ABSTRACT
There is a lack of relevant prognostic and predictive factors in neurooncology besides mutation of isocitrate dehydrogenase 1, codeletion of 1p/19q and promoter hypermethylation of O (6) -methylguanine-DNA-methyltransferase. More importantly, there is limited translation of these factors into clinical practice. The cancer genome atlas data and also clinical correlative analyses suggest a pivotal role for the epidermal growth factor receptor /protein kinase B/mammalian target of rapamycin (mTOR) pathway in both biology and the clinical course of gliomas. However, attempts to stratify gliomas by activating alterations in this pathway have failed thus far. The tumors of 40 patients with WHO grade II gliomas without immediate postoperative genotoxic treatment and known progression and survival status at a median follow-up of 12.2 years were analyzed for expression of the mTOR complex 2 downstream target N-myc downstream regulated gene (NDRG)1 using immunohistochemistry. Baseline characteristics for NDRG1 absent/low versus moderate/high patients were similar. Time to reintervention was significantly longer in the NDRG1 group (P = 0.026). NDRG1 may become a novel biomarker to guide the decision which WHO°II glioma patients may be followed without postsurgical intervention and which patients should receive genotoxic treatment early on. Validation of this hypothesis will be possible with the observational arm of the RTOG 9802 and the pretreatment step of the EORTC 22033/26032 trials.
Subject(s)
Brain Neoplasms/diagnosis , Brain Neoplasms/metabolism , Cell Cycle Proteins/metabolism , Glioma/diagnosis , Glioma/metabolism , Intracellular Signaling Peptides and Proteins/metabolism , Adult , Aged , Astrocytoma/diagnosis , Astrocytoma/metabolism , Astrocytoma/pathology , Astrocytoma/therapy , Biomarkers, Tumor/metabolism , Brain Neoplasms/pathology , Brain Neoplasms/therapy , Follow-Up Studies , Glioma/pathology , Glioma/therapy , Humans , Immunohistochemistry , Middle Aged , Neoplasm Grading , Oligodendroglioma/diagnosis , Oligodendroglioma/metabolism , Oligodendroglioma/pathology , Oligodendroglioma/therapy , Prognosis , Prospective Studies , Retreatment , Survival Analysis , Time FactorsABSTRACT
An essential mode of acquired resistance to radiotherapy (RT) appears to be promotion of tumor cell motility and invasiveness in various cancer types, including glioblastoma, a process resembling 'evasive resistance'. Hence, a logical advancement of RT would be to identify suitable complementary treatment strategies, ideally targeting cell motility. Here we report that the combination of focal RT and mammalian target of rapamycin (mTOR) inhibition using clinically relevant concentrations of temsirolimus (CCI-779) prolongs survival in a syngeneic mouse glioma model through additive cytostatic effects. In vitro, the mTOR inhibitor CCI-779 exerted marked anti-invasive effects, irrespective of the phosphatase and tensin homolog deleted on chromosome 10 status and counteracted the proinvasive effect of sublethal irradiation. Mechanistically, we identified regulator of G-protein signaling 4 (RGS4) as a novel target of mTOR inhibition and a key driver of glioblastoma invasiveness, sensitive to the anti-invasive properties of CCI-779. Notably, suppression of RGS4-dependent glioma cell invasion was signaled through both mTOR complexes, mTORC1 and mTORC2, in a concentration-dependent manner, indicating that high doses of CCI-779 may overcome tumor-cell resistance associated with the sole inhibition of mTORC1. We conclude that combined RT and mTOR inhibition is a promising therapeutic option that warrants further clinical investigation in upfront glioblastoma therapy.
Subject(s)
Protein Kinase Inhibitors/therapeutic use , RGS Proteins/metabolism , Sirolimus/analogs & derivatives , TOR Serine-Threonine Kinases/antagonists & inhibitors , Adult , Aged , Animals , Astrocytoma/drug therapy , Astrocytoma/radiotherapy , Cell Line, Tumor , Cell Movement/drug effects , Female , Glioblastoma/drug therapy , Humans , Male , Mice , Mice, Inbred Strains , Middle Aged , Neoplasm Invasiveness/prevention & control , Sirolimus/therapeutic useABSTRACT
The editor of a non-subscription publication for dentists explains the advantages of having a journal whose contents are driven by advertising revenue unrelated to products or services mentioned in the journal and free from political influence as well. The drive on the publication is reader interest rather than author or publisher philosophy, and surveys and other methods are used to stay close to the issues practicing dentists are interested in.
