2019 Invest in Research Winners

Dr. Phedias Diamandis

Growing Artificial Human Brains to Refine Glioblastoma Drug Development Efforts

Glioblastoma (GBM) is the most common and aggressive form of brain cancer, killing most patients within 12- 15 months of diagnosis. Unfortunately, despite numerous clinical trials, this grim outlook has only marginally improved over the past 50 years. However, while traditional GBM models have largely considered this disease to be comprised of identical tumour cells, new research shows that GBM is instead a mix of biologically distinct cell types.

One GBM subpopulation is known to share many of the biological properties of “stem cells,” primitive cells that facilitate the growth and cell diversity of our body during early life. These “cancer stem cells” have shown to be the driving force in GBM growth and highly resistant to traditional therapy. This may explain why drugs developed to target the overall cancer biology, and not specifically designed to kill cancer stem cells, eventually lead to recurrence and treatment failure. Unfortunately, stem cell biology, especially within the human brain, has been relatively inaccessible and difficult to study in laboratories.

To overcome this, Dr. Diamandis’ team will take advantage of recent advances in tissue bioengineering to grow artificial human brain-like tissue, known as “cerebral organoids,” to better understand how stem cells regulate their growth and survival. We hope that the parallels between normal and cancerous stem cells will help scientists discover new and more effective therapeutic targets for patients with GBM.

By studying the protein changes of these cells as they mature using a technology known as mass spectrometry, the team will be able to pinpoint the most important molecules stem cells rely on to carry out their functions. Similarly, they will take advantage of chemicals known to activate that excess stem cell migration to better understand shared pathways that normal and cancer stem cells use to seamlessly migrate through the brain. The most relevant and promising pathways identified using these tools will be then validated in patient-derived GBM tissue and GBM cells infiltrating through organoids.

Dr. Diamandis’ group is optimistic that these sophisticated artificial brains will help uncover more relevant stem cell-specific biology, which can be leveraged to develop therapies that effectively destroy GBM stem cells and ultimately lead to improved outcomes for patients with GBM in future clinical trials.

Dr. Marianne Koritzinsky

Mechanisms of PRDX4 addiction in pancreatic cancer

Patients with pancreatic cancer have a five-year overall survival rate of 7%. There is a dire need to better understand pancreatic cancer cell biology and develop new treatments.

We have discovered that peroxiredoxin 4 (PRDX4) is an essential protein in half of pancreatic cancer cell lines derived from different patients. Targeting this protein leads to cancer cell death without major consequences for non-cancer cells. Targeting this protein may therefore help some pancreas cancer patients without causing serious side effects.

In this project we will find out why only half of cancer cell lines depend on PRDX4 for their survival. This is important because this knowledge will help us: (i) design strategies to prevent resistance to PRDX4 targeting; (ii) develop ways to identify which patients will benefit from targeting PRDX4. PRDX4 is an anti-oxidant protein that helps cancer cells combat oxidative damage. Our previous research suggests that it is how cancer cells use nutrients for their metabolism that determines if PRDX4 is important for their survival. Some cancer cells have high metabolic activity that creates damaging oxidants and a dependency on anti-oxidants like PRDX4.

In this project we will find out exactly which enzymes are responsible for the high oxidant production. We will use this knowledge to manipulate cancer cells to be more dependent on PRDX4 and die when PRDX4 is targeted. We will also use this knowledge to create tests that will identify patients who will benefit from PRDX4 targeting.

We believe that our research will propel development of new personalized treatment options for pancreatic cancer patients, and lead to better outcomes for this devastating disease.