In the Kats laboratory, we are interested in developing new therapeutic strategies for aggressive blood cancers.
We use advanced genetic tools and small molecule inhibitors to uncover oncogene dependencies and synthetic lethal interactions in genetic contexts that occur commonly in human cancer.
Targeting IDH mutations in acute myeloid leukaemia
Mutations in genes that encode the metabolic enzymes IDH1 and IDH2 are a frequent event in acute myeloid leukaemia (AML). The mutant IDH proteins have a novel enzymatic activity that produces a rare metabolite called 2-HG. 2-HG deregulates numerous biological pathways implicated in cancer, and small molecule inhibitors that target mutant IDH proteins have recently entered clinical trials. While these compounds are showing early promise in patients, as with all classes of cancer drugs, monotherapy with these agents is likely to result in up-front therapy failure in some cases and development of resistance in others. Our studies are aimed at gaining a detailed understanding of molecular determinants of therapy response and resistance based on established pre-clinical in vivo models.
Identification of novel therapeutic targets in leukaemic cells with aberrant DNA methylation
Genes that regulate DNA methylation are frequently altered in blood cancers. As these mutations invariably result in loss of enzymatic activity, they cannot be directly reversed using small molecule inhibitors. However, these mutations likely confer on the cells a dependence on specific biochemical pathways that are not essential for normal cells. We are using advanced CRISPR-based genetic screens to identify these so-called "synthetic lethal" interactions. Selected hits from the genome-wide analysis are subsequently validated across a range of in vitro and in vivo models, to identify new strategies for specifically targeting leukaemic cells.
Ghisi M, Kats L, Masson F, Li J, Kratina T, Vidacs E, Gilan O, Doyle MA, Newbold A, Bolden JE, Fairfax KA, de Graaf CA, Firth M, Zuber J, Dickins RA, Corcoran LM, Dawson MA, Belz GT, Johnstone RW (2016). Id2 and E proteins orchestrate the initiation and maintenance of MLL-rearranged acute myeloid leukemia. Cancer Cell.30(1):59-74.
Gregory GP, Hogg SJ, Kats LM, Vidacs E, Baker AJ, Gilan O, Lefebure M, Martin BP, Dawson MA, Johnstone RW, Shortt J (2015). CDK9 inhibition by dinaciclib potently suppresses Mcl-1 to induce durable apoptotic responses in aggressive MYC-driven B-cell lymphoma in vivo. Leukemia.29(6):1437-41.
Wei S, Kozono S, Kats L, Nechama M, Li W, Guarnerio J, Bozkurt G, Luo M, You M-H, Yao Y, Kondo A, Hu H, Moerke NJ, Cao S, Reschke M, Rego EM, LoCoco F, Cantley L, Lee TH, Wu H, Zhang Y, Pandolfi PP, Zhou XZ, Lu KP (2015). Active Pin1 is a key target of all-trans retinoic acid in acute promyelocytic leukemia and breast cancer. Nat Med.21(5):457-66.
Xie H, Hanai J*, Ren JG*, Kats L*, Burgess K, Bhargava P, Signoretti S, Billiard J, Duffy KJ, Grant A, Wang X, Lorkiewicz PK, Schatzman S, Bousamra M 2nd, Lane AN, Higashi RM, Fan TW, Pandolfi PP, Sukhatme VP, Seth P (2014). Targeting lactate dehydrogenase-A inhibits tumorigenesis and tumor progression in mouse models of lung cancer and impacts tumor-initiating cells. Cell Metab.19(5):795-809. (* Equal contribution)
Kats LM*, Reschke M*, Taulli R, Pozdnyakova O, Burgess K, Bhargava P, Straley K, Karnik R, Meissner A, Small D, Su SM, Yen K, Zhang J, Pandolfi PP (2014). Proto-oncogenic role of mutant IDH2 in leukemia initiation and maintenance. Cell Stem Cell.14(3):329-41. (* Equal contribution)
Dos Santos GA*, Kats L*, Pandolfi PP (2013). Synergy against PML-RARa: targeting transcription, proteolysis, differentiation, and self-renewal in acute promyelocytic leukemia. J Exp Med.210(13):2793-802. (* Equal contribution)
Honours and PhD projects are available.