Three lines of evidence have converged to confirm the importance of epigenetic deregulation in leukemias: (i) The epigenome is markedly abnormal in leukemic cells;(ii) mutations in epigenetic regulators are very frequent in myeloid leukemias and (iii) drugs that modulate the epigenome (DNA methylation inhibitors, histone deacetylase inhibitors) are clinically effective in subsets of patients with myeloid leukemia. In the previous funding period, we developed a cellular screening system to identify drugs that reactivate the expression of an epigenetically silenced reporter gene. Using this model, we demonstrated that chromatin resetting and nucleosome depletion are key to reactivation of gene expression, and that demethylation is essential to ensure long term expression. We then screened a drug library of FDA approved compounds for single agent activity, as well as activity in combination with DNA methylation inhibitors. This screen identified dozens of drugs with epigenetic activity, including all three known epigenetic regulators in the library (decitabine, azacitidine, vorinostat). Some of the drugs identified have known anti-neoplastic properties (e.g. arsenic trioxide) but most did not, and instead were developed for other medical indications (e.g. cardiac drugs). Many of these drugs share the property of affecting calcium fluxes, and we traced their epigenetic effects to signaling through calmodulin kinase resulting in displacement of methyl-binding proteins. In the synergy screens, we found strong synergy between hypomethylators and DNA damaging agents such as carboplatin which we traced to disruption of binding by HP1, a chromatin regulator essential for gene silencing. Thus, we have identified new ways of reactivating gene expression that can be readily exploited therapeutically in clinical trials. These observations led to the hypotheses that drugs that work through therapeutic displacement of methyl-binding proteins and HP1 can augment epigenetic reprogramming of leukemic cells, and that these will increase the molecular and clinical efficacy of known epigenetic drugs. To test these hypotheses, we propose three specific aims: (1) Mechanism of action and therapeutic potential of drugs that reactivate gene expression through calcium signaling. (2) Mechanism of action and therapeutic potential of drugs that synergize with hypomethylating agents in activation of gene expression. (3) Clinical trials of novel, mechanism based DAC combinations in relapsed/refractory AML and MDS. This grant proposal aims at improving the efficacy of epigenetic therapy in myeloid leukemias, an approach that has already contributing to prolonging sun/ival in these diseases.
This project aims at developing new strategies for epigenetic therapy - a form of anti-cancer therapy that relies on reprogramming the epigenome or reeducation of the cancer cells to become closer to normal cells. The strategy has been successful in the past, and the new treatments approaches developed have the potential to increase cure rates in myeloid leukemias and could also find wide application in oncology.
|Sekihara, Kazumasa; Saitoh, Kaori; Han, Lina et al. (2017) Targeting mantle cell lymphoma metabolism and survival through simultaneous blockade of mTOR and nuclear transporter exportin-1. Oncotarget 8:34552-34564|
|Johanning, Gary L; Malouf, Gabriel G; Zheng, Xiaofeng et al. (2017) Expression of human endogenous retrovirus-K is strongly associated with the basal-like breast cancer phenotype. Sci Rep 7:41960|
|Katerndahl, Casey D S; Heltemes-Harris, Lynn M; Willette, Mark J L et al. (2017) Antagonism of B cell enhancer networks by STAT5 drives leukemia and poor patient survival. Nat Immunol 18:694-704|
|Kanagal-Shamanna, Rashmi; Loghavi, Sanam; DiNardo, Courtney D et al. (2017) Bone marrow pathologic abnormalities in familial platelet disorder with propensity for myeloid malignancy and germline RUNX1 mutation. Haematologica 102:1661-1670|
|Mu, Yunxiang; Zelazowska, Monika A; McBride, Kevin M (2017) Phosphorylation promotes activation-induced cytidine deaminase activity at the Myc oncogene. J Exp Med 214:3543-3552|
|Kelly, A D; Kroeger, H; Yamazaki, J et al. (2017) A CpG island methylator phenotype in acute myeloid leukemia independent of IDH mutations and associated with a favorable outcome. Leukemia 31:2011-2019|
|Nieborowska-Skorska, Margaret; Sullivan, Katherine; Dasgupta, Yashodhara et al. (2017) Gene expression and mutation-guided synthetic lethality eradicates proliferating and quiescent leukemia cells. J Clin Invest 127:2392-2406|
|Pratz, Keith W; Levis, Mark (2017) How I treat FLT3-mutated AML. Blood 129:565-571|
|Kerros, Celine; Tripathi, Satyendra C; Zha, Dongxing et al. (2017) Neuropilin-1 mediates neutrophil elastase uptake and cross-presentation in breast cancer cells. J Biol Chem 292:10295-10305|
|Kayser, Sabine; Levis, Mark J (2017) Advances in targeted therapy for acute myeloid leukaemia. Br J Haematol :|
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