See February’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:
Genome-wide association study of glioma subtypes identifies specific differences in genetic susceptibility to glioblastoma and non-glioblastoma tumors: Melin B, Barnholtz-Sloan J, Wrensch M et al (2017) Nature Genetics. DOI:10.1038/ng.3823 – link to paper
The identification of genes that increase risk for gliomas provides insight into understanding the mechanisms underlying glioma development. This study represents the largest genome-wide association study on glioma to date, with a total of 12,496 glioma cases and 18,190 controls. The authors identified new single-nucleotide polymorphisms at 13 different chromosomal loci influencing risk of gliomas, 5 for glioblastoma (GBM) and 8 for non-GBM tumors. The risk loci that were identified include: 1p31.3, 11q14.1, 16p13.3, 16q12.1, and 22q13.1 for GBM; and 1q32.1, 1q44, 2q33.3, 11q21, 14q12, and 16p13.3 for non-GBM tumors. Most of these variants increase relative risk of primary adult glioma ranging from 14% to 33% compared to a person who did not inherit the variant. The study also confirmed previously identified genetic risk loci at 17p13.1 for all gliomas, 5p15.33, 7p11.2, 9p21.3, and 20p13.33 for GBM; for non-GBM the confirmed loci are 8q24.21, 11q23.2, 11q23.3, and 15q24.2. These data support that genetic susceptibility to GBM and non-GBM tumors are highly distinct, reflecting different etiologies between different types of tumors. The results of this study also provide further evidence for a polygenic basis of genetic susceptibility to glioma and help inform further research towards the development of new therapeutic agents.
Disrupting the CD47-SIRPa anti-phagocytic axis by a humanized anti-CD47 antibody is an efficacious treatment for malignant pediatric brain tumors: Gholamin S, Mitra SS, Feroze AH et al (2017) Sci. Transl. Med. 9, (381), eaaf2968 DOI: 10.1126/scitranslmed.aaf2968 – link to paper
Previous studies have shown that the majority of cancers use the molecule CD47 as a “don’t eat me” signal to escape from being attacked and eliminated by the immune system cells, specifically, macrophages. By binding and activating signal regulatory protein–a (SIRPa), an inhibitory protein expressed on the surface of myeloid cells, CD47 serves as an anti-phagocytic signal. Prior studies in preclinical cancer models have shown that by blocking CD47-SIRPa interaction, macrophages can be induced to selectively engulf cancer cells while sparing normal cells.
In this study, researchers tested the anti-tumor effects of a humanized anti-CD47 antibody (Hu5F9-G4) against five of the most malignant pediatric brain tumors: group 3 medulloblastoma, atypical teratoid rhabdoid tumor (AT/RT), primitive neuroectodermal tumor (PNET), pediatric glioblastoma and diffuse intrinsic pontine glioma (DIPG). Results show that CD47 is expressed on the cell surface of all the pediatric tumor types tested and that Hu5F9-G4 induced phagocytosis by both human and mouse macrophages in vitro in all types of pediatric malignant brain tumor cell culture models. In vivo studies with Hu5F9-G4 in patient-derived orthotopic xenograft mouse models for the various pediatric brain tumor types, showed that the antibody produced a significant decrease in tumor cell growth in the brain, with an associated influx of macrophages within the tumor site. These studies also showed a significant improvement in survival after treatment with Hu5F9-G4 compared to controls in all the tumor models tested. Furthermore, in vitro and in vivo studies showed that the antibody appeared to selectively target tumor cells with no sign of toxicity against normal CNS cells in these models.
In the case of MYC-amplified group 3 medulloblastoma, Hu5F9-G4 was not only highly efficacious against the primary tumor site but also against spinal metastases. Direct delivery into the cerebrospinal fluid accelerated the anti-tumor effect on disseminated metastatic disease both in the forebrain and in the spine. In addition, the researchers observed a decrease in CD15 positive tumor- initiating medulloblastoma cells after Hu5F9-G4 treatment, suggesting Hu5F9-G4 may help to eliminate cancer stem cells and potentially prevent tumor relapse.
The researchers noted that Hu5F9-G4 did not completely eliminate all tumors and propose combining anti-CD47 antibody with other immunotherapy agents may help maximize efficacy. Taken together, these results are encouraging of advancing Hu5F9-G4 to clinical trials for these highly malignant pediatric brain tumors.
In 2016, National Brain Tumor Society together with Oligo Nation, awarded a two year grant to Samuel Cheshier, MD, PhD (lead author for this study) to investigate the effects of anti-CD47 based immunotherapy against malignant oligodendroglioma.
Therapeutic targeting of polycomb and BET bromodomain proteins in diffuse intrinsic pontine gliomas: Piunti A, Hashizume R, Morgan M et al (2017) Nature Medicine DOI: 10.1038/nm.4296 – link to paper
In children up to 14 years of age, DIPG accounts for 80% of brainstem gliomas with a dismal prognosis and median survival of only 9 months. With no progress made over the past five decades for improving the outcome of this disease, DIPG represents a compelling therapeutic challenge for the field of pediatric neuro-oncology. H3K27M is a heterozygous point mutation of histone H3 that occurs in more than 80% of DIPG tumors. H3K27 is the target of post-translational modifications in the form of methylation (mono-di-tri) or acetylation (ac) which have opposing biological functions. H3K27me3 is a repressive mark which increases recruitment of the polycomb complex (PRC) that represses transcription and cell differentiation.
The results of this study advance our understanding of the role of H3K27M mutation in driving DIPG oncogenesis. Using human DIPG cell lines, the researchers characterized genome-wide deposition of the H3K27M mutant histone by chromatin immunoprecipitation which showed a genome-wide distribution of H3K27M that is highly correlated with active transcription, as indicated by the colocalization of H3K27ac and RNA polymerase II (RNA pol II). The researchers also found that H3K27M is largely excluded from regions that are occupied by PRC2 and H3K27me3. Previously, H3K27M had been hypothesized to drive gliomagenesis through PRC2 inhibition, suggesting that a lack of PRC2 function is an important contributing factor to the development of H3K27M tumors. However, the results in this study indicate that both PRC2 and H3K27me3, are present at thousands of loci in DIPG cells and that residual PRC2 activity is required to maintain DIPG proliferative potential, by repressing neuronal differentiation and function
Further, H3K27M enriched nucleosomes for acetylated H3K27 and demonstrated high co-occupancy with bromodomain proteins. The co-occupancy between BRD2 and BRD4 proteins and H3K27M-K27ac heterotypic nucleosomes suggests a potential role of BRD proteins in DIPG pathogenesis. Consistent with this point, the proliferation of DIPG cells treated with JQ1, a well-known bromodomain and extra-terminal domain (BET) inhibitor, was inhibited accompanied by an upregulation of differentiation markers in the compound treated DIPG cells. Further interrogation showed that the effects of JQ1 were independent of reducing MYC (a downstream target of JQ1) but involved the sonic hedgehog (SHH) pathway. JQ1 and a second BET inhibitor I-BET15 were also tested in a K27M DIPG xenograft mouse model, with both compounds causing a reduction in tumor size, and an extension in animal survival, as compared to vehicle-treated mice. Taken together this study provides evidence that PRC2 and BET bromodomain proteins are potential therapeutic targets for DIPG.
If you want to help fund research for new and better treatments for brain tumors – and ultimately a cure – please consider making a gift here.