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.
  • Epigenetic therapy
    Epigenetic 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.
  • Immunotherapy
    Studying 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 cells
    Many 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.

Related Links

Lab Website
The Mitochondrial Transacylase, Tafazzin, Regulates for AML Stemness by Modulating Intracellular Levels of Phospholipids.
Cell Stem Cell. 2019 Apr 04;24(4):621-636.e16
Seneviratne AK, Xu M, Henao JJA, Fajardo VA, Hao Z, Voisin V, Xu GW, Hurren R, Kim S, MacLean N, Wang X, Gronda M, Jeyaraju D, Jitkova Y, Ketela T, Mullokandov M, Sharon D, Thomas G, Chouinard-Watkins R, Hawley JR, Schafer C, Yau HL, Khuchua Z, Aman A,...
Epigenetic therapy in immune-oncology.
Nat Rev Cancer. 2019 Mar;19(3):151-161
Jones PA, Ohtani H, Chakravarthy A, De Carvalho DD
A chemical biology toolbox to study protein methyltransferases and epigenetic signaling.
Nat Commun. 2019 Jan 03;10(1):19
Scheer S, Ackloo S, Medina TS, Schapira M, Li F, Ward JA, Lewis AM, Northrop JP, Richardson PL, Kaniskan HÜ, Shen Y, Liu J, Smil D, McLeod D, Zepeda-Velazquez CA, Luo M, Jin J, Barsyte-Lovejoy D, Huber KVM, De Carvalho DD, Vedadi M, Zaph C, Brown PJ,...
Sensitive tumour detection and classification using plasma cell-free DNA methylomes.
Nature. 2018 Nov 14;:
Shen SY, Singhania R, Fehringer G, Chakravarthy A, Roehrl MHA, Chadwick D, Zuzarte PC, Borgida A, Wang TT, Li T, Kis O, Zhao Z, Spreafico A, Medina TDS, Wang Y, Roulois D, Ettayebi I, Chen Z, Chow S, Murphy T, Arruda A, O'Kane GM, Liu J, Mansour M,...
TGF-β-associated extracellular matrix genes link cancer-associated fibroblasts to immune evasion and immunotherapy failure.
Nat Commun. 2018 Nov 08;9(1):4692
Chakravarthy A, Khan L, Bensler NP, Bose P, De Carvalho DD
The Cancer Epigenome: Exploiting Its Vulnerabilities for Immunotherapy.
Trends Cell Biol. 2018 Aug 25;:
Loo Yau H, Ettayebi I, De Carvalho DD
Deregulation of Retroelements as an Emerging Therapeutic Opportunity in Cancer.
Trends Cancer. 2018 Aug;4(8):583-597
Ishak CA, Classon M, De Carvalho DD
LSD1 Ablation Stimulates Anti-tumor Immunity and Enables Checkpoint Blockade.
Cell. 2018 Jun 18;:
Sheng W, LaFleur MW, Nguyen TH, Chen S, Chakravarthy A, Conway JR, Li Y, Chen H, Yang H, Hsu PH, Van Allen EM, Freeman GJ, De Carvalho DD, He HH, Sharpe AH, Shi Y
Apoptotic cell-induced AhR activity is required for immunological tolerance and suppression of systemic lupus erythematosus in mice and humans.
Nat Immunol. 2018 May 14;:
Shinde R, Hezaveh K, Halaby MJ, Kloetgen A, Chakravarthy A, da Silva Medina T, Deol R, Manion KP, Baglaenko Y, Eldh M, Lamorte S, Wallace D, Chodisetti SB, Ravishankar B, Liu H, Chaudhary K, Munn DH, Tsirigos A, Madaio M, Gabrielsson S, Touma Z, Wither...
Soluble CD30, Acute Rejection, and Graft Survival: Pre- and 6-Month Post-Transplant Determinations-When Is the Best Time to Measure?
Transplant Proc. 2018 Apr;50(3):728-736
de Holanda MI, Matuck T, de Carvalho DDBM, Domingues EMFL, Curvo R, Glasberg DS, Santos AMG, Borela ÁM, Pôrto LC

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Senior Scientist, Princess Margaret Cancer Centre

Assistant Professor, Department of Medical Biophysics, University of Toronto