2016 Research Grant
July 2016- 2018
Round 18

Dr. Jason Berman from IWK was awarded $99,930 for his grant entitled "Stromal Antigen 2 (STAG2): A novel metastatic pathway in Ewing sarcoma".
Funded in partnership with the Ewings Cancer Foundation of Canada and Childhood Cancer Canada Foundation.

Awarded to Dr. Jason Berman
Summary Brief:

Many forms of cancer become most harmful when they spread from one location of the body to another (metastasis). Ewing sarcoma is a bone cancer in children and adolescents, and once it spreads, it becomes very difficult to treat. A better understanding of how bone cancer cells spread will enable us to prevent metastasis with new treatments. The zebrafish is an excellent model to study metastasis, as zebrafish are small, transparent, and genetically similar to humans.

They offer the complexity of a whole animal not found in studies of cells in a Petri dish. Human cells are easily transplanted into fish embryos and their see-through nature allows for direct tracking of cell movements not possible in mouse models.

We have developed techniques to directly transplant human cancer cells and measure their growth and spread within zebrafish embryos. Recently, the loss of a protein called stromal antigen 2 (STAG2) has been found to be associated with poor outcome in Ewing sarcoma.

We will use our zebrafish-transplant system to examine whether loss of STAG2 and its target proteins may contribute to the spread of Ewing sarcoma. Some of these proteins might serve as new treatment targets to prevent metastatic disease.

2014 Research Grants
June 2014- 2016
Round 16

Dr. Adam Shlien and Dr. David Malkin of The Hospital for Sick Children were awarded $100,000 for their research project "The Transcriptional Consequences of Somatic Mutation in Ewings Sarcoma". Funded in partnership with the Ewings Cancer Foundation of Canada and Childhood Cancer Canada Foundation.

In August 2014, Drs. Adam Shlien and David Malkin (Hospital for Sick Children) embarked on an ECFC and C17 Council funded research project with the exciting potential to advance the diagnosis and treatment of Ewing sarcoma. Whole genome sequencing (WGS) and other advanced genetic testing techniques have allowed their research team to delve into and paint a complete genetic picture of Ewing sarcoma. They are applying these genetic tests to Ewing sarcoma tumour samples, grouped by disease characteristics such as aggressiveness, treatment response, and outcomes, and are looking at similarities and differences in the genetic makeup and biology that separates these groups. If researchers can identify what genetic changes indicate characteristics such as more aggressive tumours or more favourable outcomes, they can help physicians personalize treatment options and move away from the current general, "one-size fits all" treatment approach. These differences also will direct researchers towards new drugs that target these specific genetic features, with the goal of developing new treatments that effectively control Ewing sarcoma tumour growth.

Now at the end of the official two-year grant, Ewing sarcomas from 78 patients have been sequenced using WGS and other technologies. Drs. Shlien and Malkin have generated complete and accurate maps of all the genetic changes in these patients' tumours and have used these maps to discover novel genetic changes and to start connecting patient genetics to tumour characteristics. They have discovered that the genetics of Ewing sarcoma are even more complex than imagined. This research is ongoing in the laboratories of Drs. Shlien and Malkin as they test additional patients, and use what they have learned to start answering questions such as "Does the degree of complexity predict tumour recurrence?" and "Do the changes in biology, caused by the genetic changes, cooperate to drive tumour growth?".

Interested in more details? Adam has shared that the results are exciting enough that they are keeping specific details under wraps until published. Stay tuned for a summary of their published paper.

Interested in how research like this moves out of the research laboratory and is used to help patients? Read on about the new Precision Medicine study that has been initiated in Canada. This study is working towards being able to connect Ewing sarcoma relapse patients to novel treatment approaches based on the genetic characteristics of their tumour.

Traditional anti-cancer treatment, or chemotherapy, is based on drugs that damage cells when they are actively multiplying; the faster a cell type multiplies the more sensitive it should be to these types of drugs. The fact that cancer is characterized by out of control cell multiplication is behind the theory that these drugs can be used at a level that kills the cancer cells at a faster rate than normal cells. Through testing of drug levels and combinations, treatments for different cancer types have been developed that, for most patients, kill the cancer cells while trying to minimize the damage to the rest of the patient's body.

If you have ever used a clinical trials database to look for treatment options, you may have noticed that a search for "Ewing sarcoma" does not identify all of the available clinical trials, particularly if you are looking for a "cutting-edge" new study drug for a patient who is not responding to current treatment or has relapsed. The specific search term does not work well because initial studies done with new drugs for non-responding pediatric tumours tend to be grouped into studies for solid tumours, blood cancers or brain tumours (or a combination of these). This illustrates the challenges with the one-size fits all approach that has been traditionally used to test new treatments, where a drug is used against all types of cancers to see if it might work in some.

Although great advances in survival in pediatric cancer have been made over the past 30 years using these approaches - up to 83% overall survival - there are cancer types such as aggressive Ewing sarcoma, that do not respond as well to the drugs that are currently available. The patients need more than the testing of new chemotherapy drugs. They need new and innovative treatment approaches.

Targeted therapy refers to an anti-cancer agent that is engineered to specifically hone in on a particular protein that is uniquely abnormal in the cancer cells; this concept holds the potential of being more successful in treating specific cancers more precisely than the 'one-size fits all' approach. To be effective, the agent targeting this protein must either trigger the death of the cancer cell or stop it from multiplying. A classic example is "BCR-ABL" in a specific form of leukemia - chronic myelogenous leukemia (CML). BCR-ABL is called a fusion protein because it is the result of chromosomes breaking and reattaching incorrectly (a translocation). The result is the fusion of the two genes, which in turn makes a protein that does not occur in normal cells. BCR-ABL sends out an uncontrolled signal to multiply. The drug Imatinib binds to BRC-ABL and stops this signaling; Imatinib and similar drugs have more than doubled survival rates for CML patients.

Eighty-five percent of Ewing sarcoma tumours carry another fusion protein called EWS-FLI1, and researchers know that shutting down EWS-FLI1 is capable of killing Ewing sarcoma cells in the lab. However, the resulting protein has proven difficult to target, and no drug that targets EWS-FLI has made it to the clinic. New approaches are required to targeting this fusion protein, or proteins with which it cooperates.

Research funded by ECFC, in partnership with the C17 Council, is laying the important groundwork required to help deliver these new approaches. The whole genome sequencing project of Drs. Adam Shlien and David Malkin from The Hospital for Sick Children (Toronto, Ontario) has painted a genetic picture of Ewing sarcoma (see research update in this issue) that may help to find new proteins that can be targeted with the potential to stop tumour growth. This genetic approach is not limited to looking for partners of EWS-FLI1, but allows Drs. Shlien and Malkin to look for new proteins, and combinations of proteins, to be targeted. What is exciting is that this research is opening the door for Precision Medicine (PM) for Ewing sarcoma patients, and paving the way for PM in many other relapsed and other hard-to-cure pediatric cancers.

More exciting news is that the Precision Medicine research in pediatric oncology is not limited to Ewingsarcoma. The KiCS (SickKids Cancer Sequencing Initiative) in Toronto, Pediatric POG (Personalized Oncogenomics) in Vancouver, and TRICEPS (Personalized Targeted Therapy in Refractory or Relapsed Cancer in Childhood) initiative in Montreal have all recently emerged as major national programs for genome-wide sequencing to identify actionable targets for incorporation into novel drug delivery for any child, adolescent or young adult with 'hard-to-cure' cancer on a patient-by-patient basis. A major effort has been initiated to consolidate these efforts in partnership with all the C17 pediatric oncology programs and numerous other stakeholders across Canada. More details will be available on these exciting initiatives in the next few months.

Precision Medicine
With each patient that has their tumour tested by WGS, more information is added to the knowledge-base and the better the approach works. For Ewing sarcoma, Drs. Shlien and Malkin have been building this knowledge-base for over two years and have tested over 78 Ewing sarcoma patients. This is a tremendous head start for Precision Medicine in Ewing sarcoma.

Precision Medicine for Canadian children and AYA with cancer is no longer a distant hope-it is visible on the horizon.

To learn more about Precision Medicine programs for children and AYA with cancer in Canada, visit these sites.

2012 Research Grant
July 2012- 2014
Round 14

Dr. Jason Berman of IWK Health Centre and Dr. Poul Sorensen of the University of
British Columbia were awarded $100,000 for their research project "Elucidation of YB-1 as a metastasis driver through angiogenic mechanisms in Ewing family tumours using zebrafish and mouse models". Funded in partnership with the Ewings Cancer Foundation of Canada, Childhood Cancer Canada Foundation and the Coast- to- Coast Against Cancer Foundation.

In initially funded in 2012, Dr. Jason Berman (IWK Health Centre) and Poul Sorensen (University of British Columbia) discovered that a protein called YB-1 promotes the spread of sarcoma and has potential as a new target for which drugs can be developed to prevent tumour spread. Also, they learned what communication pathways inside the cell are changed by YB-1; these pathways are also potential drug targets. If drugs can be found that slow the spread of Ewing Sarcoma, this disease will be easier to control and cure. This research was published in the highly prestigious journal Cancer Cell in May (2015). In follow-up to the identification of YB-1 as a potential drug target for Ewing Sarcoma, Berman and Sorensen are exploring other novel communication pathway that are required for tumour growth and spread-it is hoped that these studies will result in additional potential drug target for Ewing Sarcoma.

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Research results and publication references are posted as they become available.