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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
2P50CA100632-11
Application #
8499744
Study Section
Special Emphasis Panel (ZCA1-RPRB-7 (J1))
Project Start
2013-05-01
Project End
2018-08-31
Budget Start
2013-09-13
Budget End
2014-08-31
Support Year
11
Fiscal Year
2013
Total Cost
$899,671
Indirect Cost
$579,350
Name
University of Texas MD Anderson Cancer Center
Department
Type
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
St John, Lisa S; Wan, Liping; He, Hong et al. (2016) PR1-specific cytotoxic T lymphocytes are relatively frequent in umbilical cord blood and can be effectively expanded to target myeloid leukemia. Cytotherapy 18:995-1001
Lee, H J; Gallardo, M; Ma, H et al. (2016) p53-independent ibrutinib responses in an Eμ-TCL1 mouse model demonstrates efficacy in high-risk CLL. Blood Cancer J 6:e434
Pemmaraju, Naveen; Kantarjian, Hagop; Ravandi, Farhad et al. (2016) Patient Characteristics and Outcomes in Adolescents and Young Adults (AYA) With Acute Myeloid Leukemia (AML). Clin Lymphoma Myeloma Leuk 16:213-222.e2
Van Roosbroeck, Katrien; Fanini, Francesca; Setoyama, Tetsuro et al. (2016) Combining anti-miR-155 with chemotherapy for the treatment of lung cancers. Clin Cancer Res :
Ravandi, Farhad; Jorgensen, Jeffrey L; O'Brien, Susan M et al. (2016) Minimal residual disease assessed by multi-parameter flow cytometry is highly prognostic in adult patients with acute lymphoblastic leukaemia. Br J Haematol 172:392-400
Chawla, Akhil; Alatrash, Gheath; Philips, Anne V et al. (2016) Neutrophil elastase enhances antigen presentation by upregulating human leukocyte antigen class I expression on tumor cells. Cancer Immunol Immunother 65:741-51
Wen, Sijin; Huang, Xuelin; Frankowski, Ralph F et al. (2016) A Bayesian multivariate joint frailty model for disease recurrences and survival. Stat Med 35:4794-4812
Kanagal-Shamanna, Rashmi; Luthra, Rajyalakshmi; Yin, Cameron C et al. (2016) Myeloid neoplasms with isolated isochromosome 17q demonstrate a high frequency of mutations in SETBP1, SRSF2, ASXL1 and NRAS. Oncotarget 7:14251-8
Pan, D; Jiang, C; Ma, Z et al. (2016) MALT1 is required for EGFR-induced NF-κB activation and contributes to EGFR-driven lung cancer progression. Oncogene 35:919-28
Saenz, D T; Fiskus, W; Manshouri, T et al. (2016) BET protein bromodomain inhibitor-based combinations are highly active against post-myeloproliferative neoplasm secondary AML cells. Leukemia :

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