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

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,...
Nat Commun. 2018 Nov 08;9(1):4692
Chakravarthy A, Khan L, Bensler NP, Bose P, De Carvalho DD
Trends Cell Biol. 2018 Aug 25;:
Loo Yau H, Ettayebi I, De Carvalho DD
Trends Cancer. 2018 Aug;4(8):583-597
Ishak CA, Classon M, De Carvalho DD
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
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...
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
Semin Oncol. 2017 Oct;44(5):330-346
Burgener JM, Rostami A, De Carvalho DD, Bratman SV
Oncoscience. 2017 Sep;4(9-10):115-116
Classon M, LaMarco K, De Carvalho DD
Cell Death Dis. 2017 Oct 12;8(10):e3114
Pereira WO, De Carvalho DD, Zenteno ME, Ribeiro BF, Jacysyn JF, Sardinha LR, Zanichelli MA, Hamerschlak N, Jones GE, Pagnano KB, Castro FA, Calle Y, Amarante-Mendes GP

Pages


 

Assistant Professor, Department of Medical Biophysics, University of Toronto