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READ MOREPublished on November 15, 2016 in Brain Tumor Information, Research
NOTE: In October, our 2016 NBTS Scientific Summit Recap replaced our typical monthly Brain Tumor Research Highlights. We posted the September Highlights as usual.
Over the years, NBTS has given more than $32 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:
Single-cell RNA-seq supports a developmental hierarchy in human oligodendroglioma: Tirosh, I, Hebert, C, Escalante, L, et al (2016) Nature 539, 309-313; DOI 10.1038/nature20123
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Evidence suggests that cancer stem cells (CSC’s), defined as cells that can self-renew and differentiate into multiple types of cells found in tumors, play a role in the development and progression of tumors. This hypothesis supports that stem cells can drive tumor growth and cell differentiation by a hierarchy related to developmental pathways and epigenetic programs.
Previous studies in cellular and animal models involving human grade III-IV gliomas have reported isolation of CSC’s but the significance of these findings has been limited by the use of experimental conditions to demonstrate “stemness.” In this study, researchers analyzed the genomic profile of 4,347 individual cells from IDH1 or IDH2 mutant oligodendrogliomas from six different patients to examine tumor cell heterogeneity directly in human tumor samples in situ. The research team found two prominent groups of cells that expressed either oligodendrocytic or astrocytic markers suggesting that oligodendrogliomas are primarily composed of two subpopulations of glial cells. A third group of cells was associated with a ‘stemness’ or stem/progenitor cell program. These three developmental signatures were found in distinct genetic clones (cells with identical patterns of genetic mutations) of tumor cells indicative of non-genetic developmental programs within these tumors.
Prior studies have reported that oligodendrogliomas may arise from the transformation of oligodendrocyte progenitor cells (OPCs). However, in this study, the researchers found that cells with expression signatures for proliferation were not found in OPC’s but were only found in the rare stem/progenitor and undifferentiated subpopulation of the tumor suggesting that this is the compartment fueling the growth of oligodendrogliomas in humans. The research showed that almost all reproducing cancer cells came from the stem and undifferentiated subpopulation of tumor cells. This pattern was confirmed in a cohort of ten additional tumors. There was also a strong correlation between cell cycle and stem/progenitor cell signatures across 69 oligodendroglioma samples in The Cancer Genome Atlas.
This work identifies for the first time the existence of CSC’s in human oligodendroglioma tumors and that CSCs are primarily responsible for fueling the growth of these tumors in humans. These findings highlight that targeting a specific stem cell phenotype may be an actionable therapeutic approach for patients with oligodendroglioma.
*This research was supported by a National Brain Tumor Society Oligodendroglioma Research Grant (to Mario L. Suvà and David N. Louis).
Recurrent MET fusion genes represent a drug target in pediatric glioblastoma: Bender S., Gronych J, Warnatz H-J et al (2016) Nat Med 22, 1314-1320 ; DOI:10.1038/nm.4204
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As part of the International Cancer Genome Consortium (ICGC) Pediatric Brain Tumor project, genomic abnormalities (somatic mutations, abnormal expression of genes, epigenetic modifications) were investigated in tumor and blood DNA samples from 53 pediatric glioblastoma patients as well as some cell lines derived from patient tumor samples expressing histone H3.3 mutations. The most commonly altered pathway (83% of all samples) identified was found to be associated with cell division/cycle regulation, with mutations present in genes: TP53 or PPM1D, or homozygous deletion of CDKN2A and CDKN2B. In addition, numerous other genetic lesions were found that are likely to result in the aberrant activation of growth factor receptor tyrosine kinase – PI3K-MAPK signaling. RNA sequencing revealed fusion transcripts (composed of coding DNA regions from two or more different genes) that were the result of structural rearrangements in most samples. These often involved known cancer-associated genes, such as FGFR2, NTRK2 and PIK3R2. The most frequently affected gene was MET, which encodes an oncogenic tyrosine kinase and was detected in around 10% of pediatric glioblastoma cases. Three MET fusion variants were identified: 1) MET kinase domain was fused to TRK-fused gene (TFG); 2) CLIP2-MET fusion, and 3) PTPRZ1- MET fusion. All pediatric glioblastomas bearing a MET fusion were found to have impaired cell cycle regulation as a result of TP53 mutation or homozygous deletion of the CDKN2A and CDKN2B locus.
To characterize the impact of MET-fusion variants on tumor growth, the researchers established experimental cell and animal high grade glioma models bearing MET fusion proteins. Results suggested that MET-fusion-induced tumorigenesis is dependent on additional genetic lesions affecting cell cycle regulation. Preclinical testing of the MET inhibitor foretinib slowed tumor growth and prolonged overall survival in animals dosed with the compound.
To advance preclinical findings, further clinical investigation was undertaken as part of the pilot phase of the INFORM personalized oncology program (German Clinical Trials Register ID: DRKS00007623) with crizotinib, (a Food and Drug Administration–approved kinase inhibitor with activity against MET). The drug was administered to a 8-year-old male patient treated 3 years previously for a group 3 medulloblastoma who had subsequently developed a secondary glioblastoma with PTPRZ1-MET fusion protein expression. Magnetic resonance imaging (MRI) evaluation, 2 months after treatment initiation revealed a partial response with shrinkage of the primary lesion and concomitant relief of symptoms. However, several new treatment-resistant lesions were also observed and rapid progression of those lesions ultimately resulted in the death of the patient.
These results highlight a new mechanism of tumor recurrence in pediatric glioblastoma and underline the importance of molecular characterization of patient tumors as a basis for treatment planning. The data from this study also provide strong rationale for investigating MET inhibitors, in combination with other targeted therapies to abrogate acquired resistance to MET inhibition, in future pediatric glioblastoma clinical trials.
CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2009–2013: Ostrom QT, Gittleman H, Xu J et al (2016) 18 (suppl 5):v1-v75.doi: 10.1093/neuonc/now207
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This report shows the latest available data on all newly diagnosed primary brain and CNS tumors in the United States from the Centers for Disease Control and Prevention (CDC), National Program of Cancer Registries (NPCR), and the National Cancer Institute (NCI), Surveillance, Epidemiology, and End Results (SEER) program for diagnosis years 2009–2013. The report provides a comprehensive summary of the current descriptive epidemiology of primary brain and other central nervous system (CNS) tumors in the United States (US) population.
Some key data in the report includes:
Analysing data from patient-reported outcome and quality of life endpoints for cancer clinical trials: a start in setting international standards: Bottomley, A, Pe, M, Sloan, J, et al (2016) Lancet Oncol 17, 11, e510-14; DOI 10.1016/S1470-2045(16)30510-1
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Cancer clinical trials are beginning to increase their focus on endpoints of health-related quality of life (HRQOL) and other patient-reported outcomes that quantify how a patient feels or functions. However, there are many ways of analyzing and interpreting patient-reported outcome endpoints, which makes comparison between cancer clinical trials difficult. Efforts exist to standardize specific aspects of patient-reported outcome evaluations, but guidelines and best practices are insufficient for the analysis and interpretation of patient-reported endpoints in cancer clinical trials. The Setting International Standards in Analyzing Patient-Reported Outcomes and Quality of Life Endpoints Data (SISAQOL) consortium is a collaborative initiative from the European Organisation for Research and Treatment of Cancer (EORTC) to address the concerns regarding guidelines and best practices for the analysis and interpretation of patient-reported outcome endpoints in cancer clinical trials. This work will pave the way to incorporate more insights into the patient experience of treatment effects, and will improve the ability for stakeholder decision making.
The initial goal of the SISAQOL consortium is to standardize the analysis of HRQOL patient-reported outcomes and then broaden to include other HRQOL measurement methods. Many examples exist in the literature where different methods of analyzing HRQOL data lead to different, even contradictory, results. The consortium identified several areas that need to be addressed in order to fix the issues caused by non-standardized analysis of HRQOL data. These include a lack of consensus in basic terminology, how to treat missing data, which statistical methods should be used for certain types of research questions, etc. SISAQOL has begun to address some of these and plan to produce tools, guidance, and international standards for the analysis of patient-reported outcome data from clinical trials.
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