Ongoing RB Research

Dr. Rod Bremner| Dr. Helen Dimaras | Dr. Rob Downie | Dr. Ben Dunkley| Dr. Jennifer Steeves | The Human Visual Neuroscience Laboratory

Dr. Rob Bremner’s lab

Website | Publications

Our lab’s goal is to understand the molecular wiring that drives retinoblastoma and other tumors that lack the RB gene, then exploit those insights to develop new approaches both to treat and prevent these cancers.  Preventing cancer is important for those with familial retinoblastoma (a defective RB gene in every cell in the body) as they are at risk for other tumors later in life.  We use so-called “genomics” technologies to dissect the molecular wiring.  These techniques allow us to study many thousands of genes that are active or silent in a cell at once.  There are approaches to define which genes are on or off, which genes are up or down in cancer relative to normal tissue, we can study these effects even in single cells, and we have strategies to manipulate any gene that we think might be contributing to tumor growth.  We use cell culture systems to identify and study key genes, including human retinoblastoma cells or human fetal retina, and we can purify and study the specific retinal cells from which retinoblastoma arises. We also use human and mouse retinoblastoma samples to define disease progression.  This includes studying the difference between retina, retinoblastoma and a benign harmless version of the latter, called retinoma. We use mouse models of retinoblastoma to study the initiation and progression of the disease, allowing us to manipulate targets or signaling networks in vivo.  These models include genetic deletion of the RB gene in the mouse retina, or growth of human retinoblastoma cells in the murine eye.  Once we define key targets, we can then ask whether there are pharmaceutical (i.e. drug-based) strategies to cripple key regulatory hubs that are crucial to the cancer cells.

A useful analogy is to think of a cell as an electrical wiring diagram, but instead of wires and switches, there are genes and proteins. Our goal is to find the right wires or switches to cut.

Our work has led us to several new drug-based approaches for the disease.  One of these is at an advanced stage of “pre-clinical” development, meaning we have done numerous tests in vitro and in animals.  These include showing that we can deliver the drug at high enough concentrations to the retina in a large mammalian eye, which is encouraging as it should be viable in a child’s eye.  Another drug we are testing is showing excellent efficacy in mouse models of retinoblastoma, and we have also developed combinations of drugs that are even more effective.  In addition, we have several exciting new molecular insights that have exposed entirely new avenues to treat and prevent retinoblastoma.  For the strategy that is closest to the clinic we have established links with ophthalmologists, drug delivery experts, and the pharmaceutical industry so that once the safety and efficacy tests are complete we can begin to design and execute a clinical trial for the prevention of retinoblastoma in RB1+/- newborn children.   Patients and parents are, naturally, anxious to know how long it will take before a new treatment is available. Scientists and MDs, wanting to be helpful, often say things like “5 to 10 years”, but these are just wild, inaccurate guesses.  The process is actually very unpredictable; otherwise it would not be research.  Science is not like building a bridge, where the entire process can be mapped out and predicted quite accurately because all the steps are well

understood and it’s been done many times before.  Instead, science is like exploration:  You know where you want to go, you believe it exists, but it might not, and you will certainly meet unexpected barriers and problems on the way that could be solvable, or not. The vast majority of drugs that go into clinical trial fail because they cause more problems than they solve (toxicity), they fail to reach the target tissue/cell, and/or they are ineffective for one or more reason. The enormous complexities associated with drug development emphasize the need for more funding for high end research to provide more options.  More options, more chance of success. Columbus was not the first guy who tried to find the New World.  Funding excellent people doing cutting edge science is, literally, the only way forward.


 Dr. Helen Dimaras’ lab

Website | Pubmed | LinkedIn | Twitter

Dr. Dimaras’ research spans the disciplines of global health, cancer genetics and clinical science. Her studies have contributed to the understanding of the molecular genetic development of retinoblastoma. She is currently studying approaches to reduce the global retinoblastoma survival gap that results in poor survival in developing countries. Key initiatives include the establishment of a centralized digital pathology laboratory in Nairobi; design of comprehensive cancer genetics services to meet the needs of low-resource settings; and the development of a global retinoblastoma map, One Retinoblastoma World, to track patients and treatment resources worldwide.

Dr. Dimaras teaches undergraduate courses in genetics and global health within the U of T Human Biology Program, and a module on technology & innovation for global health within the Global Health Education Initiative at the Dalla Lana School of Public Health. Her interest in global health education has also led her to study the ethics of voluntourism and global health study abroad/service learning experiences.


Dr. Ben Dunkley

Website | Pubmed Twitter

Ben’s current research involves studying the role of brain oscillations and connectivity in cognition and perception in clinical populations. He uses brain imaging to measure these phenomenon in a number of different clinical groups spanning a variety of neurological and psychiatric conditions, including those who have had retinoblastoma. Ben studies these phenomena using magnetoencephalography, or MEG, which allows the firing of neurons in the brain to be non-invasively measured, either during rest or when performing a cognitive task. He integrates these measures with diffusion tensor imaging, or DTI, which tells us about the physical connections in the brain and how different areas are wired together. Using these technologies, and measures of behavior and perception, it is possible to examine the rewiring that takes place in the brain after enucleation and how this affects the development of brain networks at a critical juncture in life.


Dr. Rob Downie

LinkedIn

Rob is currently Manager, Institutional Research at Fanshawe College in London, Ontario. He leads a cross-functional decision support team providing data integration, analytics, and dashboard visualizations for operational and strategic research. His research is tied to retinoblastoma through studying stress and coping when a child has retinoblastoma.

Currently, child psychosocial oncology research offers limited examination of fathers’ and dyadic stress and coping. Dr. Downie completed a qualitative sociological study examines individual and dyadic stress and coping across 4 fatherhood role categories when their child is diagnosed/treated for Retinoblastoma. Using purposive sampling, 23 Canadian Rb couples and 7 unmatched parents completed individual in-depth, semi-structured interviews.

Findings confirm fatherhood role identity is diverse, influenced by the current situation, elements of discourse, and cultural references. Often contested in public and private spheres, fathering roles show transitional or permanent change tied to circumstance and dyadic support. In a stress process model, fathers primarily relied on problem-oriented and instrumental coping. Partners were the primary mediator of stress for all fathers, providing extensive emotional and informational supports. Using a systemic-transactional model of coping, most study dyads, or pairs, used positive coping strategies and were often supported by the extended clinical team and Social Worker. These dyads showed symmetrical coping that enhanced short and long term well-being. A life course perspective emerges for individuals with heritable Rb. Mothers focused on their child’s future health risk and Rb transmission to future generations. Fathers focused on possible socioeconomic disadvantage for their child. A disease-treatment matrix impacts the life course experience. Heritable Rb is referred to the single tertiary treatment centre in Canada. Regular travel from home and the absence of common social supports increases individual and dyadic stress for many affected parents.

Implications for clinical practice include the importance of face-to-face meetings with clinicians as a primary parent coping strategy. Fathers should be actively encouraged to attend Rb appointments with their partner and child whenever possible. Those that did so enhanced both individual coping and positive dyadic coping outcomes. After clinician information, parents preferred brief, plain language pamphlets and brochures for take-away information. These were commonly lacking and internet resources were the default information source for parents. Some Rb parents gain substantial informal informational and social support from peer parents. Social media is the emerging channel among younger parents for that informal peer support.


Dr. Jennifer Steeve’s lab

Website | PublicationsLinkedIn | Twitter

Our lab has been studying visual and auditory plasticity in individuals with one eye. We draw on a rare patient population who have undergone unilateral eye enucleation subsequent to retinoblastoma that has been diagnosed in the first few months of life. We have recently documented adaptive changes in auditory and audiovisual processing as a result of the loss of one eye early in life. This indicates cross-sensory plasticity in the visual system that is partially deafferented. We have also been examining the underlying neural substrates using magnetic resonance imaging (MRI). We have observed structural changes at the cortical and subcortical levels that indicate that the neural substrates in the one-eyed brain have been rewired. The plastic mechanisms may be multifaceted to include cellular atrophy on one hand and recruitment of deafferented cells on the other. Nonetheless, the behavioural plasticity in vision and hearing in people with one eye are supported by the morphological changes in the brain. In short, the loss of one eye does not impair daily function, but rather the brain is able to rewire itself to allow for full advantage of remaining vision and other senses.


 

The Human Visual Neuroscience Laboratory

Website

The Human Visual Neuroscience Laboratory is interested in understanding development and plasticity of the human visual cortex. Of relevance to retinoblastoma, we are investigating the impact of abnormal binocular vision on neural connectivity within the visual cortex. Our previous work involving behavioral measures of vision, neuroimaging and brain stimulation techniques has contributed to current understanding of visual processing in conditions ranging from perinatal risk factors such as prenatal drug exposure to amblyopia (“lazy eye”). Amblyopia is a condition in which unequal or mismatched visual input from two eyes during early childhood causes abnormal visual cortex development. We are particular interested in how the visual cortex develops with the complete absence of visual input from one eye, as is the case for patients who have undergone enucleation due to retinoblastoma. Currently, as part of an ongoing collaboration with the Hospital for Sick Children, we are studying neural connectivity within the primary visual cortex and associated brain areas of children who experienced unilateral enucleation at an early age. Primarily, we are interested in understanding how children with one eye perceive moving objects, since previous studies have reported motion perception deficits following uniocular development. Our preliminary results have supported the presence of abnormal motion processing. Through structural and functional magnetic resonance imaging and magnetoencephalography studies we are now exploring the neural basis for this abnormal motion processing.

Advertisements