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Brain Tumor Research Highlights: June 2016

SEE THE MAY BRAIN TUMOR RESEARCH HIGHLIGHTS HERE.


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:


Migration Phenotype of Brain Cancer Cells Predicts Patient Outcomes: Smith C, Kilic O, Schiapparelli P et al (2016) Cell Reports – link to paper

Glioblastoma (GBM) is the most common, aggressive, and lethal primary malignant brain tumor. GBM tumor cells can spread from the primary tumor without detection and invade surrounding normal brain tissue to form new tumor “satellites” that lead to tumor recurrence. Such local infiltration with the brain remains an important cause of mortality and underscores the need to study tumor invasiveness. In this study, the authors describe an experimental model – which mimics a cellular environment similar to the native brain conditions – that allows researchers to visualize how over time cancerous cells migrate from the primary GBM tumor cells in response to a growth factor stimulus. The results show that there is substantial variability in the mechanisms of migration of cells from 14 different patient-derived glioblastoma samples, but that migratory behavior of tumor cells was predictive of tumor location and clinical outcomes, including time to recurrence of disease. The authors suggest that this kind of model could be used for individual patient diagnosis and prognostication.

Association of the Extent of Resection With Survival in Glioblastoma – 
A Systematic Review and Meta-analysis: Brown TJ, Brennan MC, Li M, et al (2016) JAMA Oncol. doi:10.1001/jamaoncol.2016.1373. Published online June 16 – link to paper

Many large retrospective studies – looking back on past data collected – have found that survival outcomes are directly correlated to the extent of surgical resection of tumor (EOR) in patients with newly diagnosed GBM. Yet there still has been some disagreement in the field about the optimal EOR. This has prevented professional societies from laying out consensus guidelines regarding the optimal EOR. This new report represents one of the largest systematic reviews and provides a quantitative “meta-analysis” to examine whether gross total resection (GTR; total resection of tumor in addition to the surrounding abnormal regions of the tumor with no obvious tumor detectable on a brain imaging scan) compared with subtotal resection (STR; portion of the tumor can still be seen on a post-operative brain scan) or biopsy (just taking a small sample of tumor tissue for diagnostic purposes) is associated with prolonged overall and progression-free survival.

“When clinically feasible, the body of literature favors GTR in all patients with newly diagnosed GBM.”

Based on 37 published studies, the authors report that GTR probably increases the likelihood of 1-year survival compared with STR by about 61% and increases the likelihood of 2-year survival by about 19%. Similar improvements (51%) are seen in 12-month progression-free survival. They conclude: “When clinically feasible, the body of literature favors GTR in all patients with newly diagnosed GBM.” However, it should be kept in mind that the available studies that have provided data are retrospective and carry a high-risk for bias. To address this issue, the authors recommend that a high-quality, audited, registry of patients with GBM would provide valuable prospective information for identifying factors that affect patient outcomes such as EOR.

Socioeconomic position and the risk of brain tumour: a Swedish national population-based cohort study: Khanolkar AR, Ljung R, Talbäck M et al (2016) J Epidemiol Community Health 0:1–7. doi:10.1136/jech-2015-207002 – link to paper

To date research has shown that heritable genetic factors and ionizing radiation exposure have the strongest evidence supporting their association with risk of developing brain tumors; while many other potential risk factors previously investigated showing inconsistent results. However some risk factors are still being studied for example: cellphones and electromagnetic radiation.

In a new paper, findings are reporter from a large prospective observational study involving more than 4.3 million Swedish citizens, all of whom were born between 1911 and 1961 and living in Sweden in 1991. The subjects were monitored between 1993 and 2010 to see if they developed a primary brain tumor, and information on educational attainment, disposable income, marital status, and occupation was obtained from national insurance, labor market, and national census data. The results suggest that high levels of education are linked to an association with developing brain tumors. In particular, glioma (including both low- and high- grade tumors) were found to be more common among university-educated men and women than for those individuals with only primary education. Women with university education also had increased risk of meningioma compared to those with primary education. Men and women in intermediate and higher non-manual occupations had increased risk of glioma compared to low manual groups. In terms of marital status, being single or previously married/cohabiting was associated with decreased risk of glioma in men. Men in non-manual occupations had ~50% increased risk of acoustic neuroma compared to men in low manual occupations.

Because this is an observational study it is not possible to attribute association with actual causation and the researchers point out a lack of information about lifestyle factors that may influence risk. The authors also point out that incomplete reporting to cancer registry for different socioeconomic groups may introduces a detection bias that may explain the findings.

NBTS provided the following statement regarding this study to several media out lets that inquired about this study and its relevance to the brain tumor community:

National Brain Tumor Society (NBTS) appreciates the continued efforts by researcher such as Drs. Khanolkar and Feychting and their colleagues to study brain tumor epidemiology and etiology. If the neuro-oncology field is better able to understand the risk factors for developing brain tumors, it might one day be possible to create preventative measures, which this field, unfortunately, currently lacks. We would also like to praise the study’s authors for the collaboration across institutes and across borders, as well as for their exhaustive efforts to examine a great deal of cases, leading to a significant sample size with prospective study.

That said, the author’s own conclusion states that what they have found from this study is an “association.” An “association” does not constitute cause or risk factor, and does not necessarily infer that education, money, and/or marriage have any prospective effect on whether individuals, or groups of people, may develop a brain tumor. Moreover, this study does not provide insight into potential oncogenic, epigenetic, or environmental factors that would lead to tumorigenesis, with authors offering that, “completeness of cancer registries and detection bias may be possible explanations,” for their findings in this particular study.

As such, NBTS believes we cannot draw any appreciable or cogent conclusions in regards to brain cancer risk from these findings at this time.

PRMT5-PTEN molecular pathway regulates senescence and self-renewal of primary glioblastoma neurospheres cells: Banasavadi-Siddegowda YK, Russell L, Frair E, et al (2016) Oncogene, doi:10.1038/onc.2016.199. Published online 13 June – link to paper

Poor outcomes  for GBM patients highlight the critical and urgent need to identify novel therapeutic targets against this tumor type. One of the causes for poor patient outcomes is the heterogeneity (how different each tumor is from the next) of GBM tumors, where patients have both differentiated cells and undifferentiated stem-like cells. These cells behave differently and thus respond differently to therapies. An gene called PRMT5, which when “turned-on” – or expressed – gives the cell instructions to produce a protein by the same name, has been shown to be “overexpressed” (or at higher levels than in healthy cells) in more aggressive GBMs. This new study looked at the significance of PRMT5 in primary patient-derived GBM cells grown in lab cultures as immature undifferentiated neurospheres (neural stem cells) and mature differentiated cells. The results suggest that PRMT5 is required for proliferation and self-renewal of primary GBM neurospheres, whereas in GBM differentiated cells it is essential for survival. The results also show that PRMT5 regulates cell cycle in GBM neurospheres by regulating hypophosphorylated-retinoblastoma – a tumor suppressor protein that is dysfunctional in cancers. In addition, in these immature tumor cells, PRMT5 regulated the expression of another major tumor-suppressor gene called PTEN , which has a key role in their proliferation and self-renewal ability. However, the same was not true for GBM differentiated cells. In further experiments, the authors knocked-down PRMT5 in experimental models, which caused cancer cell-death in GBM differentiated cells and the loss of cancer cells’ ability to grow and divide in GBM neurospheres. In mice implanted with both primary tumor-derived neurospheres or differentiated cells, inhibiting PRMT5 reduced intracranial tumour size and growth rate in mice. Overall, this study showed that PRMT5 may be an important target for both GBM differentiated cells and undifferentiated neurospheres, though via different mechanisms.

Improved 6-year overall survival in AT/RT—results of the registry study Rhabdoid 2007: Bartelheim K, Nemes K, Seeringer A, et al (2016) Cancer Medicine doi: 10.1002/cam4.741 30 March – link to paper

Atypical teratoid rhabdoid tumors (AT/RT) are characterized by mutations of a gene known as SMARCB1, and rarely, SMARCA4, with high-rate of occurrence in young children, and poor outcomes with survival ranging from 15-40%. From 2005-2009, 35 patients from 4 countries were enrolled in the registry study called, “Rhabdoid 2007.” The registry provides basic clinical data, as well as a system of high-quality reference diagnostics and expert counseling, for AT/RT diagnostic and therapeutic measures. The treatment schedule used – and also termed Rhabdoid 2007 – for patients in the registry included elements of anthracyclines, intraventricular methotrexate and early start of radiotherapy. Thirty-one of the 35 patients in the registry were treated according to Rhabdoid 2007. The results of Rhabdoid 2007 therapy were 46% 6-year overall survival and 45% event-free survival. The study showed that complete remission and the application of radiotherapy were positive prognostic factors. For this study, patients had a high likelihood of survival if they reached 3 years post-diagnosis without relapse. However, this patient cohort also showed indications of chemotherapy resistance.

The study showed a need for relapse trials with innovative concepts in AT/RT, as well as a significant beneficial effect of radiotherapy of overall survival, with 60% of irradiated patients being under three years of age. The recommended treatment of Rhabdoid 2007 showed feasibility and safety, though due to the voluntary nature of the registry, underreporting of adverse events may have occurred.


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.

 

*Cover image courtesy of the website of the National Cancer Institute (cancer.gov)

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