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Brain Tumor Research Highlights: January 2017

Over the years, NBTS has given more than $34 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:


Bacterial Carries for Glioblastoma Therapy: Mehta, N, Lyon, J, Patil, K, et al (2016) Molecular Therapy Oncolytics 4, 1-17 – link to paper

Over the years, it has proven difficult to deliver drugs to solid tumors (like brain tumors). The main strategy for overcoming barriers to drug-deliver is known as “Convection Enhanced Delivery,” which uses pressure to overcome the barriers; however, this strategy can lead to problems when used in the brain. Another proposed method for delivering therapeutics to solid tumors is the use of nanoparticles, but studies have suggested that as little as 0.7% of the administered dose reaches solid tumors. Therefore, the research team in this study used a bacterial carrier, an avirulent strain of S. typhimurium, to deliver treatments to brain tumors.

The team edited the genes of the bacteria so that it would be deficient in synthesized purines, something tumors are a rich source of, so the bacteria would move toward the tumors. Once at the tumor and in the hypoxic (low oxygen) conditions of the tumor, alterations in the genetics of the bacteria made them express Azurin and wild-type p53, a tumoricidal protein and tumor suppressor protein respectively. Azurin is also thought to act in a way that protects p53 from degradation.

In rat models, 19% of treated rats showed extended survival with no toxicity effects from the bacteria. Some animals did not show response to the treatment until after the second injection of the bacterial carriers, suggesting that an increased number of carriers or altered injection schedule may produce an improved response rate. In the non-responders, there was evidence suggesting that the tumor proliferation rate overcame the therapeutic response.

5-Hydroxymethylcytosine localization to enhancer elements and is associated with survival in glioblastoma patients: Johnson, K, Houseman, E. A., King, J, et al (2016) Nature Communications 7, Article number 13177; DOI: 10.1038/ncomms13177 – link to paper

The epigenome refers to modifications to the genome that are not related to changes in DNA sequence, but rather to the distribution of chemical tags on DNA that determines which parts of the genome are available for reading (i.e. which genes are turned off and on). Previous studies have shown that epigenentic regulation is altered in GBM tumors, but this still remains an understudied area.

In this new study, researchers used state-of-the-art molecular biology and statistical approaches to identify the levels of the distinct epigenetic DNA modifications across the critical regions of the genome in a set of 30 glioblastomas and identified the functional role of two distinct DNA modifications” 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5-hmC). The study showed that 5-hmC is depleted in glioblastoma compared with normal brain tissue and that patients with low 5-hmC patterns have significantly poorer overall survival.

Total levels of 5hmC varied across different GBM tumors, and patients with less 5hmC present on select parts of their tumor DNA had a worse prognosis. People with low amounts of this chemical tag lived for only around two months compared to over 12 months for those with higher 5hmC. The study shows that specific DNA 5mC and 5hmC patterns are disrupted in GBM and uniquely characterize the molecular switches of the genome known as “enhancers.” Regions of the genome with elevated 5-hmC were associated with active transcription and gene regulatory regions. Changes in 5-hmC may be an indicator of disease progression. Several genes that are frequently mutated in GBM were found to have high levels of 5-hmC, suggesting that loss of 5-hmC may reflect a loss of genome integrity.

These findings underline the importance of epigenetic patterns and other molecular-level changes in driving glioblastoma. These results prompt the need for further studies to characterize the epigenome in GBM tumors to determine whether this information will be useful for providing more accurate prognosis and in guiding the selection of treatments.

Anti-PD-1 antitumor immunity is enhanced by local and abrogated by systemic chemotherapy in GBM: Mathios, D, Kim, J. E., Mangraviti, A, et al (2016) Science Translational Medicine 8, 370ra180 – link to abstract

The chemotherapy Temodar (temozolomide) is the standard treatment for most high-grade glioma patients. A new category of treatments known as immunotherapy is now also emerging and being evaluated as potential treatments for high-grade gliomas. However, while combining these two treatment categories has been hypothesized as a potentially providing a more effective antitumor response in patients, a major challenge has been the often immunosuppressive effects of chemotherapy. Thus, there is considerable interest in identifying the conditions under which chemotherapy can potentiate the use of immunotherapy. In this study, researchers tested the hypothesis that local chemotherapy, unlike systemic chemotherapy, would allow for an antitumor immune response. Using a mouse model, the researchers tested combinations of either locally administered chemotherapy or systemically administered chemotherapy with an anti-programmed cell death protein 1 (PD-1) antibody. The results showed that local chemotherapy allowed for a better immune response when combined with anti-PD-1 immunotherapy and resulted in a survival benefit. The study went on to show that local chemotherapy in combination with anti-PD-1 immunotherapy, resulted in an increase in memory immune cells, allowing for resistance to tumor re-challenge in mice. Compared with systemic chemotherapy, local chemotherapy also boosted immune response. Importantly, the research data shows that systemic chemotherapy does not work synergistically with anti-PD-1. Though systemic chemotherapy alone and in combination with anti-PD-1 did slow progression, the tumors recurred. Also, combination of systemic chemotherapy with anti-PD-1 was inferior to anti-PD-1 alone.

The researchers suggest a strategy whereby rather than viewing chemotherapy as a definitive therapy, chemotherapy is used as an initiator of a definitive immuno-based therapy. This approach could be readily translated into clinical trials due to the approval of local chemotherapy agents (such as BCNU-eluting polymers – i.e. gliadel wafers), already approved for recurrent and newly diagnosed GBM patients. Importantly, the study also demonstrated that the timing of chemotherapy can affect the efficacy of immunotherapy. Currently, immunotherapy is administered after patients have failed their initial chemotherapy regimen. The data in this study suggest that administering systemic chemotherapy before immunotherapy could inhibit the ability of the immune system to generate an effective antitumor immune response.


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