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As Co-Director of the Krembil Brain Institute at Toronto Western Hospital, neurosurgeon Dr. Gelareh Zadeh is on a mission to prolong the lives of patients with glioblastoma, a very aggressive form of malignant brain tumour. Dr. Zadeh, who is also UHN's Head of Surgical Oncology, a neurosurgeon-scientist at Princess Margaret Cancer Centre and Program Medical Director for Krembil Neuroscience Centre, sat down with UHN News to discuss the recently published study she led which shows that a class of anti-fungal drugs may help block the growth of glioblastoma tumours.
Q: What can you tell us about glioblastoma?
A: Glioblastoma is the most common adult brain cancer. It remains the most lethal cancer, most malignant brain tumour, and is, unfortunately, incurable. From the time of diagnosis to the time that you pass away, it's approximately 18 to 20 months and the prognosis for patients has not changed significantly in the last decade or two. Being able to identify drugs that can effectively reach the tumour, prevent its progression and prolong a patient's survival is a huge area of unmet need.
Q: How are gliobastomas treated?
A: Currently the treatment is surgical resection, with as maximum a resection as possible, followed by chemo and radiation. Since glioblastomas are very vascular tumours, they create a lot of their own blood vessels and as a consequence, the thought has been, if you stop the blood vessels from forming, the tumour would stop growing. Unfortunately, in large clinical trials, blocking the blood vessels did not show a significant benefit. In fact, there has been some concern that there may be some detrimental, more aggressive tumour cells that emerge as a consequence of blocking the tumor vessel formation – referred to as anti-angiogenesis.
A more promising area that's being explored, is to look at how cancer cells metabolize glucose. Cancer cells in glioblastoma aren't focused on generating ATP, the units of energy. They're focused on using glucose to create proteins and factors that can allow them to tolerate harsher tumour micro-environments, such as low oxygen (hypoxia), high acidity (high-lactate), become more invasive, etc. So one approach is to see whether we can tackle the pathways that have altered metabolism, to make the tumour cells more vulnerable and stop their growth as a consequence. That is what our study examines. Specifically – can we attack that pathway and be able to halt the tumour's growth by altering its metabolism?
Q: What does your study show?
A: The study shows that there are compounds that can attack the metabolism of the glioblastoma cell and as a consequence, reduce the growth of the tumour cells. Hopefully, this could one day be a therapeutic option. The advantage is that we are using already existing drugs, and repurposing them for use in glioblastoma. This means we would not have to create a compound from scratch, which is a fairly large undertaking and needs many years of work before getting it to clinical trials. Instead, we are repurposing existing drugs that we know cross the blood-brain barrier and hopefully will have the desired effects.
Q: What is the next phase in this research?
A: Based on the work that we've done, we've taken the findings back to clinic and started a clinical trial. The clinical trial's design is very new to glioblastoma – using a neo-adjuvant, or a so-called Phase 0 design. The patient receives the drug prior to surgery. The reason to do that is to better understand if the drug is making it to the tumor, at the appropriate concentration and if it's having the desired effect. Neo-adjuvant studies are extremely rare in glioblastoma research.
Q: What could this mean for glioblastoma patients?
A: To put it into perspective, there are very few drugs for glioblastoma, that are FDA or Health Canada approved, outside of the traditional chemotherapies that we use. Being able to demonstrate that there is a drug or a compound that could potentially extend survival with a glioblastoma by even a few months, is quite impactful in the field. If we can give the compound prior to surgery, it will really be transformative in how we understand targeted therapy in glioblastomas, in general.
Q: As a neurosurgeon who treats glioblastoma patients every day, how exciting is this research for you personally?
A: This is probably one of the few opportunities where we've taken a compound that was tested in the lab and actually translated it into a clinical trial in glioblastoma. As a physician and a clinician-scientist, that's really completing the full cycle of why we do the research on a daily basis, to make a difference in the outcome of diseases we manage and especially, for our patients. So, having that ability and the opportunity to really test something that we've proven works in the laboratory in a clinical setting, makes a tremendous difference.