All too often individuals with cancer hear the term ‘drug resistance’—i.e., when cancer cells acquire the ability to survive and grow in the presence of drugs designed to kill them. Resistance is a serious problem for those with acute myeloid leukemia (AML)—an aggressive cancer of the blood and bone marrow.
About a third of AML cases do not respond to conventional chemotherapy, and many cancers that respond well to treatment initially, eventually worsen as the cancer becomes resistant. Unfortunately, next-generation therapies that have proven effective in treating AML also face the same challenge of resistance. One such example is a new drug known as venetoclax, which has shown promise in several types of blood cancers.
Princess Margaret Cancer Centre’s Dr. Steven Chan and his team sought to address this issue by finding a way to combat venetoclax resistance in AML. To do this, the researchers performed a large genetic screen and discovered that turning off genes that are essential to the function of mitochondria—tiny structures in the cell that produce energy—made leukemia cells more sensitive to the drug.
“These findings are clinically translatable as many of the commonly used antibiotics that are prescribed for bacterial infections interfere with mitochondrial function. Because antibiotics are already clinically approved, we saw an opportunity to combine them with venetoclax to see whether leukemia cells would be less resistant,” explains Dr. Chan.
Using experimental models of human AML, the team showed that the combination of venetoclax with antibiotics was more effective in killing leukemia cells than venetoclax alone. The addition of another anticancer drug that inhibits DNA modification further heightened cancer cell death.
“Future work will focus on testing this new drug combination in patients within a clinical trial setting, which we hope will demonstrate improved clinical outcomes for adults with AML,” says Dr. Chan.
To watch a video of Dr. Chan describing his research study, click here.
This work was supported by the Cancer Research Society, the Leukemia and Lymphoma Society of Canada, the Canadian Institutes of Health Research, and The Princess Margaret Cancer Foundation.
Sharon D, Cathelin S, Mirali S, Di Trani JM, Yanofsky DJ, Keon KA, Rubinstein JL, Schimmer AD, Ketela T, Chan SM. Inhibition of mitochondrial translation overcomes venetoclax resistance in AML through activation of the integrated stress response. Sci Transl Med. 2019 Oct 30. doi: 10.1126/scitranslmed.aax2863.
Obesity is often an inherited condition. Many of those who are living with obesity also experience mental health concerns or illnesses. Researchers around the world are trying to understand the underlying factors for why these conditions often go hand-in-hand.
Dr. Satya Dash, Scientist at Toronto General Hospital Research Institute (TGHRI), is using genetic analysis to explore the association between obesity and a variety of mental illnesses.
To do this, Dr. Dash and his team conducted genetic analyses in 149 individuals that were referred to weight loss surgery at the University Health Network. Around 80% of these individuals had experienced mental health concerns. The team found that some rare genetic changes, which were previously associated with conditions such as bipolar disease, schizophrenia and autism, were more common in these individuals.
To confirm that the identified genetic changes were associated with both obesity and mental illnesses, Dr. Dash, in collaboration with Drs. Rachel Batterham and Ingrid Dahlman, compared his results with those from genetic studies of obese patients in the United Kingdom and Sweden.
“We compared our data with these studies because they excluded those with either any mental illness or those with severe mental illness. We did this so that we could see whether exclusion of individuals with mental illness affected the occurrence of genetic changes that we identified,” says Dr. Dash.
As expected, the study that excluded severe mental illness had less of the identified genetic changes, and the study that excluded all mental illness did not have any of the genetic changes. These results support the idea that rare genetic changes identified by Dr. Dash’s team may contribute to both conditions.
Dr. Dash comments, “I hope that these findings help remove some of the stigma associated with living with obesity and mental health concerns, which have a strong genetic basis. The next step will be to translate these findings into effective treatments for patients affected by extreme obesity and mental illness.”
This work was supported by Diabetes Canada, the Banting & Best Diabetes Centre, the Toronto General Hospital Research Institute, the National Institute for Health Research (UK) and the Rosetrees Trust. A Bassett holds a Tier I Canada Research Chair in Schizophrenia Genetics and Genomic Disorders.
Stahel P, Nahmias A, Sud SK, Lee SJ, Pucci A, Yousseif A, Yosseff A, Jackson T, Urbach DR, Okrainec A, Allard JP, Sockalingam S, Yao J, Barua M, Jiao H, Magi R, Bassett AS, Paterson AD, Dahlman I, Batterham RL, Dash S. Evaluation of the Genetic Association Between Adult Obesity and Neuropsychiatric Disease. Diabetes. 2019 Sep 10. doi: 10.2337/db18-1254.
Radiation treatments are now being generated using artificial intelligence (AI) for prostate cancer patients at the Princess Margaret Cancer Centre. This advancement is the culmination of years of research led by medical physicist Dr. Tom Purdie and computer scientist Dr. Chris McIntosh of the Techna Institute, in collaboration with RaySearch Laboratories’ in-house machine learning department.
Radiation therapy is required in approximately 40% of cancer cases. Each patient receiving radiation therapy needs a treatment plan, which must carefully balance the delivery of radiation to the tumour while minimizing the dose received by nearby healthy organs. Each patient’s body shape and cancer are unique, so creating the plan traditionally requires a team of professionals working for hours or even days.
The AI planning system developed by Drs. Purdie and McIntosh dramatically reduces the time and associated costs required to generate radiation treatments: it can create a high-quality treatment plans in just minutes. The system uses AI that compares patients’ medical images with a database of previously high-quality treatment plans created by experts at Princess Margaret. It can then use the information contained in the previous treatment plans to generate a new plan that is personalized to the patient. A preliminary study presented by radiation oncologist Dr. Alejandro Berlin, the clinical lead of the work, found that AI treatment plans were preferred or found equivalent to human-generated treatment plans that had been used for patient care in 88% of cases according to a panel of clinical experts.
The system is now being used to generate plans for patients under the direction of Dr. Berlin. Every patient with localized prostate cancer treated at the Princess Margaret Cancer Centre now has two plans created for them: one using the traditional manual system and another using the new machine-learning automated system. A physician reviews both plans, and chooses one for further review and quality assurance before it is used to guide radiation therapy for the patient.
For more information please see the press release from RaySearch Laboratories.
A study led by Krembil Senior Scientist Dr. Robert Inman reveals key differences between immune cells in the joints of healthy individuals and those with a form of arthritis known as ankylosing spondylitis.
The study was initiated to shed light on why new treatments are providing mixed results. “We have made great strides in understanding the underlying cause of this form of arthritis, which affects the joints in the spine. Specifically, we have found that the immune system in the gut may drive the disease. However, new therapies that target the cross talk between the gut and inflamed spinal joints have failed to improve symptoms in all patients,” says Dr. Inman.
With the ultimate aim of refining treatment approaches, Zoya Qaiyum in Dr. Inman’s lab examined the immune cells in affected joints. She studied proteins on the surface of immune cells known as integrins. These proteins can be seen as the traffic police of the immune system: they direct immune cells as they move between different tissues.
When comparing immune cells in healthy individuals with those with ankylosing spondylitis, Zoya found heightened levels of an immune cell—known as a CD8+ T cell—in individuals with arthritis. Furthermore, these cells have a unique combination of different integrins on their surface.
“Interestingly, some of these integrins are also found on immune cells in the gut. This suggests that the CD8+ T cells that we identified may be involved in the cross talk between the gut and the spine,” says Dr. Inman.
Future research will establish the role of this unique cell population in disease with the aim of fine-tuning immune-based therapies and maximizing benefits to patients.
This work was supported by the Canadian Institutes of Health Research, the University of Toronto, and the Toronto General & Western Hospital Foundation.
Integrin and transcriptomic profiles identify a distinctive synovial CD8+ T cell subpopulation in spondyloarthritis. Qaiyum Z, Gracey E, Yao Y, Inman RD. Ann Rheum Dis. 2019 Nov. doi: 10.1136/annrheumdis-2019-215349.
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