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. 2014 Apr 28;3(2):99–103. doi: 10.2217/cns.14.9

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PMCID: PMC6128190
CNS Oncol. 2014 Apr 28;3(2):99–103.

New target of glioblastoma multiforme invasiveness discovered

Glioblastoma multiforme (GBM) is the most common and lethal brain tumor in adults, with a median survival rate of 1 year. It is impossible to surgically remove owing to the vital nature of the surrounding tissue and impossible to cure due to the migration ability of single GBM cells; this leaves a bleak outlook for those patients who are diagnosed with the disease. Therefore, it is of vital importance that novel therapeutic targets for the disease are uncovered.

Researchers from Virginia Commonwealth University Massey Cancer Center (USA) and Virginia Commonwealth University Institute of Molecular Medicine (USA) therefore set out to investigate the role of the gene MDA-9, or syntenin, in GBM. The gene already has many established roles, including cell–cell and cell–matrix adhesion, signal transduction, gastrulation, and nervous system development. MDA-9/syntenin also has a role in melanoma pathogenesis, prompting researchers to explore whether it also plays a role in GBM.

Results demonstrated that GBM tumors had the highest expression of MDA-9/syntenin compared with lower-grade tumors; overexpression of the gene led to increased invasiveness compared with knockdown of the gene, which led to decreased invasiveness. The mechanisms by which MDA-9/syntenin can influence invasiveness seem to be many. One possible mechanism appears to be the activation of c-Src and downstream effects on the p38MAPK pathway, while another is by mediating integrins, responsible for facilitating the binding of GBM cells to the extracellular matrix. A further mechanism is the activation of NF-kB and, finally, by inducing HIF-1α, responsible for the evasion of GBM cells from existing antiangiogenic therapy.

This multitude of effects on the invasiveness of GBM, which is responsible for a large part of the devastating resistance of GBM to current therapy, therefore raises the exciting possibility that MDA-9/syntenin could be a novel target for the successful treatment of this disease.

– Written by Luke Worley

Source: Kegelman TP, Das SK, Hu B et al. MDA-9/syntenin is a key regulator of glioma pathogenesis. Neurooncol. 16(1), 50 (2013)

CNS Oncol. 2014 Apr 28;3(2):99–103.

Potential breakthrough in targeting brain tumor-initiating cells in glioblastoma reported

Glioblastoma is a particularly aggressive cancer, one that has a proclivity to recur even after strenuous medical intervention, which ordinarily includes surgery, chemotherapy and radiotherapy. Recurrence of glioblastoma usually proves fatal, giving rise to an average patient survival time of less than 2 years. A new study carried out by researchers from the Montreal Neurological Institute and Hospital at McGill University (Canada) has deepened our understanding of how stem-like tumor cells may reinitiate glioblastoma tumor growth if they are not completely eradicated by treatment. The findings were published online recently in Nature Communications.

A glioblastoma tumor is formed of a complex combination of several distinct cell types, including these stem-like cells, termed brain tumor-initiating cells (BTICs). BTICs are believed to be partially responsible for the regeneration of brain tumors if they are not entirely eradicated by medical interventions. BTICs, therefore, represent a significant target for the development of further glioblastoma therapies.

“We wanted to find out how glioblastomaderived BTICs are able to initiate a tumor with the ultimate goal of preventing the regrowth of this deadly form of brain cancer,” explained Stefano Stifani, senior investigator on the paper (Montreal Neurological Institute and Hospital). “What we found is that by impairing the activity of two transcription factors, termed FOXG1 and TLE, we can significantly reduce the ability of BTICs to give rise to brain tumors.”

Using an in vivo mouse model of human glioblastoma-derived BTICs, the team demonstrated that these two proteins appeared to be imperative to the tumor-forming ability of these BTICs. As these transcription factors are known to control the expression of many genes, future research will focus on identifying exactly which genes are under their control and which of them may be involved in glioblastoma tumorigenesis. In the long term, this could lead the development of targeted therapeutics that are able to impair the tumor-forming ability of these BTICs.

“The implication of transcription factors FOXG1 and TLE in the tumor-forming ability of BTICs opens the door to possible strategies to block tumor growth – a major advance in the fight against glioblastoma,” concluded Stifani.

– Written by Emily Brown

Source: McGill University press release: www.mcgill.ca/channels-contribute/channels/news/stopping-tumours-their-path-232355

CNS Oncol. 2014 Apr 28;3(2):99–103.

Hide and seek: new research unveils how cancer cells are evading current treatments

Researchers from the University of California, San Diego School of Medicine (CA, USA) have discovered a mechanism by which cancer cells are able to hide for the duration of an administered therapy, and become active again once the therapy has stopped. Although therapies can be effective at targeting the underlying mutation causing the disease and killing cancer cells, resistance mechanisms are becoming more common, making it more difficult to develop therapies that will result in good outcomes.

Much of current research is focused on these resistance mechanisms, such as second-site mutations, and alternative kinases or enzymes that produce growth-promoting signals to the cancer, and how to prevent them. Paul Mischel (Ludwig Institute for Cancer Research, NY, USA; University of California, San Diego School of Medicine) commented: “…one thing that has not been carefully considered is whether cancer cells can modulate the levels of – and thus their dependence on – the target of the drug, evade therapy, and then re-acquire the oncogene to promote tumor growth when the drug is withdrawn.”

To further investigate, Mischel and colleagues focused their attention on glioblastoma multiforme, the most common malignant primary brain disease in adults. Each year, 9000 new cases of this disease are diagnosed and the median survival rate is only 14 months, mainly due to the highly treatment-resistant and aggressive tumors. The causative mutation of glioblastoma multiforme is a variation of EGFR, called EGFRvIII, which is present on the extrachromosomal DNA of cancer cells. The mutation promotes tumor growth, and although treatments can be effective to begin with, resistance mechanisms soon take effect. The researchers found that cancer cells may go unnoticed by ‘hiding’ their EFGRvIII, meaning that they are therefore no longer a target of the drug. Once therapy is stopped, EGFRvIII is picked up again and tumor growth can recommence.

This new research helps to uncover mechanisms of resistance and Mischel hopes that it will “shift the discussion about what directions need to be taken to improve the success rate for targeted cancer treatments.”

– Written by Emily Hargrave

Source: Nathanson DA, Gini B, Mottahedeh J et al. Targeted therapy resistance mediated by dynamic regulation of extrachromosomal mutant EGFR DNA. Science 343(6166), 72–76 (2013).

CNS Oncol. 2014 Apr 28;3(2):99–103.

New role for PKM2 in cell proliferation identified

A team of researchers have identified a new role for a protein known to be involved in cancer, notably in some brain tumors. PKM2, a pyruvate kinase, has been demonstrated to have a role in cell division, proliferation and brain tumor growth. The findings were recently reported in the journal Molecular Cell.

PKM2 has been identified as a protein involved in mitosis, during which it regulates a checkpoint by acting as a protein kinase and activating other proteins involved in cell division by phosphorylation. PKM2 is believed to normally be activated in infancy and turned off later in life. However, in some glioblastoma cells, PKM2 is turned back on by increased levels of EGFR, which commonly occurs in cancers.

Zhimin Lu, from the University of Texas MD Anderson Cancer Center (USA) explained: “Without PKM2 regulating a checkpoint in mitosis, the tumor cell would not successfully divide.” Lu continued: “Depleting PKM2 led to an uneven distribution of DNA to the two new cells, triggering programmed cell death, or apoptosis, of those cells after division.”

The team demonstrated that if PKM2 was activated in a brain tumor mouse model, then abnormal mitosis occurred, resulting in increased tumor cell proliferation; however, if PKM2 was deactivated, then a decrease in tumor volume of 83% occurred, along with survival time doubling from 20 to 40 days. The team then studied 50 human glioblastoma and 50 lung cancer tumor samples, and demonstrated that this PKM2 deactivation increases survival time.

It was observed that PKM2 phosphorylates Bub3, which then interacts in a protein complex to ensure mitosis occurs correctly. Inhibition of Bub3 phosphorylation by PKM2 resulted in abnormal mitosis. Bub3 activation was then confirmed in 50 glioblastoma samples. Fifteen of the patients displayed low Bub3 phosphorylation levels and were associated with a survival time of 69.8 weeks, whereas the 35 individuals with high Bub3 phosphorylation levels had a lower survival time of 40.5 weeks.

“This new, additional role for PKM2 in cancer development and survival may provide a molecular basis for diagnosing and treating tumors with unregulated PKM2,” Lu reported. “Our research further highlights the importance of PKM2 in human cancers and of developing ways to target its activity and use it as a biomarker to guide treatment.”

– Written by Nicole Spray

Sources: Jiang Y, Li X, Yang et al. PKM2 regulates chromosome segregation and mitosis progression of tumor cells. Mol. Cell 53(1), 75–87 (2013); University of Texas M. D. Anderson Cancer Center press release: www.mdanderson.org/newsroom/news-releases/2013/division-of-tumor-cells.html

CNS Oncol. 2014 Apr 28;3(2):99–103.

Animal experiments using immunotherapy for treating glioblastoma report positive results

We wanted to establish whether we can actually elicit an immune response to a tumor growing within the brain,” comments Burkhard Becher of the University of Zurich (Switzerland). Research recently published in The Journal of Experimental Medicine reports a potentially effective treatment for glioblastoma involving immunotherapy.

Glioblastoma presents with very low survival rates, even after aggressive treatment with chemotherapy, radiation and surgery. Treatment of brain tumors is increasingly difficult as T cells build up in the tumor and prevent attack from the immune system. However, the present study investigated a novel treatment that encourages an individual’s immune system to attack and destroy the tumor cells.

In order to bypass the tumor’s external barrier, the investigators utilized IL-12, which, when produced in the tumor, stimulates local immune cells, encouraging them to attack the tumor itself. IL-12, an immune messenger, worked well in animal models of early-stage tumors. The researchers then waited for the next stage of development to test IL-12’s efficacy in a more advanced tumor. At this time point, the tumors are very large and life expectancy of the mice is decreased to less than 3 weeks. The success rate was low in the advanced tumors, as Johannes von Berg (University of Zurich) explains: “we … injected biopharmaceutical IL-12 into the large brain tumor. This did induce an immune response but only led to tumor rejection in one-quarter of the animals.”

By utilizing a recent development in treating skin cancer, the intravenous administration of an immunostimulating drug, the researchers managed to gain more successful results. This involved combining administration of the drug with intratumoral IL-12; the immunostimulating drug acts on Tregs, suppressing their activity. In this way, tumor rejection was initiated in 80% of the animals involved, a great improvement from the previous 25%. Similar success was also seen in a further joint trial using a more accurate animal model of a brain tumor patient.

The authors propose the next step for these results to be clinical trials. Becher concludes: “we are cautiously optimistic but it’s time that we adopted completely new strategies to really get to grips with this fatal tumor.”

– Written by Elizabeth Webb

Source: University of Zurich press release: www.mediadesk.uzh.ch/articles/2013/immuntherapie-gegen-gehirntumor_en.html

CNS Oncol. 2014 Apr 28;3(2):99–103.

Survival times for glioblastoma multiforme patients demonstrated to improve with an experimental treatment

Research reported by Cedars-Sinai Medical Center (CA, USA) demonstrates promising results for individuals suffering from glioblastoma multiforme, a most aggressive malignant brain tumor. The study findings, presented at the Fourth Quadrennial Meeting of the World Federation of Neuro-Oncology (21–24 November 2013, San Francisco, CA, USA), reported an experimental immune system therapy to increase patient survival rates to over 5 years after initial diagnosis.

The Phase I clinical study of the immune system therapy involved 16 participants suffering from glioblastoma multiforme originally entering the study at Cedars-Sinai Johnnie L. Cochran, Jr. Brain Tumor Center between May 2007 and January 2010. The treatment given involved a vaccine (ICT-107), which is proposed to activate a tumor-killing response in the immune system. ICT-107 does this by targeting six antigens involved in the progression of glioblastoma cells, causing the body’s defense system to recognize and kill the cancer cells.

Survival times range from 60.7 to 82.7 months after diagnosis, with seven of the 16 participants still being alive. Six of these survivors did not have recurring tumors or require further treatment, meaning they were ‘progression free’ for over 5 years. Four individuals were still disease free at the time the research was reported. The standard survival time for this aggressive cancer, with treatment involving surgical removal of the tumor followed by chemotherapy and radiation, is 15 months after initial diagnosis. The current trial presented a median overall survival with ICT-107 treatment to be 38.4 months (calculated in January 2013).

All of the participants in this study presented with at least four of the antigens targeted by ICT-107, and all long-term survivors presented tumors with at least five of these antigens. Surasak Phuphanich, director of the Neuro-Oncology Program at the Cochran Brain Tumor Center commented: “our findings suggest that targeting antigens that are highly expressed by cancer stem cells may be a viable strategy for treating patients who have glioblastomas. Long-term remission of disease in this group of patients was correlated with the expression of cancer stem cell tumor-associated antigens.”

Following on from this Phase I clinical trial, ICT-107 entered a Phase II, randomized, multicenter, placebo-controlled trial.

– Written by Elizabeth Webb

Source: Cedars-Sinai Medical Center press release: www.cedars-sinai.edu/About-Us/News/News-Releases-2013/Update-50-Percent-of-Patients-in-Cedars-Sinai-Brain-Cancer-Study-Alive-After-Five-Years.aspx

CNS Oncol. 2014 Apr 28;3(2):99–103.

New Phase I trial aims to evaluate dendritic cell vaccine for gliobastoma multiforme

Researchers at Cedars-Sinai Medical Center (CA, USA) have launched an early-stage clinical trial to evaluate an experimental dendritic cell vaccine that targets cancer stem cells in patients with glioblastoma multiforme, the most common and aggressive malignant brain tumor. The trial is a collaboration between the Department of Neurosurgery, Johnnie L. Cochran, Jr. Brain Tumor Center and Department of Neurology.

Many current anticancer therapies are unable to destroy cancer originators, resulting in a tumor returning after treatment. However, if cancer stem cells can be destroyed, then the tumor may not be able to sustain itself. This Phase I trial will enroll approximately 45 patients and last for a duration of 2 years. The aim of the trial is to evaluate the safety and dosing of a dendritic cell vaccine created individually for each participant and designed to target CD133, a protein found on cancer stem cells of some brain tumors. The trial is open to patients whose gliobastoma multiforme has returned following surgical removal, with the vaccine, tests and follow-up care being provided at no cost.

The use of dendritic cell vaccines has been shown to be effective in several trials of cancer therapy. The dendritic cells used as part of the vaccine will be derived from each patient’s blood and then combined with commercially available glioblastoma proteins. By being loaded with specific protein fragments of CD133, the dendritic cells will recognize the protein and trigger an immune response when contact is made. The cells will be injected under the skin as a weekly vaccine for 4 weeks, and then once every 2 months going forward.

This new trial is the latest step in Cedars-Sinai’s research into dendritic cell vaccines, which were first introduced experimentally in patient trials in 1998. It is hoped that vaccines targeting cancer stem cells could provide a new therapy for brain cancer patients where conventional treatment methods have been unsuccessful.

–Written by Jonathan Wilkinson

Source: Cedars-Sinai Newsroom: http://cedars-sinai.edu/About-Us/News/News-Releases-2014/Cedars-Sinai-Clinical-Trial-Studies-Vaccine-Targeting-Cancer-Stem-Cells-in-Brain-Cancers.aspx

CNS Oncol. 2014 Apr 28;3(2):99–103.

Personalized brain tumor vaccine may benefit patients with recurrent glioblastoma multiforme

A new study, published recently in the journal Neuro-Oncology, reveals that an experimental personalized vaccine that is made from the patient’s own resected tumor tissue may improve survival rates for patients with glioblastoma multiforme (GBM).

GBM is the most common primary brain malignancy; however, prognosis is still poor. Even with standard treatment, the median survival from diagnosis remains approximately 15 months. Orin Bloch, Assistant Professor of Neurology at Northwestern University Feinberg School of Medicine (IL, USA) and lead author of the study, explained why the research is important: “We are talking about fast-growing tumors that invade normal brain tissue and are very difficult to treat. These tumors occur in up to 23,000 Americans annually, and are typically treated with surgical resection of the tumor followed by chemotherapy and radiation treatment.”

It is thought, therefore, that immunotherapy could potentially hold the key for GBM treatment as it may produce a more sustained and less toxic effect than conventional therapy. There are currently vaccines available for cancer treatment; however, as yet, none have been approved for use against GBM. In this open-label, single-arm, Phase II study, the researchers enrolled 41 adults with recurrent GBM tumors between 2007 and 2011, and developed a vaccine, called HSPPC-96, which was specific to each patient by using their own resected tumor tissue. On average, each individual received six doses of the HSPPC-96 vaccine.

At a 6-month follow-up after treatment, 90.2% of patients were alive (95% CI: 75.9–96.8) and 29.3% were alive at 12 months (95% CI: 16.6–45.7). The median overall survival was 42.6 weeks (95% CI: 34.7–50.5) and there were no treatment-related deaths.

Further study is needed to determine the efficacy of HSPPC-96 for the treatment of recurrent GBM because GBM almost always returns after treatment. As Bloch explained: “The grim prognosis is exactly why new research is important. GBMs have been around for a long time, and still outcomes are poor. With studies such as this one, I believe we can change that.” Andrew Parsa, corresponding author of the study, Chair of the Department of Neurological Surgery at Feinberg School of Medicine, added: “When it comes to brain tumor research, I picture our Northwestern Medicine team climbing a mountain and with every new discovery that shows the potential to prolong survival, we are establishing a new base camp. Someday, thanks to studies like this one, we’ll get to the top of the mountain and convert this particular cancer into a chronic disease – something that patients can live with, controlled by medication.”

– Written by Natasha Leeson

Sources: Bloch O, Crane CA, Fuks Y et al. Heat-shock protein peptide complex-96 vaccination for recurrent glioblastoma: a Phase II, single-arm trial. Neuro Oncol. 16(2), 274–279 (2014); Northwestern University Feinberg School of Medicine press release: www.feinberg.northwestern.edu/research/news/2013/brain-tumor-vaccine.html

CNS Oncol. 2014 Apr 28;3(2):99–103.

Study reveals distinct molecular subtypes of diffuse intrinsic pontine glioma

In a collaborative study between researchers from across the USA, new data have revealed two distinct subtypes in pediatric diffuse intrinsic pontine gliomas (DIPGs). The results were published recently in Acta Neuropathologica.

DIPG is a highly aggressive and morbid form of pediatric brainstem glioma. It accounts for approximately 10–15% of all childhood CNS tumors and are equally as common in girls and boys. The cause of this tumor is currently unknown and, owing to its location, the tumors are typically not biopsied. Consequently, few tissue samples have been analyzed. In this study, the researchers presented protein, mRNA and methylation profiles of fresh-frozen DIPG specimens, normal brain tissue and other pediatric brain tumors (n = 14, n = 10 and n = 17, respectively). Within this cohort, two distinct subtypes of DIPGs were indicated by comparisons with mRNA expression profiles generated from tumor and adjacent normal brain. They also identified potential molecular pathways that lead to poorer overall survival of patients with histone 3 mutations.

Javad Nazarian, author and researcher for the Children’s National Health System (Washington, DC, USA), explained the importance of the study: “Pediatric DIPGs are almost always lethal, and most children do not survive beyond 18 months with this type of tumor. Our results have shown that a multidimensional molecular analysis can contribute to our understanding of DIPGs and guide future research for developing therapeutics.”

– Written by Natasha Leeson

Sources: Saratsis AM, Kambhampati M, Snyder K et al. Comparative multidimensional molecular analyses of pediatric diffuse intrinsic pontine glioma reveals distinct molecular subtypes. Acta Neuropathol. doi:10.1007/s00401-013-1218-2 (2013) (Epub ahead of print); Children’s National Health System press release: www.childrensnational.org/pressroom/NewsReleases/childrens-national-researcher-authors-study-on-pediatric-brain-stem-tumors.aspx

Articles from CNS Oncology are provided here courtesy of Taylor & Francis

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