As the most common and aggressive cancerous brain tumour in adults, a glioblastoma diagnosis remains a death sentence due to its resistance to all currently-available treatments. Research in this area has been slow and steady to date. Now, with promising new findings, a Canadian team of scientists is ushering brain cancer research into a new realm: the field of neurodegenerative medicine and neurochemical signalling.
A study led by The Hospital for Sick Children (SickKids) explores new links between glioblastoma and dopamine, a chemical signal of the brain’s reward system. Brain scientists have long understood that when the brain does not have sufficient amounts of dopamine, or if dopamine signalling is interrupted, the severe neurodegenerative condition known as Parkinson’s disease will occur. In the new study, the team identified chemicals that block dopamine function in glioblastoma tumours in the lab, essentially making glioblastoma stem cells (the cells that drive tumour formation) undergo a rapid neurodegenerative process. But instead of causing Parkinson’s, this process degraded or killed the glioblastoma stem cells. The paper is published in the June 13 online edition of Cancer Cell.
“This research opens a door – it sets a new proof of principle in thinking about cancer in the brain and how it’s growing,” says the study’s principal investigator, Dr. Peter Dirks, Staff Neurosurgeon and Senior Scientist at SickKids. “These cancers adopt many of the same pathways and systems that are normally utilized to enable brain function. Our findings suggest that we really need to think about brain chemistry, and how to tweak brain chemistry. If we can do that we might be able to get these tumour cells to die in a clinical setting.”
Building on previous research, the scientists tested 680 neurochemicals on glioblastoma stem cells grown in a culture in the lab (from tissue donated by patient families), exploring a number of pathways, specifically on the dopamine pathway. A variety of experiments showed that drugs targeting the dopamine receptor DRD4, can limit the growth of – or kill – those cells.
They then studied the mechanism by which the cells would die, including the natural process of cellular recycling. Existing research indicates that stem cells need to undergo autophagy, the constant recycling of used-up molecules (known as cellular garbage) in order to maintain the health of the cell. “In this study, we show that the DRD4 inhibitors impair autophagy and the glioblastoma stem cells basically swell up, grow slowly, and are more likely to die,” says co-author Dr. John Brumell, Senior Scientist at SickKids. “This study points the way to new cellular pathways that control autophagy in the context of cancer development and may lead to new cancer treatments.”
The research team plans to build upon this research by testing drugs to see if they can replicate this dopamine-inhibiting mechanism in glioblastoma stem cells. They hope to adopt a repurposing strategy as they develop future testing of existing, approved medications that have previously been indicated for conditions like schizophrenia and depression. By adjusting these existing drugs, they hope to be able to bring new treatments to the clinic faster.
Dirks notes that existing literature demonstrates a lower incidence of brain tumours in people with Parkinson’s disease than in other people of the same age who have sufficient amounts of dopamine. As a result, further research is being done to explore whether dopamine depletion may be a cancer suppressor in this population of patients with Parkinson’s.
Historically, the research into brain function and brain cancers have not overlapped very much, with the neurobiologists focused more on how other processes and conditions in the brain relate to their work, and oncologists primarily looking at how other types of cancer may influence brain cancer research. Dirks suggests that this paper may help bridge a longstanding gap between neurobiological and brain cancer research.
Glioblastoma affects about 1,500 adults and 150 children in Canada every year.
The lead author of this paper is Sonam Dolma. This study is a collaboration between SickKids, University of Toronto, University Health Network, and Université de Montréal.
Dirks also holds a Garron Family Research Chair in Childhood Cancer Research and is Professor in the Departments of Neurosurgery, Molecular Genetics, and Laboratory Medicine and Pathobiology at the University of Toronto.
This study was funded by the Ontario Institute for Cancer Research, the Canadian Cancer Society Research Institute, Genome Canada, Canadian Institutes of Health Research, Jessica’s Footprint, Hopeful Minds, B.R.A.I.N.child and SickKids Foundation.
Source of text and image: SickKids Hospital
Original research article:
Dolma S, Selvadurai HJ, Lan X, Lee L, Kushida M, Voisin V, Whetstone H, So M, Aviv T, Park N, Zhu X, Xu C, Head R, Rowland KJ, Bernstein M, Clarke ID, Bader G, Harrington L, Brumell JH, Tyers M, Dirks PB. Inhibition of Dopamine Receptor D4 Impedes Autophagic Flux, Proliferation, and Survival of Glioblastoma Stem Cells. Cancer Cell. 2016 Jun 13;29(6):859-73. doi: 10.1016/j.ccell.2016.05.002.