A novel therapy to treat breast cancer

John A. Hassell, PI, McMaster University
Rima Al-awar, co-PI, OICR

We are developing a novel therapy to treat breast cancer involving serotonin, which we have shown is required for tumour growth. Serotonin is commonly associated with the nervous system, where it is made in specific nerve cells in the brain and then released to engage receptors on the surface of other nerve cells. Our research is focused on determining whether one of the serotonin receptors, which we have implicated in breast cancer, is required for breast tumour cell survival, and if it eliminates the gene encoding the receptor from breast tumour cells. Additionally, we are determining whether chemicals that specifically block the receptor can be developed into drugs to treat this disease.

Discovering drugs for the pediatric brain cancer diffuse intrinsic pontine glioma

Cynthia Hawkins, PI, The Hospital for Sick Children (SickKids)

Diffuse Intrinsic Pontine Glioma (DIPG) is a devastating brain tumour arising in the brainstem of children. Despite current multimodal therapies, DIPG remains incurable with a median survival of less than one year, making it the leading cause of brain tumour-related death in children. We now understand that DIPG has mutations in histone genes, which is a unique underlying biology making it distinct from other brain tumours. It also suggests this may be a good way to target the cancer cells. With the resources provided by the Cancer Therapeutics Innovation Pipelines, we will utilize high throughput screening to uncover drugs that have targets showing synthetic lethality with the mutant histone, allowing us to develop new treatment strategies for this devastating disease.

Targeting conserved ATPases to treat hepatocellular carcinoma

Walid A. Houry, PI, University of Toronto

Pontin and Reptin are two homologous and highly conserved ATPases. These ATPases have recently been implicated in carcinogenesis, especially in hepatocellular carcinoma, the most common type of liver cancer. In this project, high throughput activity assays will be used in a campaign to screen for inhibitors of Pontin and Reptin. The Houry group at the University of Toronto has biochemical and cell biology expertise working with Pontin and Reptin. This project could have important impact in developing new anticancer compounds against new protein targets.

An integrated functional genomics platform for the discovery and translation of novel immunotherapy targets for kidney cancer

Jason Moffat, PI, University of Toronto
Sachdev Sidhu, co-PI, University of Toronto

The ability to harness the power of the immune system (known as immunotherapy) to treat cancer has emerged as a one of the most promising strategies to invoke long-term cures for patients with advanced disease. Unfortunately, these dramatic responses to therapy are limited to a small subset of patients, with the majority developing resistance. By utilizing state-of-the-art CRISPR gene-editing technology, our proposal seeks to identify genes that are responsible for directly mediating resistance to immunotherapy and subsequently leveraging this information to develop novel antibody-based drugs that can be used together with existing immunotherapies to circumvent resistance. Our ultimate goal is to develop the necessary preclinical data required to support the clinical testing of our novel therapeutic strategy.

Development of screening assays for Cbl-b inhibitors

Rima Al-awar, PI, OICR
Jonathan Bramson, PI, McMaster University

An exciting and promising new avenue for cancer treatment is the inhibition of agents that promote immune evasion. Immune evasion is a strategy employed by tumors to escape the host immune system’s ability to recognize and destroy cancer cells. Immunotherapies including antibodies, transplanted stem cells, and engineered T-cells, vaccines, cytokines and T-cell checkpoint blockers have shown efficacy against hematologic and solid tumors. Owing to the complexity of immune evasion, combination protocols will likely be needed for optimal therapeutic management. Side effects associated with current immunotherapies, including severe autoimmune diseases, also support development of alternative immune-oncology agents. Thus, there is much interest among biotech, pharmaceutical companies and academic laboratories to find small molecules that promote anti-tumor immunity. A promising new target is a protein called Cbl-b, primarily expressed in immune cells (e.g., cytotoxic T-cells and Natural killer cells) and is critical to immune suppression. Loss of Cbl-b results in enhanced T-cell activation, hence, our goal is to identify small molecule inhibitors of Cbl-b.

Selection of guanine quadruplex binders for the RET promoter, towards novel therapeutics for RET-receptor associated cancers

Anne Petitjean, PI, Queen’s University
Lois Mulligan, PI, Queen’s University

The RET protein is a significant contributor to growth and spread of a number of cancers, including thyroid, pancreatic, breast and lung tumours, making it an important target for anticancer strategies. However, to date, there are no drugs able to act exclusively on the RET protein, and the current clinically used drugs also affect other vital processes, leading to side effects and a limited useful time window of treatment. This project aims to use a different approach to RET’s cancer-causing effects by reducing the production of the protein altogether. We have shown that reducing the levels of RET protein present can limit the growth and invasion of RET-associated cancers. We are therefore developing a library of small molecules aiming to interfere with the ability of the cell to make RET (at the DNA level). We will explore these small molecules using chemical, biophysical and biochemical assays. Our goal is to validate these assays against this important target, and identify a preliminary subset of serious candidates for further optimization, towards an application to RET-associated cancers in the clinic.

Developing novel kinase inhibitors for the treatment of glioblastoma

Rima Al-awar, PI, OICR
David Kaplan, co-PI, The Hospital for Sick Children (SickKids)

We aim to discover potent, selective, orally bioavailable small molecule inhibitors capable of crossing the blood-brain barrier to treat glioblastoma. The inhibitors will target a kinase involved in regulating pre-mRNA splicing and regulating cellular division. Genetic silencing of this kinase has been demonstrated to inhibit the proliferation and survival of a variety of cancers including diffuse large B-cell lymphoma, pancreatic, breast and colorectal cancer. Evidence coming from the lab of Dr. David Kaplan has also implicated this target in glioblastoma, a cancer for which new treatment options are desperately needed.

Developing novel inhibitors of the mitochondrial protease, ClpP

Aaron Schimmer, PI, Princess Margaret Cancer Centre
Rima Al-awar, co-PI, OICR

The mitochondrial protease, ClpP, rids mitochondria of excess and misfolded proteins. We showed that ClpP is over-expressed in a subgroup of acute myeloid leukemia (AML) patients. Inhibiting ClpP killed AML cells over normal cells in cell culture models and in mouse models of leukemia. In collaboration with the OICR Drug Discovery team, we are developing small molecule ClpP inhibitors as leads for potential new therapies for this hard-to-treat blood cancer.

Targeting lipid-degrading enzymes in cancer chemotherapy

Gil Privé, PI, Princess Margaret Cancer Centre

Some of the lipids that make up the membranes of our cells have roles in determining whether our cells remain stable, grow or die. Some cancer cells have abnormal lipid profiles, and this contributes to their aggressive growth properties. This is particularly true of cancer cells that no longer respond to chemotherapy or radiotherapy. We will develop drugs that will selectively kill cancer cells by reducing the levels of growth-promoting signaling lipids. We expect that these drugs will be able to treat multiple cancers, including melanoma, prostate cancer and leukemia.

Identification of kinase inhibitors to block the tumour-promoting activity of YAP/TAZ for cancer therapeutics

Liliana Attisano, Principal Investigator, University of Toronto
Rima Al-awar, Principal Investigator,OICR
The highly conserved Hippo pathway is a key regulator of cell and tissue growth. Virtually all solid tumours display pathway disruptions, which drive cancer initiation and progression. Mutations in pathway components are rare, making it unclear how to target the pathway for cancer treatment. This research group has shown that certain kinases are key regulators of the pathway that promotes tumorigenicity and observed that diverse human cancers display elevated levels of these kinases. Kinases are highly amenable to the development of targeted inhibitors; therefore, this project will identify potent and specific inhibitors with the long-term goal of establishing novel cancer therapeutics.

Development of kinase inhibitors for ovarian cancer: A novel first in-class immune-oncology therapeutic agent targeting tumor intrinsic stress states

Rob Rottapel,  Principal Investigator, Princess Margaret Cancer Centre
Tracy McGaha,  Principal Investigator, Princess Margaret Cancer Centre
Rima Al-awar,  Principal Investigator, OICR

The development of new cancer immune therapeutics has triggered a revolution with the recent advent of diverse strategies that engage the patient’s immune system. This research group has identified a novel kinase target that has the unique property of being both an emergent essential gene in high-grade serous ovarian cancer and a repressor of the innate and adaptive immune system. Additionally, they have demonstrated that target inhibition sensitizes cancer cells to cisplatin – a standard of care chemotherapy drug. This project will work to develop a “first-in-class” dual-action, anti-tumour and immune-oncology kinase inhibitors for ovarian cancer and potentially other cancer types.

Unique and selective targeting of cdk activity in aggressive carcinomas

Lisa Porter, PI, University of Windsor
John Trant, PI, University of Windsor

As tumours progress they accumulate mutations making them increasingly aggressive and resistant to therapies. Many of these mutations cripple the normal protective cellular mechanisms that halt cell growth and trigger the death of cells with damaged DNA. Reinstalling these protective pathways represents an attractive mechanism to sensitize some of the most aggressive cancer cells to treatment. One family of protective proteins lost or blocked by aggressive cancers are Cyclin Dependent Kinase Inhibitors (CKIs). Basic research and pharma development have led to synthetic CKIs, which have seen variable success in the clinic. One issue not considered by these drugs, is the existence of Speedy/Ringo, a family of proteins capable of overriding CKI activity. Spy1, a member of this family, is elevated in many aggressive cancers. Pre-clinical data in cells and animals supports our contention that developing drugs to block Spy1 function is a promising therapeutic approach. This project will support an interdisciplinary team of researchers well positioned to make advances in developing compounds to block the mechanism of Spy1 through a rational drug design program. This project focuses on a critical step in that process, developing a high-throughput assay to screen for the most effective compounds in a cost- and time-effective manner.

An ALK2 inhibitor for diffuse intrinsic pontine glioma

Aled Edwards, PI, Agora Open Science Trust
Rima Al-awar, co-PI, OICR
Paul Brennan, SGC Oxford, Oxford, UK

Agora Open Science Trust, OICR and a range of collaborators from around the world are launching a drug discovery program to create affordable precision medicine for diffuse intrinsic pontine glioma (DIPG). This project is groundbreaking in two ways: it seeks to develop a new medicine specifically for children’s cancer and it pioneers “open science” not only to accelerate medicinal discovery, but also to validate open science as a viable corporate model that will allow Agora Open Science Trust to lower discovery and development costs and enable more affordable pricing of the marketed medicine.

Designer drugs for brain tumours

Donald Weaver, PI, Krembil Research Institute
Christopher Paige, co-PI, Princess Margaret Cancer Centre

Glioblastoma multiforme (GBM) is a devastating form of brain cancer. There is a need to devise new, innovative therapies for this type of cancer. A relatively new approach is to manipulate the immune system within the brain to inhibit tumour growth. We will achieve this goal using computer-aided drug design. We have targeted a protein that regulates the immune system in the brain. By developing detailed three-dimensional maps of this protein, we are designing drugs to bind to this receptor and to function as new therapies for the treatment of GBM.

Developing inhibitors of a novel kinase target for cancer immunotherapy

Rima Al-awar, PI, OICR

We aim to discover potent, selective and orally bioavailable small molecule inhibitors of a kinase which is involved in negatively regulating the proliferation of primary T-cells in response to T-cell receptor stimulation. We believe that inhibiting this kinase may amplify the anti-tumour activity of immune cells and could prove to be synergistic with current and future immunotherapies.