SEE THE JULY 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:
Access to Children’s Oncology Group and Pediatric Brain Tumor Consortium phase 1 clinical trials: Racial/ethnic dissimilarities in participation: Nooka AK, Behera M, Lonial S, Dixon MD et al (2016) Cancer. First published online 12th July; DOI:10.1002/cncr.30090 – link to paper
Unlike for adult cancer patients where only 3-7% of adults participate in clinical trials, a high number of pediatric patients, approximately 60%, participate in clinical trials. Children’s Oncology Group (COG) and Pediatric Brain Tumor Consortium (PBTC), both facilitated by the National Cancer Institute (NCI), have enabled clinical trial accrual for pediatric patients and provide access to newer therapeutic trials.
The purpose of a phase 1 clinical trial is to evaluate the safety of a potential therapy in humans. In such trials it is important to ensure that results are representative of racial and ethnic variations in how an investigational drug reacts in the body, and how the body reacts to the drug.
In this paper, researchers have evaluated the observed participation rates of various patient groups by race, ethnicity, sex, and age in the national phase 1 consortia, COG and PBTC during the period of 2000-2008, and compared them to the expected pediatric cancer rates from the Surveillance, Epidemiology, and End Results (SEER) database during the same time period to assess for dissimilarities in the representation of various patient groups.
The results suggest that the majority of racial/ethnic, age, and sex groups are proportionally represented in phase 1 trials. However, underrepresentation of a few specific groups, specifically in Hispanic populations, were noted. Overall Hispanic families may benefit from focused recruitment with an intent to achieve the ultimate goal of superior outcomes for every racial/ethnic and age group.
Because discussions of phase 1 trials occur throughout the continuum of care, with some discussions occurring before the patient is eligible, a better awareness of underrepresented groups by clinicians would allow the timely discussion of phase 1 trials and also the opportunity to discuss barriers that limit access for the underrepresented groups.
Mitochondrial Akt Regulation of Hypoxic Tumor Reprogramming: Chae Y-C, Vaira V, Caino C et al (2016) Cancer Cell 30, 257–272. DOI: http://dx.doi.org/10.1016/j.ccell.2016.07.004 – link to paper
In medical terms “hypoxia” refers to lack of oxygen in cells. In normal, healthy cells, hypoxia is a bad thing and weakens the cell. However, malignant tumor cells are able to compensate for hypoxia and continue to multiply (proliferate) even more aggressively in such an unfavorable environment. This paper reports on the discovery of the activation of a novel pathway that occurs in glioma tumor cells that allows tumor cells to thrive despite a low oxygen environment and leads to an unfavorable prognosis for patients with gliomas.
Mitochondria, known as the “powerhouse” of cells because of their role in energy production, are the main source of hypoxia-induced changes in tumors. The researchers showed that a protein called “Akt,” which plays a key role in cell signaling and metabolism, accumulates in mitochondria during hypoxia. When this happens, another protein called “PDK1” is impacted, leads to the shutdown of cellular respiration. PDK1 is a part of a mitochondrial multi-enzyme complex that is responsible for cellular respiration and the regulation of homeostasis of carbohydrate fuels in mammals. The pathway then uses the tumor’s metabolism to break down glucose and use its energy to reduce cell death and maintain proliferation.
In a cohort of 116 patients with gliomas, the mitochondrial signaling between Akt and PDK1 was progressively increased in different types of gliomas, with the highest activity seen in patients with glioblastoma, one of the most malignant brain tumors.
This work underlines how tumor cells are able to get the energy they need to persist when faced with unfavorable conditions and suggest that the pathway, including Akt, would be a valuable therapeutic target to impair the ability of brain tumors to adapt to hypoxic conditions.
Comparing Intelligence Quotient Change After Treatment With Proton Versus Photon Radiation Therapy for Pediatric Brain Tumors: Kahalley LS, Ris MD, Grosshans DR et al (2016) J Clin Oncol.34(10):1043-9. doi: 10.1200/JCO.2015.62.1383 – link to paper
There are different types of radiation therapy. They can be classified according to the various types of radiation particles or waves that are used to deliver the treatment, such as photons, electrons, or protons. Photon beams are the same type of beam that are used in diagnostic X-ray machines, such as those used to take chest X-rays; however, in X-ray radiotherapy (XRT), much higher energy photon beams are used.
Protons are hydrogen atoms whose electrons have been removed and therefore carry a positive charge. Just as XRT using photons can to treat both benign and malignant tumors, proton beams can be used to irradiate tumors in a similar way. There is no significant difference in the biological effects of protons versus photons. However, protons deliver a dose of radiation in a much more confined way to the tumor tissue than photons. After they enter the body, protons release most of their energy within the tumor region and, unlike photons, deliver only a minimal dose beyond the tumor boundaries.
Impairments in basic functions, such as thinking, problem solving, reading, and writing, have been associated with the late effects of XRT on pediatric brain tumor patients. Because proton beam radiation therapy (PBRT) reduces the impact on normal tissue around the tumor, it may have the potential to result in better neurocognitive outcomes for patients, particularly pediatric patients. With this in mind, the authors of this paper have undertaken a study involving a retrospective analysis comparing IQ scores obtained from 60 pediatric patients with brain tumors previously treated with photon X-ray radiotherapy (XRT) to IQ scores of 90 patients treated with proton beam therapy (PBRT) between the years 2007 and 2012 at the Texas Children’s Hospital/MD Anderson Proton Therapy Center.
When the overall data was analyzed, the survivors treated with PBRT did not demonstrate a significant decline on average IQ scores, whereas those treated with XRT showed, on average, a statistically significant decline of 1.1 in IQ points per year. However, the IQ scores between these two groups, plotted on a chart, did not differ significantly, as the trajectories of both groups declined over time.
When the data was analyzed by considering “field of radiation,” the PBRT and XRT groups who received craniospinal irradiation (i.e. entire brain and spine are treated), IQ scores were stable over time, and the slopes between the groups, once again, did not significantly differ. In contrast, a statistically significant difference between the two groups was displayed after receipt of focal radiation therapy to part of the brain. The IQ scores were stable for the PBRT group, but significantly declined for the XRT group by an average of 1.57 points per year, whereas the trajectory of slopes over time between the two groups did not significantly differ. These results suggest that focal/local radiation therapy is the optimal scenario in which PBRT provides maximal benefits to patients by minimizing the scatter of radiation to the surrounding healthy brain tissue, as opposed to craniospinal irradiation, in which the entire brain and spine are treated.
Taken together, the authors conclude that the study data do not provide clear evidence that proton beam radiation therapy results in significant, meaningful clinical benefit – when it comes to sparing longterm IQ – compared to modern X-ray (photon) radiation therapy treatment. Additional long-term data are needed to fully understand the neurocognitive impact of proton beam radiation therapy in survivors of pediatric brain tumors.
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