Following the mutation screening of genes known to cause amyotrophic lateral sclerosis (ALS) in index cases from 107 familial ALS (FALS) kindred, a point mutation was identified in vesicle-associated membrane protein-associated protein B (VAPB), or VAMP-associated protein B, causing an amino acid change from threonine to isoleucine at codon 46 (T46I) in one FALS case but not in 257 controls. This is an important finding because it is only the second mutation identified in this gene that causes ALS. In order to investigate the pathogenic effects of this mutation, we have used a motor neuron cell line and tissue-specific expression of the mutant protein in Drosophila. We provide substantial evidence for the pathogenic effects of this mutation in abolishing the effect of wild type VAPB in the unfolded protein response, promoting ubiquitin aggregate formation, and activating neuronal cell death. We also report that expression of the mutant protein in the Drosophila motor system induces aggregate deposition, endoplasmic reticulum disorganization, and chaperone up-regulation both in neurons and in muscles. Our integrated analysis of the pathogenic effect of the T46I mutation and the previously identified P56S mutation indicate extensive commonalities in the disease mechanism for these two mutations. In summary, we show that this newly identified mutation in human FALS has a pathogenic effect, supporting and reinforcing the role of VAPB as a causative gene of ALS.

Glioblastoma multiforme (GBM) is the most frequently occurring primary brain tumor and has a very poor prognosis, with only around 5% of patients surviving for a period of 5 years or more after diagnosis. Despite aggressive multimodal therapy, consisting mostly of a combination of surgery, radiotherapy, and temozolomide chemotherapy, tumors nearly always recur close to the site of resection. For the past 15 years, very little progress has been made with regards to improving patient survival. Although immunotherapy represents an attractive therapy modality due to the promising pre-clinical results observed, many of these potential immunotherapeutic approaches fail during clinical trials, and to date no immunotherapeutic treatments for GBM have been approved. As for many other difficult to treat cancers, GBM combines a lack of immunogenicity with few mutations and a highly immunosuppressive tumor microenvironment (TME). Unfortunately, both tumor and immune cells have been shown to contribute towards this immunosuppressive phenotype. In addition, current therapeutics also exacerbate this immunosuppression which might explain the failure of immunotherapy-based clinical trials in the GBM setting. Understanding how these mechanisms interact with one another, as well as how one can increase the anti-tumor immune response by addressing local immunosuppression will lead to better clinical results for immune-based therapeutics. Improving therapeutic delivery across the blood brain barrier also presents a challenge for immunotherapy and future therapies will need to consider this. This review highlights the immunosuppressive mechanisms employed by GBM cancers and examines potential immunotherapeutic treatments that can overcome these significant immunosuppressive hurdles.

Glioblastoma (GBM) is inevitably refractory to surgery and chemoradiation. The hope for immunotherapy has yet to be realised in the treatment of GBM. Immune checkpoint blockade antibodies, particularly those targeting the Programme death 1 (PD-1)/PD-1 ligand (PD-L1) pathway, have improved the prognosis in a range of cancers. However, its use in combination with chemoradiation or as monotherapy has proved unsuccessful in treating GBM. This review focuses on our current knowledge of barriers to immunotherapy success in treating GBM, such as diminished pre-existing anti-tumour immunity represented by low levels of PD-L1 expression, low tumour mutational burden and a severely exhausted T-cell tumour infiltrate. Likewise, systemic T-cell immunosuppression is seen driven by tumoural factors and corticosteroid use. Furthermore, unique anatomical differences with primary intracranial tumours such as the blood-brain barrier, the type of antigen-presenting cells and lymphatic drainage contribute to differences in treatment success compared to extracranial tumours. There are, however, shared characteristics with those known in other tumours such as the immunosuppressive tumour microenvironment. We conclude with a summary of ongoing and future immune combination strategies in GBM, which are representative of the next wave in immuno-oncology therapeutics.

Current treatments for glioblastoma (GBM) have limited efficacy and significant morbidity and therefore new strategies are urgently needed. Dendritic cells have the power to create anti-tumor immune responses. The greater potency of circulating dendritic cells (DC) over laboratory-generated monocyte-derived DC makes them exciting new immunotherapeutic candidates. To determine the immune status of GBM patients we initially investigated the frequency and function of circulating DC subsets. Furthermore, we tested the therapeutic potential of inhibiting the p38 mitogen-activated protein kinase pathway (p38i) in circulating DC to overcome DC dysfunction. GBM patients (n = 16) had significantly reduced numbers of the major myeloid circulating dendritic cell (cDC2) and plasmacytoid DC vs healthy controls; 1736 vs 4975 (p = 0.028) and 893 vs 2287 cells/mL (P = <0.001) respectively. This inversely correlated with dexamethasone (Dex) dose in a log-linear model, and disease status. Patients’ cDC2 were immature with impaired interleukin (IL)-12 secretion, reduced IL-12:IL-10 ratio, and low HLA-DR and CD86 expression. Exposure of healthy donor cDC2 to Dex or GBM cell lysate resulted in a similar low IL-12:IL-10 ratio. Inhibition of p38 restored the IL-12:IL-10 balance in Dex or tumor lysate-conditioned healthy cDC2 and enhanced T-cell proliferation and interferon-gamma (IFNγ) production. Importantly, patient-derived cDC2 showed a similar reversal of DC dysfunction with p38i. This study demonstrates the therapeutic potential of developing the next generation of DC vaccines using enhanced p38i-conditioned cDC2. We will therefore shortly embark on a clinical trial of adoptively transferred, p38 MAPK-inhibited cDC2 in adults with GBM.

Oncogenic osteomalacia is a rare paraneoplastic metabolic syndrome that is characterised by severe hypophosphataemia, hyperphosphaturia and osteomalacia secondary to renal loss of phosphate. It is commonly caused by overproduction of fibroblast growth factor-23 (FGF23) from benign tumours of mesenchymal origin. Currently, there is no clear evidence on the management of oncogenic osteomalacia in patients with metastatic solid tumours. We report a case of breast cancer-induced oncogenic osteomalacia and discuss its diagnosis and management. A 71-year-old woman with advanced breast cancer developed symptomatic oncogenic osteomalacia with raised FGF23, severe hypophosphataemia and hypocalcaemia. The electrolytic disturbances were exacerbated after the administration of bisphosphonates in the context of her oncological treatment. Systemic chemotherapy and maintenance endocrine treatment along with phosphate and calcium supplementation reduced the activity of oncogenic osteomalacia and resolved the electrolytic imbalances. To our knowledge, this is the first reported case of oncogenic osteomalacia in a patient with breast cancer. Oncogenic osteomalacia constitutes a diagnostic and therapeutic challenge. Pre-clinical and clinical evidence suggest that a possible underlying mechanism is the presence of molecular alterations in the FGF/FGFR signalling pathway leading to overexpression of FGF23. In metastatic setting, anticancer treatment can potentially lead to the normalisation of the electrolytic disturbances and reduction of the activity of oncogenic osteomalacia. The use of antiresorptive therapy in patients with bone metastases can potentially trigger FGF23 overexpression. Its use should be guided by the patients’ risk of skeletal-related events and electrolytic disturbances as well as the degree of activity of oncogenic osteomalacia.

Denosumab, a fully humanised monoclonal antibody, is licensed for treatment of postmenopausal osteoporosis, hormone ablation-induced bone loss and for prevention of skeleton-related events in patients with bone metastases from solid tumours. In pivotal phase 3 randomised trials, denosumab caused profound hypocalcaemia in patients with normocalcaemia despite oral calcium and vitamin D supplementation. This significant hypocalcaemic effect can be exploited to treat hypercalcaemia of malignancy (HCM). Recent reports from the USA suggest that denosumab is an effective treatment of HCM. According to our knowledge, we report the first two cases in UK with bisphosphonate refractory hypercalcaemia who responded to denosumab injections. Our first case gained 7 months of stabilisation of hypercalcaemia following prolonged admissions with life-threatening levels, while our second case achieved rapid normalisation of serum calcium levels for the first time in 14 months. We conclude that denosumab should be the treatment of choice for patients with bisphosphonate refractory hypercalcaemia.