See March’s Brain Tumor Research Highlights, here.
Over the years, NBTS has given more than $35 million to brain tumor research projects. We’re very proud of the impact this funding has made in advancing the neuro-oncology field closer to better treatments and ultimately a cure. And while NBTS is currently focused on driving our flagship research projects – like the Defeat GBM Research Collaborative – forward, there also continues to be great scientific research efforts happening in the neuro-oncology field, en masse. This is critical, as no one researcher, one lab, or one institution can cure this disease alone. Below are highlights of some newly published research from the brain tumor scientific and medical community, compiled by NBTS Director of Research & Scientific Policy, Ann Kingston, PhD and NBTS Research Programs Associate, Amanda Bates:
Decoupling genetics, lineages, and microenvironment in IDH-mutant gliomas by single-cell RNA-seq and resistance to therapy: Venteicher AS, Tirosh I, Hebert C et al (2017) Science 355, eaai8478 DOI: 10.1126/science.aai8478 – link to paper
Previous studies such as The Cancer Genome Atlas (TCGA) have helped define the genetic landscape of glioblastoma (GBM) and low grade glioma (LGG) tumors. A limitation of this work, however, is that the molecular expression profiles obtained from bulk samples of tumors represents an overall average of the individual tumor cell phenotypic and genotypic characteristics, and the tumor microenvironment, which limits a full appreciation of intra-tumoral heterogeneity, cancer cell programs, and the influence of the microenvironment. In this study, the RNA profiles of a number of IDH-mutant gliomas: astrocytoma (IDH-A) and oligodendroglioma (IDH-O) were analyzed at the single cell level and the results were then combined with data from a larger cohort of bulk tumor samples (from TCGA dataset), to decipher differences between the two types of glioma’s.
A total of 9879 single cell RNA-seq (scRNA-seq) profiles from 10 IDH-A tumors, 4347 scRNA-seq profiles from six IDH-O tumors, and 165 TCGA bulk RNA profiles were investigated. In comparing the TCGA bulk profiles, around 550 genes were found to be differentially expressed in the different types of glioma’s suggesting the existence of distinct regulatory programs. Further study at the single cell level, revealed that the differences in bulk profiles between IDH-A and IDH-O tumors could be primarily explained by distinct non-malignant cells in the tumor microenvironment (TME) together with signature genetic events in the malignant cells of the tumor. Single cell analysis showed that undifferentiated cells from these tumor types had similar gene expression programs, raising the possibility of a shared cell of origin for IDH-A and IDH-O. There was also a high similarity in DNA methylation between IDH-A and IDH-O relative to both IDH–wild-type gliomas and IDH-mutant non-glioma tumors. In both IDH-A and IDH-O, ~4% of cells were found to be in a proliferative state with a higher overall fraction of cycling cells and undifferentiated cells in the IDH-A tumors. These results suggest that both IDH-A and IDH-O share a common progenitor and the same developmental hierarchy, consisting in each case of three subpopulations of malignant cells: nonproliferating cells differentiated along the astrocytic and oligodendrocytic lineages, and proliferative undifferentiated cells that resemble neural stem/ progenitor cells. For higher-grade tumors there was enhanced proliferation, larger pools of undifferentiated glioma cells, and an increase in macrophage over microglia programs in the tumor microenvironment.
IDH-A and IDH-O were also found to differ significantly in their TME in the abundance of microglia/ macrophage cells. IDH-A tumors were associated with more microglia/macrophages and fewer neuronal cells than IDH-O tumors. Microglia and macrophages also differed between IDH-A tumors of different grades.
Taken together the results of this study have implications for both clinical management and for investigation of novel approaches to treating patients with these brain tumors.
NBTS contributed to the funding of this research study through a Oligodendroglioma Community Research Fund grant to Drs. Mario Suva and David Louis.
Tumor-derived fibulin-3 activates pro-invasive NF-κB signaling in glioblastoma cells and their microenvironment: Nandhu MS, Kwiatkowska A, Bhaskaran V et al (2017) Oncogene (17 April) DOI:10.1038/onc.2017.109 – link to paper
Fibulin-3 is one of seven members of the fibulin family that are found in the basal lamina of blood vessels and the extracellular matrix (ECM) of connective tissues. The protein has been previously shown to activate the Notch pathway in GBM cells resulting in increased tumor invasion, angiogenesis and chemoresistance.
This study shows that fibulin-3 has an effect on the NF-κB signaling pathway which is known to play a key role in GBM growth and invasion by enhancement of cell proliferation and apoptotic resistance, release of pro-inflammatory cytokines, and upregulation of metalloproteases in the tumor microenvironment.
Fibulin-3 expression was found to correlate with an increased pro-invasive NF-κB signature in experimental models and clinical data sets with preferential co-expression in mesenchymal GBMs and in tumor regions populated by invasive cells. Expression was also evident in peritumoral glial cells (astrocytes and microglia) surrounding the tumor. In this study, fibulin-3 was shown to promote GBM invasion by preventing ‘Tissue Inhibitor of Metalloproteases’ TIMP3 from inhibiting ADAM17 (a disintegrin and metalloproteinase 17), which is responsible for the proteolytic release of soluble TNFα to bind TNF receptors to activate canonical NF-κB.
NF-κB controls a multitude of cellular mechanisms and is considered a challenging therapeutic target because of the potential adverse consequences that may result from its complete inhibition. However, the activation of NF-κB by fibulin-3 is likely specific to GBM tumors because fibulin-3 is neither soluble in normal tissues nor expressed in the brain.
These results support that fibulin-3 is a novel oncogenic factor regulating the major canonical NF-κB axis in GBM and may be a useful mechanism to target therapeutically in GBM.
NBTS contributed to the funding of this research study through a grant awarded to Dr. Mariano Viapiano.
Tumor-treating fields plus chemotherapy versus chemotherapy alone for glioblastoma at first recurrence: a post hoc analysis of the EF-14 trial: Kesari, S, Ram, Z; on behalf of EF-14 Trial Investigators (2017) CNS Oncology. DOI:10.2217/cns-2016-0049 – link to paper
Tumor-treating fields (TTFields), delivers low-intensity, intermediate-frequency (200 kHz) alternating electric fields via transducer arrays applied to the shaved scalp and is a treatment that was recently approved by the US FDA for use in combination with temozolomide (TMZ) for newly diagnosed glioblastoma (GBM) patients based on the results of the EF-14 randomized Phase III clinical trial. In the present study, a post hoc analysis was undertaken to evaluate the efficacy and safety of TTFields when combined with second-line therapy after first recurrence in patients included in the EF-14 trial.
The study involved a total of 695 newly diagnosed GBM patients who were initially randomized 2:1 to receive TTFields plus TMZ (n=466) or TMZ alone (n= 229). At the time the EF-14 trial database was locked, the TTFields plus TMZ group had 48.9% of patients with first recurrence and 28.1% (n=131) of the patients then received TTFields plus second-line therapy. The TMZ only treatment group had 52.8% of patients with first recurrence with 31.9% (n= 73) receiving second-line chemotherapy at the time of the database lock. Thirteen patients in the TMZ alone group crossed over to receive second-line therapy after disease progression in combination with TTFields. Post-hoc analysis was based on overall survival from the day of first progression and showed that median overall survival in patients treated with chemotherapy plus TTFields after first recurrence was 11.8 months, compared with 9.2 months for patients who received chemotherapy alone (HR: 0.70; 95% CI, 0.48–1.00; p = 0.049). Safety and toxicity data were similar to the previously reported results.
It is important to point out that these results are limited by the post hoc nature of the analyses and that the second-line TTFields group was heterogeneous based on prior treatment history and included a small proportion of patients who had not received TTFields prior to first recurrence.
Short-Course Radiation plus Temozolomide in Elderly Patients with Glioblastoma: Perry JR, Laperriere N, O’Callaghan CJ, et al (2017) New Engl J Med 376;1027-1037. DOI: 10.1056/NEJMoa161197 – link to paper
Treatment of glioblastoma (GBM) in elderly patients is not well standardized or studied. This article outlines the results of a Phase III clinical trial of short-course radiation plus temozolomide versus short-course radiation alone in elderly patients (age range of 65-90) with newly diagnosed GBM. The study included 562 patients randomized 1:1 into two groups. Laboratory tissue analysis was conducted to confirm the presence of GBM in tumor samples from 503 patients; 95.4% were confirmed to be GBM with the remainder diagnosed with high-grade glioma (3.0%), diffuse glioma lacking high-grade features (1.0%), and anaplastic oligodendroglioma (0.6%).
For patients in the radiation plus temozolomide group, overall survival was longer with a median of 9.3 months compared to 7.6 months for patients treated with radiation alone (hazard ratio for death, 0.67; 95% confidence interval [CI], 0.56 to 0.80; P<0.001). Median progression-free survival was also extended with a median of 5.3 months in the radiation plus temozolomide group versus 3.9 months for radiation alone (hazard ratio for disease progression or death, 0.50; 95% CI, 0.41 to 0.60; P<0.001). In the radiation therapy alone group, the methylated O6-methylguanine–DNA methyltransferase (MGMT) status was not a prognostic factor whereas in the radiation plus temozolomide group, patients with methylated MGMG status had longer overall survival (13.5 months versus 7.7 months on radiation alone) although a clinically meaningful overall survival advantage, which did not reach statistical significance, was also observed in patients with unmethylated MGMT status (median survival, 10.0 months vs. 7.9 months; hazard ratio, 0.75; 95% CI, 0.56 to 1.01; P = 0.055; P = 0.08 for interaction). Quality of life for symptom and function domains was comparable between the two groups.
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