Our research focuses on understanding the epigenetic mechanisms underlying tumorigenesis and the translation of this knowledge into more efficient approaches for epigenetic therapy. We use a truly multi-disciplinary approach to discover what mechanisms are driving the cancer-specific epigenetic alterations and to translate this knowledge towards application. To achieve this goal, we combine advanced molecular and cellular biology techniques with Next Generation Sequencing (NGS), epigenomics and computational biology.
Daniel De Carvalho
- Epigenetic therapyEpigenetic aberrations have been casually associated with cancer. Recent advancements in the rapidly evolving field of cancer epigenetics have shown extensive reprogramming of every component of the epigenetic machinery in cancer. Currently, drugs acting on DNA methyltransferase and histone deacetylase enzymes have already been FDA approved. This provides validation that pharmacological alteration of chromatin modifications has tangible clinical benefit. A new generation of drugs acting on a broad range of epigentic enzymes that act as writers, erasers and readers of the epigenome are currently in clinical and pre-clinical evaluation. Our lab is interested in understanding their biological mechanism of action in the cancer cell and on the immune system.
- ImmunotherapyStudying the potential to modulate the immune response against tumor cells is one of the most rapidly moving and exciting areas in clinical oncology today. Over the last two decades, we have significantly improved our understanding of how the immune system interacts with cancer cells and how cancer can evade the immune response. This knowledge has led to the development of novel immunotherapy protocols, such as immune checkpoint blockade, with increasingly better clinical results. However, there is still a large proportion of patients that do not respond to cancer immunotherapy alone. Recent work from our lab suggests that DNA demethylating drugs can induce an innate immune activation on cancer cells, a process we named ‘viral mimicry’. This process may prime cancer cells for an immune response, highlighting the potential to combine epigenetic therapy with immunotherapy.
- Cancer-initiating cellsMany tumor types are organized as a cellular hierarchy sustained by a subpopulation of cancer-initiating cells (CICs). These CICs possess unique features, including long-term self-renewal, the ability to initiate tumor growth in xenograft models, and the ability to differentiate into the bulk of the tumor mass. CICs are believed to play a major role in tumor relapse and patient survival, suggesting that therapeutic strategies targeting this cell population would be highly beneficial to patient outcome. Our lab recently published that DNA demethylating agents can target colorectal CICs, highlighting the potential use of epigenetic therapy to prevent tumor relapse.
BCR-ABL1-induced downregulation of WASP in chronic myeloid leukemia involves epigenetic modification and contributes to malignancy.
Cell Death Dis. 2017 Oct 12;8(10):e3114
O-Acetylation of Peptidoglycan Limits Helper T Cell Priming and Permits Staphylococcus aureus Reinfection.
Cell Host Microbe. 2017 Sep 20;:
Epigenetic regulation of nitric oxide synthase 2, inducible (Nos2) by NLRC4 inflammasomes involves PARP1 cleavage.
Sci Rep. 2017 Feb 02;7:41686
Early-life antibiotic treatment enhances the pathogenicity of CD4+ T cells during intestinal inflammation.
J Leukoc Biol. 2016 Dec 29;:
Integrated (epi)-Genomic Analyses Identify Subgroup-Specific Therapeutic Targets in CNS Rhabdoid Tumors.
Cancer Cell. 2016 Dec 12;30(6):891-908
Mutant IDH1 Downregulates ATM and Alters DNA Repair and Sensitivity to DNA Damage Independent of TET2.
Cancer Cell. 2016 Jul 9;
Oncoimmunology. 2016 Mar;5(3):e1090077
Oncotarget. 2016 Feb 19;
DNA-Demethylating Agents Target Colorectal Cancer Cells by Inducing Viral Mimicry by Endogenous Transcripts.
Cell. 2015 Aug 27;162(5):961-73
Senior Scientist, Princess Margaret Cancer Centre
Assistant Professor, Department of Medical Biophysics, University of Toronto