Glioblastoma multiforme (GBM) has a poor prognosis-despite aggressive primary treatment composed of surgery, radiotherapy and chemotherapy, median survival is still around 15 months. It starts to grow again after a year of treatment and eventually nothing is effective at this stage. Recurrent GBM is one of the most disappointing fields for researchers in which their efforts have gained no benefit for patients. They were directed for a long time towards understanding the molecular basis that leads to the development of GBM. It is now known that GBM is a heterogeneous disease and resistance comes mainly from the regrowth of malignant cells after eradicating specific clones by targeted treatment. Epidermal growth factor receptor, platelet derived growth factor receptor, vascular endothelial growth factor receptor are known to be highly active in primary and recurrent GBM through different underlying pathways, despite this bevacizumab is the only Food and Drug Administration (FDA) approved drug for recurrent GBM. Immunotherapy is another important promising modality of treatment of GBM, after proper understanding of the microenvironment of the tumour and overcoming the reasons that historically stigmatise GBM as an 'immunologically cold tumour'. Radiotherapy can augment the effect of immunotherapy by different mechanisms. Also, dual immunotherapy which targets immune pathways at different stages and through different receptors further enhances immune stimulation against GBM. Delivery of pro-drugs to be activated at the tumour site and suicidal genes by gene therapy using different vectors shows promising results. Despite using neurotropic viral vectors specifically targeting glial cells (which are the cells of origin of GBM), no significant improvement of overall-survival has been seen as yet. Non-viral vectors 'polymeric and non-polymeric' show significant tumour shrinkage in pre-clinical trials and now at early-stage clinical trials. To this end, in this review, we aim to study the possible role of different molecular pathways that are involved in GBM's recurrence, we will also review the most relevant and recent clinical experience with targeted treatments and immunotherapies. We will discuss trials utilised tyrosine receptor kinase inhibitors, immunotherapy and gene therapy in recurrent GBM pointing to the causes of potential disappointing preliminary results of some of them. Additionally, we are suggesting a possible future treatment based on recent successful clinical data that could alter the outcome for GBM patients.

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BackgroundMetformin has been used to treat type 2 Diabetes Mellitus since long time. It has two proposed anti-neoplastic mechanisms, direct (insulin-independent) and indirect (insulin-dependent) actions. PurposeTo assess the effect of Metformin on pathological response when combined with neoadjuvant chemotherapy in breast cancer. Material and MethodsA prospective study included stage II, III non-diabetic breast cancer patients who received neoadjuvant chemotherapy in our center during the period from May 2017 to March 2019. 59 patients met our inclusion criteria and completed the study, 27 patients received 850mg Metformin every 12 hrs with chemotherapy (group A), 32 patients received chemotherapy without Metformin (group B). Pathological response was assessed by Chevallier classification and residual cancer burden score (RCB). ResultsBoth groups were well balanced regarding base line characteristics. The results of our study showed that the rate of pathological complete response (pCR) was 14.8% in group (A) vs. 6.3% in group (B) with a P-value of 0.39. RCB class 3 was 40.7% in group (A) Vs. 68.8% in group (B) which was statistically significant with a (P-value of 0.031). Patients with triple-positive histology who had RCB class 3 were only (14.3%) in group (A) versus (60%) in group B. Patients with body mass index (BMI) ≥25 who had RCB 3 were 40% and 66.7% in group (A) and (B) respectively. ConclusionMetformin may increase the pCR especially in patients with BMI≥25 and patients with triple-positive histology, a larger phase III study is needed to confirm this finding.