Ever used a jam jar as a coin bank? Or a worn-out boot as a planter? Giving old household items a new purpose is an easy and cost-effective way to solve a problem.
In rare cases, a drug developed to treat one disease is also found to be effective against another disease. However, when it comes to repurposing drugs, the stakes are often a matter of life and death, and hundreds of millions of dollars can be saved in the drug discovery process.
Dr. Gelareh Zadeh, Medical Director of the Krembil Brain Institute, Scientist and Neurosurgeon in the MacFeeters-Hamilton Neuro-oncology Program, recently discovered that two antifungal drugs hold great promise for treating glioblastoma multiforme (GBM)—the most aggressive and common form of brain cancer. This work was recently published in the journal Clinical Cancer Research.
“GBM unfortunately and sadly remains an incurable cancer and survival time from diagnosis is typically 18 to 20 months. Currently the treatment is surgery followed by chemo- and radiation therapy,” explains Dr. Zadeh. “There are very few drugs for GBM outside of traditional chemotherapies. Being able to identify drugs that effectively reach the tumour, prevent its progression and prolong patient survival is really quite critical.”
Dr. Zadeh and her team screened thousands of existing drugs for their potential to control the growth of tumour cells in the brain, before identifying the two drugs: ketoconazole and posaconazole. These drugs possess a key characteristic required to treat GBM: they can enter the brain from circulating blood through the blood-brain barrier, a highly selective filter between the brain and rest of the body.
The two drugs are effective against fungal infections because they prevent the fungus from making a key molecule that helps maintain its shape. Dr. Zadeh’s team showed that the drugs also hinder the growth and progression of GBM, but through a different mechanism: they interfere with the metabolism of tumour cells.
“Based on these results, we have started a new clinical trial. We are using a rather unexplored clinical trial design for GBMs where we first give the drug to the patient before we take the patient into surgery. Once the tumour is removed, we then test whether the drug made it to the tumour, had the desired penetrance into the tumour and had the desired impact on tumour growth,” adds Dr. Zadeh.
“If we can show that giving the drug before surgery leads to better outcomes, this will really transform how we manage GBMs. The hope is to be able to control the tumour without need for surgery at all.”
This work was supported by the Canadian Institutes of Health Research and The Princess Margaret Cancer Foundation.
Agnihotri S, Mansouri S, Burrell K, Li M, Mamatjan Y, Liu JC, Nejad R, Kumar S, Jalali S, Singh S, Vartanian A, Chen EX, Karimi S, Singh O, Bunda S, Mansouri A, Aldape K, Zadeh G. Ketoconazole and Posaconazole Selectively Target HK2 Expressing Glioblastoma Cells. Clin Cancer Res. 2018 Oct 15. doi: 10.1158/1078-0432.CCR-18-1854.
Dr. Dafna Gladman received the Distinguished Clinical Investigator Award from the American College of Rheumatology. This award is given on an annual basis to a clinical scientist who has made outstanding contributions to rheumatology, a branch of medicine devoted to arthritis and other diseases of the joints, muscles and ligaments.
Dr. Gladman is a world-renowned Rheumatologist and a Senior Scientist at the Krembil Research Institute. Her research program focuses on the prognosis, genetics and treatment of rheumatic diseases, especially psoriatic arthritis, systemic lupus erythematosus and rheumatoid arthritis. Over her 40-year career, her work has produced over 740 publications which have appeared in prestigious medical journals including the New England Journal of Medicine, The Lancet and Annals of the Rheumatic Diseases.
The American College of Rheumatology is a global medical society committed to improving care for the rheumatic diseases. It comprises 9,600 physicians, health professionals and scientists.
Congratulations Dr. Gladman!
University Health Network (UHN) is once again ranked first on the 2018 Canada’s Top 40 Research Hospitals list. The list of top research hospitals across Canada is compiled annually by RE$EARCH Infosource Inc. UHN has appeared in the top position of the list every year since its inception in 2011.
UHN’s research expenditures for the 2017 fiscal year were $350.1 million, representing 17.3% of its total hospital expenditures and an increase of 5.4% over the previous year. The Hospital for Sick Children and Hamilton Health Sciences round out the top three, with research expenditures of $209.6 and $206.95 million, respectively.
“UHN is proud to have been at the top of the list since 2011. This ranking demonstrates the value of research at UHN, in Toronto and across Canada. It is also a testament of the sustained dedication to improving and innovating health care held by UHN and its three sister foundations—the Toronto General & Western Hospital Foundation, The Princess Margaret Cancer Foundation and the Toronto Rehab Foundation,” says Dr. Brad Wouters, Executive Vice President, Science and Research at UHN.
In terms of research intensity, which measures the amount of research spending per appointed researcher, UHN placed second in the “Large Hospitals” category—climbing two spots from last year’s ranking. The top Canadian research hospital in this ranking was London Health Sciences Centre/St. Joseph’s Health Care Centre.
To view the complete list of Canada’s Top 40 Research Hospitals, click here.
RE$EARCH Infosource Inc. is a leading research, consulting and publishing firm that specializes in the areas of policy, research, business intelligence and analysis on science, technology, innovation and the Canadian R&D ecosystem. The firm also publishes an annual ranking of Canada’s Top 50 Research Universities; UHN’s affiliated university, the University of Toronto, is ranked first on this list.
A map of the cells in the human liver has been created, revealing the most comprehensive inventory of the different cells present in the liver and the differences between individual cells at the molecular level.
“For the past 20 years, we have studied the liver as a soup of cells as opposed to its individual components. This makes it difficult to target individual cells that are driving liver disease,” says Dr. Sonya MacParland, a Scientist at UHN’s Toronto General Hospital Research Institute (TGHRI), and lead author of the study published in Nature Communications.
To address this issue, Dr. MacParland and her research team used state-of-the-art genetic approaches and software engineering to map out the cellular landscape of 8,444 individual cells obtained from the tissues of healthy deceased donor human livers.
The project involved over 30 multidisciplinary experts, including transplant surgeons, immunologists, hepatologists, computer scientists and genomics researchers such as TGHRI Senior Scientist Dr. Ian McGilvray and Dr. Gary Bader, Professor at the University of Toronto’s Donnelly Centre for Cellular and Biomolecular Research.
By examining the gene expression profiles of each of the cells—about 1,500 active genes per cell—the research team found 20 distinct cell populations, including hepatocytes, endothelial cells, cholangiocytes and various immune cells such as B cells, T cells and natural killer cells.
They also discovered two new distinct populations of macrophages, known as tissue-resident macrophages. Commenting on this finding, Dr. McGilvray says. “Until this study, very little was known about the liver macrophage—the ‘tank’ of the immune system that destroys foreign substances and co-ordinates the immune response. We found that there are two distinct populations of macrophages in the human liver, one which is pro-inflammatory and the other anti-inflammatory.” This new understanding may help scientists identify new strategies to reduce organ rejection in liver transplant recipients or reduce the need for immunosuppressive medications.
While it provides a detailed picture of the cells in a healthy human liver, as the map is refined, future studies will compare these cells to those in a diseased liver, providing further insight into health and disease.
This work was supported by the University of Toronto’s Medicine by Design initiative which receives funding from the Canada First Research Excellence Fund, UHN’s Transplant Program, and the Toronto General & Western Hospital Foundation. G Keller holds a Tier 1 Canada Research Chair (CRC) in Embryonic Stem Cell Biology; JE Fish holds a Tier 2 CRC in Vascular Cell and Molecular Biology; and MD Wilson holds a Tier 2 CRC in Comparative Genomics. The findings from this study will be made available to the Human Cell Atlas Project, an international, open-access, collaborative effort to map all human cells (www.humancellatlas.org).
MacParland SA, Liu JC, Ma XZ, Innes BT, Bartczak AM, Gage BK, Manuel J, Khuu N, Echeverri J, Linares I, Gupta R, Cheng ML, Liu LY, Camat D, Chung SW, Seliga RK, Shao Z, Lee E, Ogawa S, Ogawa M, Wilson MD, Fish JE, Selzner M, Ghanekar A, Grant D, Greig P, Sapisochin G, Selzner N, Winegarden N, Adeyi O, Keller G, Bader GD, McGilvray ID. Single cell RNA sequencing of human liver reveals distinct intrahepatic macrophage populations. Nat Commun. 2018 Oct 22;9(1):4383. doi: 10.1038/s41467-018-06318-7.