February 21, 2019
OICR supports cancer drug discovery in Ontario with new funding for four promising early-stage projects
Toronto (February 21, 2019) – The Ontario Institute for Cancer Research (OICR) today announced that four Early Accelerator projects from across Ontario will each receive $100,000 for one year as part of OICR’s Cancer Therapeutics Innovation Pipeline (CTIP) initiative. The funding will be used to validate cancer targets and support experiments to screen molecules against these targets, finding those that can bind to them successfully and have potential to be developed into medicines.
CTIP is an OICR initiative that supports the local translation of Ontario discoveries into therapies with the potential for improving the lives of cancer patients. This round of funding will add to CTIP’s existing pipeline of promising molecules in development, attracting partnerships and investment to the province that are necessary for further clinical development and testing.
“These projects are great examples of the innovative thinking that is driving the success of Ontario’s cancer drug discovery sector,” says Dr. Laszlo Radvanyi, President and Scientific Director of OICR. “We are proud to support these teams, based at nine research centres across the province, and we are excited to help them progress their research towards better helping cancer patients.”
The four projects are aimed at discovering treatments for a number of cancer types, including breast, brain, thyroid, pancreatic, lung and ovarian cancers. One project aims to improve the effectiveness of a type of immunotherapy, called CAR-T therapy, in which a patient’s immune cells are reprogrammed to detect and attack cancer cells. CAR-T therapy has shown much promise in the treatment of some types of blood cancers, but has not yet been as effective in the treatment of solid tumours.
Drs. Scott McComb, National Research Council of Canada, and Naoto Hirano, University Health Network, will work to develop an improved CAR-T therapy by isolating a llama-derived antibody that will selectively bind to a specific protein present in aggressive solid tumours, allowing the patient’s immune cells to attack the cancer.
“This funding will enable us to take the first steps towards our goal of creating a new type of CAR-T therapy to treat some of the most aggressive forms of cancer, such as pancreatic and ovarian cancer,” says Hirano, who is also an OICR Clinician-Scientist. “We believe that our approach of using camelid antibodies, which are smaller than the mouse-derived antibodies typically used, could result in a major advancement in the use of CAR-T therapies for solid tumours.”
The four funded projects were selected from 18 applications by a panel of international experts in drug discovery and development. The teams comprise of 14 scientists based at nine research centres across Ontario. In addition to financial support, the awardees will benefit from the guidance of the Therapeutics Pipeline Advisory Committee, a group of industry and academic experts that provides advice on the scientific and strategic direction of CTIP projects.
Furthering the CTIP program, OICR recently launched its third funding competition, which will provide up to $250,000 in funding per year for up to two years to Late Accelerator projects. These projects focus on screening, using validated primary and secondary assays, and to deliver confirmed ‘hit’ molecules against a defined target. The deadline to submit letters of intent is February 26. More details about the competition are available at OICR’s funding opportunities page.
Cancer Therapeutics Innovation Pipeline funded Early Accelerator projects
Development of mesothelin-specific single domain antibody targeted chimeric antigen receptors
Scott McComb, PI, National Research Council and University of Ottawa
Naoto Hirano, PI, University Health Network
Risini Weeratna, Co-investigator, National Research Council
Mehdi Arbabi, Co-investigator, National Research Council and Carleton University
Jennifer Hill, Co-investigator, National Research Council
Although chimeric antigen receptor-reprogrammed T cell (CAR-T) immunotherapies have been successful in treating blood cancers, they have been less successful in the treatment of solid tumours due to low ability to discriminate between tumour cells and healthy patient tissue, inefficient tumour penetration of CAR-T cells and the suppression of CAR-T function due to tumour-mediated immunosuppression. We plan to use the unique properties of antibodies isolated from camels or closely related animals to make an improved CAR. Camelid antibodies are significantly smaller than the mouse-derived antibodies which are commonly used for CARs and therefore, have the ability to bind to smaller pockets or grooves within a protein that a larger monoclonal antibody may not be able to access. Thus, in this project we will try to isolate a camel-based antibody that could selectively bind to a specific protein, mesothelin, when it is present on aggressive solid tumours. Ultimately, we believe that this project could lead to an innovative new treatment for pancreatic, ovarian or other solid cancers by reprogramming patient immune cells.
Development of screening assays for Cbl-b inhibitors
Rima Al-awar, PI, OICR
Jonathan Bramson, PI, McMaster University
Methvin Isaac, Co-investigator, OICR
Gil Privé, Co-investigator, Princess Margaret Cancer Centre
Richard Marcellus, Co-investigator, OICR
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.
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.