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Brain Tumor Research Highlights: February 2017

See January 2017’s Brain Tumor Research Highlights here.

Over the years, NBTS has given more than $35 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:

Tumor-homing cytotoxic human induced neural stem cells for cancer therapy: Bagó, J.R., Okolie, O., Dumitru, R. et al (2017) Sci Transl. Med. 9 (375) doi: 10.11126/scitranslmed.aah6510 – link to paper

Neural stem cells are known to migrate to gliomas in response to chemotactic signals released by the tumor cells and have the potential to function as in vivo drug pumps to deliver cytotoxic agents for extended durations. Previous approaches have used stem cells taken from donors other than the patient, because obtaining neural stem cells from patients has proven challenging. However, the use of donor stem cells poses a risk of immune rejection and other safety issues and in the clinical setting, the potential of these autologous  carriers, to avoid immune rejection could provide therapeutic advantages over the allogeneic NSC therapies currently used in clinical trials.

In this study the researchers, were able to reprogram human skin cell fibroblasts through a process known as transdifferentiation (TD) into tumor-homing early-stage induced neural stem cells. The researchers used a protocol that utilized a single transcription factor SOX2 TD strategy to convert the human skin fibroblasts into human neural stems cells that were nestin+ and expressed pathways associated with tumor-homing migration, in just 4 days. The cells were also engineered to express optical reporters and different types of therapies (proapoptotic agent tumor necrosis factor–α–related apoptosis-inducing ligand or thymidine kinase/ganciclovir enzyme/prodrug therapy), and assessed for their tumor-homing migration and therapeutic efficacy in patient-derived GBM models of surgical and nonsurgical disease. Results showed that the engineered neural stem cells migrated to tumors, secreted the agents and inhibited the growth of solid GBM as well as prolonged the survival of tumor-bearing animals.

These findings should serve as a guide to design clinical trials where a patient’s own skin cells could be used to create personalized cytotoxic drug carriers that are reimplanted into the patient to maximize tumor killing.

Longitudinal analysis of treatment-induced genomic alterations in gliomas: Erson-Omay, E. Z, Henegariu, O, Günel, M et al (2017) Genome Medicine 9:12 – link to paper

This study looked at the changes in one GBM patient’s genome, using whole-genome sequencing (WES), throughout the course of treatment over 5 years. The patient’s original tumor was profiled and determined to have amplification of EGFR and an A289V mutation. After standard therapy, the patient was enrolled in a clinical trial for the receptor tyrosine kinase inhibitor, vandetanib. When the tumor recurred, the genetic profile of the recurrent tumor was determined and found similar to that of the original tumor, but with a loss of the A289V mutation and preservation of EGFR amplification. The patient was then enrolled in another clinical trial with carboxyamidotriazole orotate (CTO) to target the activated phosphoinositide 3-kinase (PI3K) pathway along with concomitant temozolomide treatment. During the trial, a second recurrence of the tumor occurred, and the second recurrence tumor was also genetically profiled. At second occurrence, the patient still had amplification of EGFR, but showed evidence of chromothripsis (shattering and reassembling of chromosomes leading to a large number of mutations) and was hypermutated (2079 somatic mutations compared to 68 in the primary tumor and 70 in the first recurrence). The patient was subsequently started on hydroxyurea and an immune checkpoint inhibitor, pembrolizumab, targeting the PD-1 molecule, together with radiation therapy, potentially helping to release the immune targets. Five months after the start of the combination therapy of pembrolizumab and hydroxurea, an MRI revealed a decrease in tumor size. However, further progression was detected nine months later, and hydroxyurea was stopped and bevacizumab was started. After being clinically stable for several months, the patient died five months later.

Because of the insight gained from the molecular findings obtained from studying the patient, the researchers explored further, the Yale-Glioma cohort (collection of tumor tissues from glioma patients) for similar chromothripsis and hypermutated phenotypes to determine how frequent the mutations are in gliomas. They found that 31% of primary GBMs and 1.7% of secondary GBMs had undergone chromothripsis in the 110 tumor-normal matched gliomas.

This study provides evidence that tumor genomic profiles can change with treatment and that genomics-guided personalized treatment can extend survival highlighting the benefit of genomic profiling and personal treatment regimens in glioma patients, even with aggressive tumors such as GBM.

Development of a questionnaire measuring instrumental activities of daily living (IADL) in patients with brain tumors: a pilot study: Oort, Q, Dirven, L, Meijer, W, M., et al (2017) Journal of Neuro-oncology, pp 1-9 – link to paper

Instrumental activities of daily living (IADL) are those activities that require a higher cognitive demand and are essential to function independently, such as shopping, housekeeping, using electronics, etc. Currently, no agreed upon measure for IADL exists for brain tumor patients. The researchers of this study set out to determine if the Amsterdam IADL Questionnaire© for dementia patients may also be applicable to brain tumor patients.

Twenty-two patients, twenty-two caregivers and six healthcare professionals participated in reviewing the Amsterdam IADL Questionnaire© for its application in glioma patients. Of the 70 items from the Amsterdam IADL Questionnaire©, 28 were found to be both affected in brain tumor patients and clearly formulated. An additional 9 items were considered to be IADL for brain tumor patients that were not on the questionnaire. After separate review by six new patients and their partners, a final list of 32 activities was created for instrumental activities of daily living in brain tumor patients.

The authors of this study suggest that one of the reasons the dementia patient questionnaire was not completely transferable to glioma patients is due to the fact that glioma patients are often impaired in more cognitive functions than memory loss. They also suggest that tumor characteristics could play a role in which cognitive functions are affected in glioma patients, whereas this is not the case with for dementia patients. Physical problems, such as loss of motor function, and epilepsy could also play a role in the effects of brain tumors on a patient’s daily activities.

A disease-specific IADL questionnaire for brain tumor patients is being created based on the list of 32 activities generated in this study. The questionnaire will be in accordance with the EORTC Quality of Life Group guidelines and include a broader patient population. It will also be validated cross-culturally.

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.

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