To see July’s Brain Tumor Research Highlights, click 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 (glioblastoma) 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 Manager, Amanda Bates:
Preclinical Research News:
AAV-mediated direct in vivo CRISPR screen identifies functional suppressors in glioblastoma: Chow RD, Guzman CD, Wang, G et al (2017) Nature Neuroscience DOI:10.1038/nn.4620 – link to paper
A causative understanding of genetic factors that regulate glioblastoma pathogenesis is of central importance. Here we developed an adeno-associated virus–mediated, autochthonous genetic CRISPR screen in glioblastoma. Stereotaxic delivery of a virus library targeting genes commonly mutated in human cancers into the brains of conditional-Cas9 mice resulted in tumors that recapitulate human glioblastoma. Capture sequencing revealed diverse mutational profiles across tumors. The mutation frequencies in mice correlated with those in two independent patient cohorts. Co-mutation analysis identified co-occurring driver combinations such as B2m–Nf1, Mll3–Nf1 and Zc3h13–Rb1, which were subsequently validated using AAV minipools. Distinct from Nf1-mutant tumors, Rb1-mutant tumors are undifferentiated and aberrantly express homeobox gene clusters. The addition of Zc3h13 or Pten mutations altered the gene expression profiles of Rb1 mutants, rendering them more resistant to temozolomide. Our study provides a functional landscape of gliomagenesis suppressors in vivo.
Neural Precursor-Derived Pleiotrophin Mediates Subventricular Zone Invasion by Glioma: Qin EY, Cooper DD, Abbott KL et al (2017). Cell 170(5), 845-859.e19 DOI: http://dx.doi.org/10.1016/j.cell.2017.07.016 – link to paper
The lateral ventricle subventricular zone (SVZ) is a frequent and consequential site of pediatric and adult glioma spread, but the cellular and molecular mechanisms mediating this are poorly understood. We demonstrate that neural precursor cell (NPC): glioma cell communication underpins this propensity of glioma to colonize the SVZ through secretion of chemoattractant signals toward which glioma cells home. Biochemical, proteomic, and functional analyses of SVZ NPC-secreted factors revealed the neurite outgrowth-promoting factor pleiotrophin, along with required binding partners SPARC/SPARCL1 and HSP90B, as key mediators of this chemoattractant effect. Pleiotrophin expression is strongly enriched in the SVZ, and pleiotrophin knock down starkly reduced glioma invasion of the SVZ in the murine brain. Pleiotrophin, in complex with the binding partners, activated glioma Rho/ROCK signaling, and ROCK inhibition decreased invasion toward SVZ NPC-secreted factors. These findings demonstrate a pathogenic role for NPC:glioma interactions and potential therapeutic targets to limit glioma invasion.
BIRC3 is a biomarker of mesenchymal habitat of glioblastoma, and a mediator of survival adaptation in hypoxia-driven glioblastoma habitats: Wang D, Berglund AE, Kenchappa RS (2017). Scientific Reports 7, Article number: 9350 DOI:10.1038/s41598-017-09503-8 – link to paper
Tumor hypoxia is an established facilitator of survival adaptation and mesenchymal transformation in glioblastoma (GBM). The underlying mechanisms that direct hypoxia-mediated survival in glioblastoma habitats are unclear. We previously identified BIRC3 as a mediator of therapeutic resistance in glioblastoma to standard temozolomide (TMZ) chemotherapy and radiotherapy (RT). Here we report that BIRC3 is a biomarker of the hypoxia-mediated adaptive mesenchymal phenotype of glioblastoma. Specifically, in the TCGA dataset elevated BIRC3 gene expression was identified as a superior and selective biomarker of mesenchymal glioblastoma versus neural, proneural and classical subtypes. Further, BIRC3 protein was highly expressed in the tumor cell niches compared to the perivascular niche across multiple regions in glioblastoma patient tissue microarrays. Tumor hypoxia was found to mechanistically induce BIRC3 expression through HIF1-alpha signaling in glioblastoma cells. Moreover, in human glioblastoma xenografts robust BIRC3 expression was noted within hypoxic regions of the tumor. Importantly, selective inhibition of BIRC3 reversed therapeutic resistance of glioblastoma cells to RT in hypoxic microenvironments through enhanced activation of caspases. Collectively, we have uncovered a novel role for BIRC3 as a targetable biomarker and mediator of hypoxia-driven habitats in glioblastoma.
Clinical Research News:
Adaptive Global Innovative Learning Environment for Glioblastoma: GBM AGILE: Alexander BM, Ba S, Berger MS et al (2017) Clin Cancer Res. Published Online August 16, doi: 10.1158/1078-0432.CCR-17-0764 – link to paper
Glioblastoma is a deadly disease with few effective therapies. While much has been learned about the molecular characteristics of the disease, this knowledge has not been translated into clinical improvements for patients. At the same time, many new therapies are being developed. Many of these therapies have potential biomarkers to identify responders. The result is an enormous amount of testable clinical questions that must be answered efficiently. The GBM Adaptive Global Innovative Learning Environment (GBM AGILE) is a novel, multi-arm, platform trial designed to address these challenges. It is the result of the collective work of over 130 oncologists, statisticians, pathologists, neurosurgeons, imagers, and translational and basic scientists from around the world. GBM AGILE is comprised of two stages. The first stage is a Bayesian adaptively randomized screening stage to identify effective therapies based on impact on overall survival compared with a common control. This stage also finds the population in which the therapy shows the most promise based on clinical indication and biomarker status. Highly effective therapies transition in an inferentially seamless manner in the identified population to a second confirmatory stage. The second stage uses fixed randomization to confirm the findings from the first stage in order to support registration. Therapeutic arms with biomarkers may be added to the trial over time while others complete testing. The design of GBM AGILE enables rapid clinical testing of new therapies and biomarkers to speed highly effective therapies to clinical practice.
Clinical trials of Dianhyrogalactitol in Patients with Chemo-resistant Glioblastoma:
Dianhydrogalactitol (VAL-083) is a chemotherapeutic agent approved for chronic myeloid leukemia and lung cancer in China. VAL-083 is a brain penetrable bi-functional alkylating agent that targets the N7 of guanine, leading to double-strand DNA breaks and tumor cell death and was shown to be effective in GBM and pediatric high grade glioma tumor cells independent of MGMT methylation status – a biomarker which is associated with TMZ resistance (link to poster). Recent studies have also demonstrated that VAL-083 induces irreversible S/G2-phase cell-cycle arrest, indicating a potential for synergy with S-phase specific chemotherapeutics, including topoisomerase and PARP inhibitors (link to poster)
In a phase I/II clinical trial in recurrent glioblastoma patients, VAL-083 was reported to be well tolerated and better than temozolomide (TMZ) in extending overall survival (link to poster). Additional trials with VAL-083 are now planned and enrolling in recurrent MGMT- methylated and – unmethylated glioblastoma patients (clinicaltrials.gov identifiers: NCT03149575 and NCT02717962) and in newly diagnosed unmethylated MGMT GBM patients (NCT03050736).
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.