2017 Invest in Research Winners


Dr. Aaron D. Schimmer, Senior Scientist
TARGETING THE “GARBAGE DISPOSAL SYSTEM” IN LEUKEMIA CELLS

Dr. Schimmer proposed using a cell’s so-called garbage disposal system to treat Leukemia. His method involved targeting the enzyme that puts the cell’s garbage into garbage bags, and leads to the cell’s death. He chose this method because it showed promise in killing leukemia cells without harming normal cells or organs. This is important research with tremendous potential to change practice and improve outcomes in AML.
 
Preliminary tests, in petri dishes and mouse models, were promising and secured an opportunity to collaborate with Takeda Pharmaceuticals to develop the world’s first drug of this nature and start a clinical trial to treat patients with relapsed and refractory acute myeloid leukemia (AML). The drug is a molecule called TAK-243.
 
Using mouse models to study response to treatment, Dr. Schimmer’s team treated half of the mice with the TAK-243 molecule and did not treat the other half. When they examined the mice a few weeks later, the mice that received treatment had almost no cancer remaining while those that were not treated experienced even more tumour growth. They were thrilled to confirm that TAK-243 had inhibited the growth of leukemia in mice!
 
In addition to the breakthrough findings of this project, Dr. Schimmer and his team were able to secure a $2 million commitment from the National Institute of Health to fund this trial and protocol in Toronto and also centres in the USA. They are now set up to lead a multi-centre International trial that will evaluate the drug TAK243 (Ubiuitin E1 inhibitor) in patients with relapsed leukemia.
 
DELIVERABLES
Through the Invest in Research grant, Dr. Schimmer and his team were able to deliver the following:
  •  Publication in a high impact publication in a medical literature
  •  Launch a clinical trial for AML patients
  • Uncover a new biology about the important pathway related to cell functions
  • Spark international collaborations
  • Secure $2 million in additional support to continue this work
  • Train the next generation of scientists
 Dr. Schimmer’s research doesn’t stop here. He plans on taking the learnings from this project further by trying to understand how the drug is blocking its target and whether this would lead to damaging effects to other normal cells. He also wants to understand why some patients may or may not respond to the drug and use this knowledge to make the next generation of molecules that can overcome drug resistance.


Dr. Vuk Stambolic, Senior Scientist
A MOLECULAR MECHANISM OF PANCREATIC CANCER ASSOCIATION WITH HYPERINSULINEMIA

Dr. Stambolic was interested in investigating the relationship between hyperinsulinemia and pancreatic cancer, because increased insulin and diabetes are associated with greater risk, aggressiveness and disease recurrence. His proposal was based on existing knowledge that obesity can increase the body’s level of insulin and lead to the development of diabetes.
 
The two objectives Dr. Stambolic hoped to address were:
 
1) Determine the extent of obesity-hyperinsulinemia-insulin receptor association in pancreatic cancer.
2) Model the obesity-hyperinsulinemia-insulin receptor relationship in cells and mice.
 
Insulin receptors are normally found in muscles, fat and liver. However, Dr. Stambolic’s prior work in breast cancer showed that 90% of breast cancer cells also had insulin receptors. Within a cohort of 165 patients that were studied, 65% of tumours expressed insulin receptors and 45% of these tumours expressed high levels of insulin receptors. This led Dr. Stambolic to believe that insulin receptors may be contributing to the severity of pancreatic cancer in these patients.
 
The pancreas has special beta cells that produce insulin. Since the cells that produce tumour and those that produce insulin are in close proximity to each other, the tumour producing cells in the pancreas are bathing in higher levels of insulin compared to other tumour producing cells in the body.
 
Another thing Dr. Stambolic investigated was knocking out PTEN, a tumour suppressor, in pancreatic tumour cells and noticing an increase in their growth. Using the CRISPR genetic alteration technology, Dr. Stambolic’s lab genetically engineered pancreatic tumour cells that lacked PTEN, injected them into the mice, and fed the mice a high fat diet to observe the rapid growth of the tumour. The mice were later treated with drugs that counter insulin to decrease the growth of the tumour.
 
DELIVERABLES
  • Uncovered the correlation between insulin receptors being present in pancreatic tumour cells and the severity of the disease
  • Based on the results of the study made possible by the Invest in Research grant, Dr. Stambolic was able to submit an application for an Impact Grant worth $1.25 million.