Dr. Tak Mak is the Director of the Campbell Family Institute for Breast Cancer Research at the Princess Margaret Cancer Centre, and a University Professor in the Departments of Medical Biophysics and Immunology at the University of Toronto. Dr. Mak is best known as the lead scientist of the group that first cloned the genes encoding the human T cell antigen receptor, a discovery that provided essential insights into the molecular basis of cellular immunity. Dr. Mak’s current research is focussed on immune system cell functions and regulation, and the role of inflammation in the progression of autoimmune diseases and cancer. He is particularly interested in the molecular pathways underlying the survival, proliferation and death of normal and malignant cells. Currently, he is investigating the mechanisms of metabolic transformation used by cancer cells to fuel their uncontrolled growth, with the goal of identifying potential targets for novel cancer therapeutics.
Industry Expertise (4)
Areas of Expertise (9)
Officer of the Order of Canada (professional)
Canada's second highest Order of Merit
Sloan Prize (professional)
Awarded by General Motors Cancer Foundation
McLaughlin Medal (professional)
Awarded by the Royal Society of Canada
E.W.R. Steacie Award (professional)
Awarded by the National Sciences and Engineering Research Council
E.W.R. Steacie Award, National Sciences and Engineering Research Council, Ottawa (professional)
Presented to a scientist who has made a distinguished contribution to chemistry while working in Canada.
Emil von Behring Prize (professional)
Phillips-Universitat Marburg, Germany
Gairdner International Award, Gairdner Foundation Canada (professional)
These awards are given to biomedical scientists who have made original contributions to medicine resulting in increased understanding of human biology and disease.
King Faisal International Prize for Medicine (professional)
Sloan Prize (professional)
General Motors Cancer Research Foundation
Novartis Immunology Prizes (professional)
Novartis, Inc., Switzerland
Killam Prize (professional)
Paul Ehrlich Prize and Ludwig Darmstaedter Prize (professional)
Premier’s Summit Awards in Medical Research (professional)
The Award forms part of a cohesive innovation strategy that focuses on excellence in research and commercialization as cornerstones of the economic future of the province of Ontario.
Dr. Chew Wei Memorial Prize in Cancer Research (professional)
University of British Columbia Faculty of Medicine
University of Alberta: Ph.D., Biochemistry 1971
University of Wisconsin: M.Sc., Biophysics 1968
University of Wisconsin: B.Sc., Biochemistry 1967
- The Campbell Family Institute for Breast Cancer Research : Director
- University of Toronto : Senior Professor of Immunology
- Ontario Cancer Institute : Scientist
- Amgen Institute, Toronto : Director
- 1986 Fellow of the Royal Society of Canada
- 1994 Fellow of The Royal Society of London
- 2000 Order of Canada, Governor General of Canada
- 2002 Foreign Associate, National Academy of Sciences
- 2005 Member, American Academy of Arts & Sciences
- 2008 Order of Ontario
- 2013 Inductee, Fellow of the AACR Academy
- 2009 Inductee to Canadian Medical Hall of Fame
Media Appearances (5)
After Surgery, Predicting a Speedy Recovery
The New York Times online
“This is by far the most detailed and deep analysis of what’s going on in your blood, which is in essence the highway of a whole country,” said Tak W. Mak, a biochemist at the University of Toronto, who was not involved in the study. “I think the promise is in the future, that we can get one complete synopsis of all the cars and trucks and bicycles and people on the highway and profile all their characteristics.”
How Tak Mak connects the dots to make medical breakthroughs
The Globe and Mail online
When it comes to scientific discovery, Tak Wah Mak is an undisputed rock star. The world-renowned Canadian scientist and researcher has devoted his life to unravelling medical mysteries in the areas of virology, immunology and cancer metabolism. His brilliant career has been punctuated by breakthroughs, including the discovery of the Holy Grail of immunology – the T-cell receptor – in 1984...
Cancer researcher Tak Mak's macadamia cookies
The Toronto Star online
These cookies transport Tak Mak far from Toronto’s cold winters to a lush seaside — and to happy moments long before he lost his wife to a disease he is fighting to cure. “The macadamia nuts remind me of my family vacations in Hawaii with my wife and two daughters many years ago,” the cancer researcher tells the Star. “And I love the sweetness of the white chocolate chips.”
Dr. Tak Mak Shares Major Cancer Breakthrough
In a media event held this morning, two of the world's most acclaimed cancer researchers, Drs. Tak Mak of the Princess Margaret Cancer Centre, and Dennis Slamon of the University of California, Los Angeles, shared news of a major breakthrough in the decade-long pursuit to develop a new class of "sharpshooter" cancer drugs...
For Dr. Tak Mak, there are only two constants: the Ontario Cancer Institute and change
In 1983, a 36-year-old scientist named Dr. Tak Mak attracted international attention for his breakthrough discovery of the T cell receptor. Mak is still a leading researcher with the Ontario Cancer Institute, but there are few other things that haven’t changed at least once over the past 30 years. When Mak began his career, scientists had known for many years that a class of white blood cells, called T cells because they are produced by the thymus gland, protect the body against many types of infection...
Event Appearances (3)
Hallmarks of Cancer: Asia Beijing, China
6th international Mutant p53 Workshop Toronto, ON.
Future Anti-Cancer Therapeutic Targets: Putting the Carts Before the Horses?
CNIO Distinguished Seminar Series Madrid, Spain
Methods and compositions for modulating toso activity
WO 2013136193 A8
The present invention is further directed to methods and compositions for modulating the activity of the Toso protein. The invention further encompasses treatment of disorders associated with inflammation, autoimmune disorders, and cancer using compositions that include a soluble Toso protein.
Kinase inhibitors and method of treating cancer with same
WO 2011123937 A1
The present teachings provide a compound represented by Strutural Formula (I): or a pharmaceutically acceptable salt thereof. Also described are a pharmaceutical composition and method of use thereof.
Mouse having a disrupted CD4 gene
US 5698765 A
A mutant mouse strain without CD4 expression has been generated by disrupting the CD4 gene using embryonic stem cell technology. In these mice CD4+ T lymphocytes are not present in peripheral lymphoid organs, but the development of CD8+ T cells and myeloid components is unaltered, indicating that expression of CD4+ on progenitor cells and CD4+ CD8+ (double positive) thymocytes is not obligatory. These mice have markedly decreased helper cell activity for antibody responses, whereas cytotoxic T cell activity against viruses was within normal range of that generated by CD4+ mice. This differential requirement for CD4+ helper T cells has important implications for the understanding of the immune function in a variety of immune disorders, including AIDS, in which the CD4+ cells are reduced or absent.
This report shows that cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) plays a key role in T cell–mediated dominant immunologic self-tolerance. In vivo blockade of CTLA-4 for a limited period in normal mice leads to spontaneous development of chronic ...
The tumour-necrosis-factor-family molecule osteoprotegerin ligand (OPGL; also known as TRANCE, RANKL and ODF) has been identified as a potential osteoclast differentiation factor and regulator of interactions between T cells and dendritic cells in ...
PTEN is a tumor suppressor with sequence homology to protein tyrosine phosphatases and the cytoskeletal protein tensin. mPTEN-mutant mouse embryos display regions of increased proliferation. In contrast, mPTEN-deficient immortalized mouse embryonic fibroblasts ...
The role of the cell-surface molecule CTLA-4 in the regulation of T cell activation has been controversial. Here, lymph nodes and spleens of CTLA-4-deficient mice accumulated T cell blasts with up-regulated activation markers. These blast cells also ...
The multiple biological activities of tumor necrosis factor (TNF) are mediated by two distinct cell surface receptors of 55 kd (TNFRp55) and 75 kd (TNFRp75). Using gene targeting, we generated a TNFRp55-deficient mouse strain. Cells from TNFRp55-/-mutant ...
We have cloned and sequenced a human mRNA specific for mammalian T-lymphoid cells. The message was found to be expressed in human and murine T lymphoblasts, thymocytes and phytohaemagglutinin-stimulated T lymphocytes. The protein deduced from the cDNA sequence has a molecular weight of 34,938 and shows extensive similarity to the entire length of the variable, joining and constant regions of mammalian immunoglobulin light chains. In addition, the relative positions of the cysteine residues are similar to those of the light chains of murine and human immunoglobulin molecules. These properties suggest that the cDNA clone may correspond to a message that specifies part of the human T-cell receptor.
The role of the cell-surface molecule CTLA-4 in the regulation of T cell activation has been controversial. Here, lymph nodes and spleens of CTLA-4-deficient mice accumulated T cell blasts with up-regulated activation markers. These blast cells also infiltrated liver, heart, lung, and pancreas tissue, and amounts of serum immunoglobulin were elevated. The mice invariably became moribund by 3 to 4 weeks of age. Although CTLA-4-deficient T cells proliferated spontaneously and strongly when stimulated through the T cell receptor, they were sensitive to cell death induced by cross-linking of the Fas receptor and by gamma irradiation. Thus, CTLA-4 acts as a negative regulator of T cell activation and is vital for the control of lymphocyte homeostasis.
PTEN is a tumor suppressor with sequence homology to protein tyrosine phosphatases and the cytoskeletal protein tensin. mPTEN-mutant mouse embryos display regions of increased proliferation. In contrast, mPTEN-deficient immortalized mouse embryonic fibroblasts exhibit decreased sensitivity to cell death in response to a number of apoptotic stimuli, accompanied by constitutively elevated activity and phosphorylation of protein kinase B/Akt, a crucial regulator of cell survival. Expression of exogenous PTEN in mutant cells restores both their sensitivity to agonist-induced apoptosis and normal pattern of PKB/Akt phosphorylation. Furthermore, PTEN negatively regulates intracellular levels of phosphatidylinositol (3,4,5) trisphosphate in cells and dephosphorylates it in vitro. Our results show that PTEN may exert its role as a tumor suppressor by negatively regulating the PI3'K/PKB/Akt signaling pathway.
Bcl10, a CARD-containing protein identified from the t(1;14)(p22;q32) breakpoint in MALT lymphomas, has been shown to induce apoptosis and activate NF-kappaB in vitro. We show that one-third of bcl10-/- embryos developed exencephaly, leading to embryonic lethality. Surprisingly, bcl10-/- cells retained susceptibility to various apoptotic stimuli in vivo and in vitro. However, surviving bcl10-/- mice were severely immunodeficient and bcl10-/- lymphocytes are defective in antigen receptor or PMA/Ionomycin-induced activation. Early tyrosine phosphorylation, MAPK and AP-1 activation, and Ca2+ signaling were normal in mutant lymphocytes, but antigen receptor-induced NF-kappaB activation was absent. Thus, Bcl10 functions as a positive regulator of lymphocyte proliferation that specifically connects antigen receptor signaling in B and T cells to NF-kappaB activation.
The phosphatidylinositol 3' kinase (PI3'K) pathway, which regulates cell survival, is antagonized by the PTEN tumor suppressor. The regulation of PTEN is unclear. A genetic screen of Drosophila gain-of-function mutants identified DJ-1 as a suppressor of PTEN function. In mammalian cells, DJ-1 underexpression results in decreased phosphorylation of PKB/Akt, while DJ-1 overexpression leads to hyperphosphorylation of PKB/Akt and increased cell survival. In primary breast cancer samples, DJ-1 expression correlates negatively with PTEN immunoreactivity and positively with PKB/Akt hyperphosphorylation. In 19/23 primary non-small cell lung carcinoma samples, DJ-1 expression was increased compared to paired nonneoplastic lung tissue, and correlated positively with relapse incidence. DJ-1 is thus a key negative regulator of PTEN that may be a useful prognostic marker for cancer.
Understanding the factors that impede immune responses to persistent viruses is essential in designing therapies for HIV infection. Mice infected with LCMV clone-13 have persistent high-level viremia and a dysfunctional immune response. Interleukin-7, a cytokine that is critical for immune development and homeostasis, was used here to promote immunity toward clone-13, enabling elucidation of the inhibitory pathways underlying impaired antiviral immune response. Mechanistically, IL-7 downregulated a critical repressor of cytokine signaling, Socs3, resulting in amplified cytokine production, increased T cell effector function and numbers, and viral clearance. IL-7 enhanced thymic output to expand the naive T cell pool, including T cells that were not LCMV specific. Additionally, IL-7 promoted production of cytoprotective IL-22 that abrogated liver pathology. The IL-7-mediated effects were dependent on endogenous IL-6. These attributes of IL-7 have profound implications for its use as a therapeutic in the treatment of chronic viral diseases.
Innate immune responses are vital for pathogen defense but can result in septic shock when excessive. A key mediator of septic shock is tumor necrosis factor-α (TNFα), which is shed from the plasma membrane after cleavage by the TNFα convertase (TACE). We report that the rhomboid family member iRhom2 interacted with TACE and regulated TNFα shedding. iRhom2 was critical for TACE maturation and trafficking to the cell surface in hematopoietic cells. Gene-targeted iRhom2-deficient mice showed reduced serum TNFα in response to lipopolysaccharide (LPS) and could survive a lethal LPS dose. Furthermore, iRhom2-deficient mice failed to control the replication of Listeria monocytogenes. Our study has identified iRhom2 as a regulator of innate immunity that may be an important target for modulating sepsis and pathogen defense.
Mutations in the IDH1 and IDH2 genes encoding isocitrate dehydrogenases are frequently found in human glioblastomas and cytogenetically normal acute myeloid leukaemias (AML). These alterations are gain-of-function mutations in that they drive the synthesis of the ‘oncometabolite’ R-2-hydroxyglutarate (2HG). It remains unclear how IDH1 and IDH2 mutations modify myeloid cell development and promote leukaemogenesis. Here we report the characterization of conditional knock-in (KI) mice in which the most common IDH1 mutation, IDH1(R132H), is inserted into the endogenous murine Idh1 locus and is expressed in all haematopoietic cells (Vav-KI mice) or specifically in cells of the myeloid lineage (LysM-KI mice). These mutants show increased numbers of early haematopoietic progenitors and develop splenomegaly and anaemia with extramedullary haematopoiesis, suggesting a dysfunctional bone marrow niche. Furthermore, LysM-KI cells have hypermethylated histones and changes to DNA methylation similar to those observed in human IDH1- or IDH2-mutant AML. To our knowledge, our study is the first to describe the generation and characterization of conditional IDH1(R132H)-KI mice, and also the first report to demonstrate the induction of a leukaemic DNA methylation signature in a mouse model. Our report thus sheds light on the mechanistic links between IDH1 mutation and human AML.
Oxidative stress plays an important role in cancer development and treatment. Recent data implicate the tumor suppressor BRCA1 in regulating oxidative stress, but the molecular mechanism and the impact in BRCA1-associated tumorigenesis remain unclear. Here, we show that BRCA1 regulates Nrf2-dependent antioxidant signaling by physically interacting with Nrf2 and promoting its stability and activation. BRCA1-deficient mouse primary mammary epithelial cells show low expression of Nrf2-regulated antioxidant enzymes and accumulate reactive oxygen species (ROS) that impair survival in vivo. Increased Nrf2 activation rescues survival and ROS levels in BRCA1-null cells. Interestingly, 53BP1 inactivation, which has been shown to alleviate several defects associated with BRCA1 loss, rescues survival of BRCA1-null cells without restoring ROS levels. We demonstrate that estrogen treatment partially restores Nrf2 levels in the absence of BRCA1. Our data suggest that Nrf2-regulated antioxidant response plays a crucial role in controlling survival downstream of BRCA1 loss. The ability of estrogen to induce Nrf2 posits an involvement of an estrogen-Nrf2 connection in BRCA1 tumor suppression. Lastly, BRCA1-mutated tumors retain a defective antioxidant response that increases the sensitivity to oxidative stress. In conclusion, the role of BRCA1 in regulating Nrf2 activity suggests important implications for both the etiology and treatment of BRCA1-related cancers.
PLK4 was identified as a promising therapeutic target through a systematic approach that combined RNAi screening with gene expression analysis in human breast cancers and cell lines. A drug discovery program culminated in CFI-400945, a potent and selective PLK4 inhibitor. Cancer cells treated with CFI-400945 exhibit effects consistent with PLK4 kinase inhibition, including dysregulated centriole duplication, mitotic defects, and cell death. Oral administration of CFI-400945 to mice bearing human cancer xenografts results in the significant inhibition of tumor growth at doses that are well tolerated. Increased antitumor activity in vivo was observed in PTEN-deficient compared to PTEN wild-type cancer xenografts. Our findings provide a rationale for the clinical evaluation of CFI-400945 in patients with solid tumors, in particular those deficient in PTEN.