Current Therapeutic Advances Targeting EGFR and EGFRvIII in Glioblastoma

EGFR and EGFRvIII analysis is of current interest in glioblastoma- the most common malignant primary CNS tumour, because of new EGFRvIII vaccine trials underway. EGFR activation in glioblastoma promotes cellular proliferation via activation of MAPK and PI3K-Akt pathways and EGFRvIII is the most common variant, leading to constitutively active EGFR. This review explains EGFR and EGFRvIII signalling in GBM; describes targeted therapy approaches to date including tyrosine kinase inhibitor, antibody-based therapies, vaccines and preclinical RNA-based therapies and discusses the difficulties encountered with these approaches including pathway redundancy and intratumoural heterogeneity

C.H.E. Det Optimisme, disiplin dan wawasan

Optimisme, disiplin dan wawasan. Tiga perkataan ini cukup untuk menggambarkan kualiti beliau. Optimisme – kepercayaan teguh beliau bahawa cita-cita yang diisi akan menatijahkan kejayaan, dan tanpa pengisian, cita-cita tersebut sekadar tinggal angan-angan. Disiplin – tunjang prinsip beliau bahawa usaha ke arah kecemerlangan menuntut sikap dan watak yang khusus, dan tanpa disiplin, kegagalan pasti menanti. Wawasan – pandangan jauh beliau bahawa kejayaan sebenar terletak kepada keupayaan untuk melestarikan pencapaian di atas garis masa yang panjang. 87 tahun usia yang bakal dilewati tanggal 20 Disember kelak, dan tiga kualiti ini – DISIPLIN, OPTIMISME dan WAWASAN terus segar mendasari penyandang keempat jawatan Perdana Menteri Malaysia, Tun Dr. Mahathir Mohamad

Glioma stem-like cells and metabolism:Potential for novel therapeutic strategies

Glioma stem-like cells (GSCs) were first described as a population which may in part be resistant to traditional chemotherapeutic therapies and responsible for tumour regrowth. Knowledge of the underlying metabolic complexity governing GSC growth and function may point to potential differences between GSCs and the tumour bulk which could be harnessed clinically. There is an increasing interest in the direct/indirect targeting or reprogramming of GSC metabolism as a potential novel therapeutic approach in the adjuvant or recurrent setting to help overcome resistance which may be mediated by GSCs. In this review we will discuss stem-like models, interaction between metabolism and GSCs, and potential current and future strategies for overcoming GSC resistance

Therapeutic Targeting of Histone Modifications in Adult and Pediatric High-Grade Glioma

Recent exciting work partly through The Cancer Genome Atlas has implicated epigenetic mechanisms including histone modifications in the development of both pediatric and adult high-grade glioma (HGG). Histone lysine methylation has emerged as an important player in regulating gene expression and chromatin function. Lysine (K) 27 (K27) is a critical residue in all seven histone 3 variants and the subject of posttranslational histone modifications, as it can be both methylated and acetylated. In pediatric HGG, two critical single-point mutations occur in the H3F3A gene encoding the regulatory histone variant H3.3. These mutations occur at lysine (K) 27 (K27M) and glycine (G) 34 (G34R/V), both of which are involved with key regulatory posttranscriptional modifications. Therefore, these mutations effect gene expression, cell differentiation, and telomere maintenance. In recent years, alterations in histone acetylation have provided novel opportunities to explore new pharmacological targeting, with histone deacetylase (HDAC) overexpression reported in high-grade, late-stage proliferative tumors. HDAC inhibitors have shown promising therapeutic potential in many malignancies. This review focuses on the epigenetic mechanisms propagating pediatric and adult HGGs, as well as summarizing the current advances in clinical trials using HDAC inhibitors

Liquid biopsies for early diagnosis of brain tumours: in-silico mathematical biomarker modelling

Brain tumours are the biggest cancer killer in those under 40 and reduce life expectancy more than any other cancer. Blood-based liquid biopsies may aid early diagnosis, prediction and prognosis for brain tumours. It remains unclear whether known blood-based biomarkers, such as glial fibrillary acidic protein (GFAP), have the required sensitivity and selectivity. We have developed a novel in silico model which can be used to assess and compare blood-based liquid biopsies. We focused on GFAP, a putative biomarker for astrocytic tumours and glioblastoma multi-formes (GBMs). In silico modelling was paired with experimental measurement of cell GFAP concentrations and used to predict the tumour volumes and identify key parameters which limit detection. The average GBM volumes of 449 patients at Leeds Teaching Hospitals NHS Trust were also measured and used as a benchmark. Our model predicts that the currently proposed GFAP threshold of 0.12 ng ml(−1) may not be suitable for early detection of GBMs, but that lower thresholds may be used. We found that the levels of GFAP in the blood are related to tumour characteristics, such as vasculature damage and rate of necrosis, which are biological markers of tumour aggressiveness. We also demonstrate how these models could be used to provide clinical insight

Carbon dot-based fluorescent antibody nanoprobes as brain tumour glioblastoma diagnostics

The development of efficient and sensitive tools for the detection of brain cancer in patients is of the utmost importance particularly because many of these tumours go undiagnosed until the disease has advanced and when treatment is less effective. Current strategies employ antibodies (Abs) to detect Glial Fibrillary Acid Protein (GFAP) in tissue samples, since GFAP is unique to the brain and not present in normal peripheral blood, and it relies on fluorescent reporters. Herein we describe a low cost, practical and general method for the labelling of proteins and antibodies with fluorescent carbon dots (CD) to generate diagnostic probes that are robust, photostable and applicable to the clinical setting. The two-step protocol relies on the conjugation of a dibenzocyclooctyne (DBCO)-functionalised CD with azide functionalised proteins by combining amide conjugation and strain promoted alkyne–azide cycloaddition (SPAAC) ligation chemistry. The new class of Ab-CD conjugates developed using this strategy was successfully used for the immunohistochemical staining of human brain tissues of patients with glioblastoma (GBM) validating the approach. Overall, these novel fluorescent probes offer a promising and versatile strategy in terms of costs, photostability and applicability which can be extended to other Abs and protein systems

Current Understanding of Circulating Tumor Cells - Potential Value in Malignancies of the Central Nervous System

Detection of circulating tumor cells (CTCs) in the blood via so-called 'liquid biopsies' carries enormous clinical potential in malignancies of the central nervous system (CNS) because of the potential to follow disease evolution with a blood test, without the need for repeat neurosurgical procedures with their inherent risk of patient morbidity. To date studies in non-CNS malignancies, particularly in breast cancer, show increasing reproducibility of detection methods for these rare tumor cells in the circulation. However, no method has yet received full recommendation to use in clinical practice, in part because of lack of a sufficient evidence base regarding clinical utility. In CNS malignancies one of the main challenges is finding a suitable biomarker for identification of these cells, because automated systems such as the widely used Cell Search system are reliant on markers such as the epithelial cell adhesion molecule (EpCAM) which are not present in CNS tumors. This review examines methods for CTC enrichment and detection, and reviews the progress in non-CNS tumors and the potential for using this technique in human brain tumors