a random subsample of mice doxycycline. RESULTS: YAP expression is elevated in GBM when compared with normal brain or lower grade gliomas (p<0.01). High YAP expression was associated with worse median survival for grade II (7.3 vs 9.8 years, p<0.01) and grade III tumours (1.9 vs 5.2 years (p<0.001), but not for patients with GBM (14 vs 14 months (p=NS). YAP overexpression was not explained by upstream mutations or copy number alterations of Hippo components. In vitro YAP knockdown resulted in up to 93% reduction in glioma cell proliferation at 7 days (p < 0.01). YAP knockdown cells would never reach full confluence despite extended culture duration. Migration was reduced by more than 90% (p<0.01), as was colony forming ability (p<0.05). These effects were noted in all cell lines examined, regardless of baseline YAP expression.In vivo YAP knockdown resulted in a 100 fold decrease in tumour size, as measured by luminescence (p<0.01). After two weeks of treatment, 72% of YAP knockdown tumours were no longer detectable on imaging. CONCLU-SION: Genetic disruption of YAP signalling results in significantly impaired glioma cellular proliferation and altered morphology in vitro, and dramatic tumour reduction in vivo. This suggests YAP is essential to glioblastoma survival and is a promising therapeutic target.
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