Colin Maslink – Studentship – 2016
Colin’s project has been generously supported by the Turek Family
About the Research
Project title: “Targeted therapeutic disruption of the blood-brain barrier in childhood brainstem cancers”
Diffuse intrinsic pontine glioma (DIPG), a tumour that involves the brainstem and occurs almost exclusively in children ages 5-9, is one of the most devastating tumours with a near 100% fatality rate within 2 years of diagnosis. Currently, there are poor treatment options due to the impermeable blood-brain barrier (BBB) that prevents chemotherapeutic drugs from entering the brain. One technique, MRI-guided focused ultrasound (MRIgFUS), has been shown to transiently disrupt the BBB, increasing the delivery of drugs to brain tumours.
The purpose of our project is to determine the effectiveness of MRIgFUS in aiding the delivery of chemotherapeutic drugs (e.g. panobinostat) to brainstem tumours, using a preclinical model of DIPG generated through transplantation of human glioma cells into mice. It is hypothesized that this technique will offer temporary disruption of the BBB, allowing focused delivery of chemotherapeutics to the brainstem. Given that MRIgFUS is already used in patients for other diseases, it is expected that enhanced drug delivery using MRIgFUS could be rapidly translated to the clinic, leading to new clinical trials aimed to improve the outcome of children suffering from DIPG and other tumours.
About Colin, in his own words…
For me, research has always been a life-altering experience. An early experience working in a neuroscience lab lead to further summers in the lab, which lead to pursuing volunteer experiences with children experiencing neurological conditions, and ultimately culminated in entering medical school with a clinical interest in the neurosciences.
Similarly, being awarded a Brain Tumour Research Studentship means much more than just having the opportunity to pursue brain tumour research, an interest that stems from my past research, the inspiration I’ve felt volunteering with affected children, and the emotional drive of seeing the toll cancer can take. It also presents an opportunity to develop research skills and experiences that I can carry forward in a career as a brain tumour researcher and beyond. Much bigger than that, it presents an opportunity to join the many researchers who are helping to impact and alter the lives of those suffering from brain tumours.
Words cannot express how thankful I am to the Turek family and to the Foundation for this opportunity to explore new treatments for pediatric brain tumours, to impact the lives of those affected, to grow as a brain tumour researcher and to join the many scientists in the endeavour of creating hope.
To date, we have evaluated the safety of MRI-guided focused ultrasound (MRIgFUS) with microbubble administration in a rat model. This is essential to do before testing treatment with a chemotherapeutic agent in order to verify that the MRIgFUS procedure itself, when targeted at the delicate and vital brainstem, is not detrimental. Safety testing was performed by monitoring cardiorespiratory vital signs before, during, and after treatment, as well as motor function before and after treatment. Preliminary data analysis suggests that MRIgFUS with microbubble treatment is a safe procedure in this model.
In addition, in-vitro experiments utilizing glioma cell lines have been performed to elucidate the most effective chemotherapeutic treatment to combine with the MRIgFUS procedure. For instance, a Western blot assay was performed to demonstrate that treating glioma cells with cisplatin conjugated to a gold nanoparticle (GNP) caused the most genetic damage to glioma cells and, thus, is the more efficacious treatment. Moving forward, we will deliver GNP-conjugated cisplatin as a chemotherapeutic agent for testing the efficacy of MRIgFUS treatment.
Finally, I personally have been able to learn several techniques central to the field of brain tumour research, such as Western blots, immunofluorescence assays, genotyping, and basic cell culture techniques, that can be utilized in our future plans of testing the efficacy of GNP-conjugated cisplatin with MRIgFUS as a treatment for DIPG.
During the past two summers, we have made significant progress in our evaluation of MRI-guided focused ultrasound (MRIgFUS) as a potential treatment for diffuse intrinsic pontine glioma (DIPG).
Firstly, we have demonstrated that MRIgFUS is a safe and well-tolerated treatment when used to achieve blood-brain barrier (BBB) disruption in the brainstem of healthy rats. No cardiorespiratory or neurological deficits were noted and no microscopic damage to the brainstem was found.
Next, we have observed that doxorubicin, when compared to other traditional chemotherapeutics, is the most cytotoxic agent against our in vitro DIPG cell lines. We have also shown that with MRIgFUS, we can deliver a 40 fold greater quantity of doxorubicin into the brainstem compared to doxorubicin administration without MRIgFUS. Thus, doxorubicin is a very promising chemotherapeutic to use in combination with MRIgFUS.
About my experience
Receiving this Studentship has had a profound impact on me, both personally and professionally. Firstly, I have been able to gain valuable lab experience and develop necessary research skills that I can carry forward in a career as a clinician-scientist. This includes learning the rationale and protocol of different molecular techniques, such as Western blots, genotyping, and RNA extractions, as well as learning the broader theoretical concepts behind developing models and experiments for preclinical neuro-oncology research. I’ve also been able to observe how much thoughtfulness, patience, and collaboration goes into designing and performing this research.