Epigenetic Approaches to Enhance Cancer Immunotherapy and to Target Cancer Initiating Cells
Description: The premise of Cancer Immunotherapy is to stimulate the patient's immune system to attack the tumour cells. Recent progress in cancer immunotherapy protocols has led to a transformation in the treatment of several types of solid tumours. However, the majority of Colorectal Cancer (CRC) patients do not respond to immunotherapy, suggesting the need to combine immunotherapies with other anti-tumour strategies. Unfortunately, chemotherapy - the mainstay of cancer treatment for over 40 years - is immunosuppressive and not suitable for combination with immunotherapy. On the other hand, the new class of therapeutics called epigenetic therapies hold great potential for enhancing anti-tumour immune response and for use in combination with immunotherapy. We have found that DNA demethylating drugs can activate immunogenic signals in cancer cells, specifically those that engage the interferon and antiviral pathways. We will investigate how this process happens and how it can be used to increase the tumour cell immunogenicity and to improve the immune response against the tumour. Another major barrier in effectively treating CRC arises from the emergence of resistance to current standard of care. The source of therapeutic resistance is due to a rare group of cells within the tumour called cancer-initiating cells (CICs, also known as cancer stem cells) that are responsible for the continued tumour self-renewal. These CICs are highly resistant to chemo- and radiation therapy. Evidence from mouse models of cancer and human clinical trials indicates anti-cancer therapies select for and increase the number of CICs in tumours, which explain why tumours tend to be more resistant following the initial rounds of therapy. We have found that DNA demethylating agents can target colorectal CICs. We will explore a strategy of targeting CICs using epigenetic therapy and how it can be used to avoid tumour recurrence with the ultimate aim of curing this disease.
Amount: CA$1,315,000
Funding type: research
Funder scheme: Foundation Grant
Start date: 2016-07-01
End date: 2021-06-30
Investigator: Daniel De Carvalho (lead)
Institutions: University Health Network, University Health Network (Toronto)
Funded outputs count: 15
Funder award ID: 148430_1
OpenAlex ID: G1237447185