epigenetic therapy
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2022 ◽  
Vol 145 ◽  
pp. 112431
Author(s):  
Hung-Yu Lin ◽  
Hsing-Ju Wu ◽  
Si-Yun Chen ◽  
Ming-Feng Hou ◽  
Chang-Shen Lin ◽  
...  

Author(s):  
Xiaoxia Su ◽  
Haoyu Zhang ◽  
Fengzhen Lei ◽  
Rui Wang ◽  
Tingting Lin ◽  
...  

Biomolecules ◽  
2021 ◽  
Vol 11 (11) ◽  
pp. 1711
Author(s):  
Michelle Bilbao ◽  
Chelsea Katz ◽  
Stephanie L. Kass ◽  
Devon Smith ◽  
Krystal Hunter ◽  
...  

Recurrent high-grade serous ovarian cancer (HGSC) is clinically very challenging and prematurely shortens patients’ lives. Recurrent ovarian cancer is characterized by high tumor heterogeneity; therefore, it is susceptible to epigenetic therapy in classic 2D tissue culture and rodent models. Unfortunately, this success has not translated well into clinical trials. Utilizing a 3D spheroid model over a period of weeks, we were able to compare the efficacy of classic chemotherapy and epigenetic therapy on recurrent ovarian cancer cells. Unexpectedly, in our model, a single dose of paclitaxel alone caused the exponential growth of recurrent high-grade serous epithelial ovarian cancer over a period of weeks. In contrast, this effect is not only opposite under treatment with panobinostat, but panobinostat reverses the repopulation of cancer cells following paclitaxel treatment. In our model, we also demonstrate differences in the drug-treatment sensitivity of classic chemotherapy and epigenetic therapy. Moreover, 3D-derived ovarian cancer cells demonstrate induced proliferation, migration, invasion, cancer colony formation and chemoresistance properties after just a single exposure to classic chemotherapy. To the best of our knowledge, this is the first evidence demonstrating a critical contrast between short and prolonged post-treatment outcomes following classic chemotherapy and epigenetic therapy in recurrent high-grade serous ovarian cancer in 3D culture.


Cancers ◽  
2021 ◽  
Vol 13 (22) ◽  
pp. 5722
Author(s):  
Maximilian Fleischmann ◽  
Ulf Schnetzke ◽  
Andreas Hochhaus ◽  
Sebastian Scholl

Treatment of acute myeloid leukemia (AML) has improved in recent years and several new therapeutic options have been approved. Most of them include mutation-specific approaches (e.g., gilteritinib for AML patients with activating FLT3 mutations), or are restricted to such defined AML subgroups, such as AML-MRC (AML with myeloid-related changes) or therapy-related AML (CPX-351). With this review, we aim to present a comprehensive overview of current AML therapy according to the evolved spectrum of recently approved treatment strategies. We address several aspects of combined epigenetic therapy with the BCL-2 inhibitor venetoclax and provide insight into mechanisms of resistance towards venetoclax-based regimens, and how primary or secondary resistance might be circumvented. Furthermore, a detailed overview on the current status of AML immunotherapy, describing promising concepts, is provided. This review focuses on clinically important aspects of current and future concepts of AML treatment, but will also present the molecular background of distinct targeted therapies, to understand the development and challenges of clinical trials ongoing in AML patients.


Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3064
Author(s):  
Geraldine Zimmer-Bensch ◽  
Hans Zempel

Genetic and sporadic forms of tauopathies, the most prevalent of which is Alzheimer’s Disease, are a scourge of the aging society, and in the case of genetic forms, can also affect children and young adults. All tauopathies share ectopic expression, mislocalization, or aggregation of the microtubule associated protein TAU, encoded by the MAPT gene. As TAU is a neuronal protein widely expressed in the CNS, the overwhelming majority of tauopathies are neurological disorders. They are characterized by cognitive dysfunction often leading to dementia, and are frequently accompanied by movement abnormalities such as parkinsonism. Tauopathies can lead to severe neurological deficits and premature death. For some tauopathies there is a clear genetic cause and/or an epigenetic contribution. However, for several others the disease etiology is unclear, with few tauopathies being environmentally triggered. Here, we review current knowledge of tauopathies listing known genetic and important sporadic forms of these disease. Further, we discuss how DNA methylation as a major epigenetic mechanism emerges to be involved in the disease pathophysiology of Alzheimer’s, and related genetic and non-genetic tauopathies. Finally, we debate the application of epigenetic signatures in peripheral blood samples as diagnostic tools and usages of epigenetic therapy strategies for these diseases.


Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2242-2242
Author(s):  
Shaun Wood ◽  
Amber Willbanks ◽  
Jason Xiaojun Cheng

Abstract Background: Drug selectivity and resistance is a major obstacle to successful cancer therapy, including traditional chemotherapies (Vasan, N. et al. Nature 2019), immunotherapy (Hu-Lieskovan, S. et al. Future Oncol, 2021), and epigenetic therapy (Saliba, A.N. et al. Cancer Drug Resist,2021). However, no reliable technologies and biomarkers have been developed to analyze and predict drug resistance in clinical settings. Nascent RNAs composed of mostly non-coding RNAs undergo extensive modifications at co- and post-transcriptional levels. Nascent RNAs, and their associated modifications and modifying proteins (RMPs), such as RNA 5-methylcytosine (RNA:m 5C) and RNA cytosine methyltransferases (RCMTs), regulate almost all essential bioprocesses, including chromatin remodeling, DNA transcription, RNA processing/splicing and protein translation. Largely due to technology limitation, the role of nascent RNAs and RNA epigenetics remain largely unknown. Our previous publication first demonstrated distinct cell lineage-associated, RCMTs/BRD4-mediated, drug (azacitidine)-resistant transcriptionally active chromatin structures (TAC) at nascent (newly synthesized) RNAs in leukemia cells (Cheng, J.X. et al. Nat Commun. 2018). The goal of this study is to develop novel nascent RNA/TAC-driven technologies and biomarkers that enable us to rapidly analyze and predict drug resistance in clinical settings. Results:  Our experimental data demonstrated that TAC and RNA epigenetics regulate the resistance to venetoclax, a selective inhibitor of the anti-apoptotic protein BCL2, in leukemia cells. There is a significant, lineage-associated, increase in specific RCMTs, such as NSUN2 and NSUN1/NOP2, in venetoclax-resistant leukemia cells. Knockdown of NSUN2 and/or NSUN1 overcome venetoclax resistance in these leukemia cells. Our data also demonstrated distinct patterns of drug- and lineage-specific RNA synthesis dynamics in drug-sensitive vs. -resistant leukemia cells. In drug-sensitive leukemia cells, dinaciclib, a potent a potent, selective small molecule inhibitor of CDKs inhibiting CDK1, CDK2, CDK5 and CDK9 at nano-molar concentrations (Parry, D. et al. Mol.Cancer Ther, 2010), completely inhibit nascent RNA synthesis within 3-5 min, while venetoclax and azacitidine partially inhibit nascent RNA synthesis within 15 min and 240 min, respectively. Such drug-induced inhibition of nascent RNA synthesis is completely independent of apoptosis and program cell death. In contrast, no drug-induced inhibition of nascent RNA synthesis is observed in drug-resistant leukemia cells. Based on our data, we have developed a novel multifactorial system that targets the unique drug- and lineage-specific features of nascent RNA synthesis, TAC and RNA epigenetics for rapid analysis and prediction of drug resistance in clinical settings. Conclusion: Our data demonstrated distinct drug- and lineage-specific patterns of RNA synthesis in drug-sensitive vs. -resistant leukemia cells, which enabled us to develop novel nascent RNA/TAC-drive technologies and biomarkers for rapid analysis and prediction of anticancer drug resistance. Disclosures No relevant conflicts of interest to declare.


2021 ◽  
Vol Publish Ahead of Print ◽  
Author(s):  
Vasu R. Sah ◽  
Joakim Karlsson ◽  
Henrik Jespersen ◽  
Mattias F. Lindberg ◽  
Lisa M. Nilsson ◽  
...  

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 625-625
Author(s):  
Liping Li ◽  
Jung-Hyun Kim ◽  
Wenyan Lu ◽  
Leslie Cope ◽  
Donna M Williams ◽  
...  

Abstract Introduction: Myeloproliferative neoplasms (MPN) are clonal hematopoietic stem cell (HSC) disorders characterized by hyperactive JAK/STAT signaling and increased risk of transformation to myelofibrosis (MF) and acute myeloid leukemia (AML). However, mechanisms driving progression remain elusive and therapies are ineffective after leukemic transformation. The High Mobility Group A1 (HMGA1) gene encodes oncogenic chromatin regulators which are overexpressed in diverse tumors where they portend adverse outcomes (Resar Cancer Res 2010; Xian et al Nature Commun 2017). Hmga1 induces leukemic transformation in transgenic mice and HMGA1 is overexpressed in refractory myeloid malignancies (Resar et al Cancer Res 2018). Further, germline lesions within the HMGA1 loci increase the risk for developing MPN (Bao et al Nature 2020). We therefore sought to: 1) test the hypothesis that HMGA1 drives MPN progression by rewiring transcriptional networks to foster leukemogenesis, and, 2) identify mechanisms underlying HMGA1 that could be targeted with therapy. Methods: To elucidate the function of HMGA1, we disrupted HMGA1 expression via CRISPR/Cas9 or short hairpin RNA (shRNA) targeting 2 different sequences per gene and assessed proliferation, colony formation, apoptosis, and leukemogenesis. We also generated JAK2 V617F transgenic mouse models of MF with Hmga1 deficiency. To dissect molecular mechanisms underlying HMGA1, we integrated RNAseq, ATACseq, and chromatin immunoprecipitation (ChIP) from MPN-AML cell lines (DAMI, SET-2). Next, we tested whether HMGA1 depletion synergizes with ruxolitinib in preventing leukemic engraftment in mice. To identify drugs to target HMGA1 networks, we applied the Broad Institute Connectivity Map (CMAP). Results: HMGA1 is overexpressed in CD34 + cells from patients with JAK2 V617F MPN with highest levels after transformation to MF or AML in 3 independent cohorts. CRISPR/Cas9 inactivation or shRNA-mediated HMGA1 silencing disrupts proliferation, decreases the frequency of cells in S phase, increases apoptosis, and impairs clonogenicity in human MPN-AML cell lines. HMGA1 depletion also prevents leukemic engraftment in mice. Surprisingly, loss of just a single Hmga1 allele prevents progression to MF in JAK2 V617Fmurine models of MPN, decreasing erythrocytosis, thrombocytosis, and preventing splenomegaly and fibrosis of the spleen and bone marrow. Further, Hmga1 deficiency preferentially prevents expansion in long-term HSC, granulocyte-macrophage progenitors, and megakaryocyte-erythroid progenitors in JAK2 V617F mice. RNAseq revealed genes induced by HMGA1 that govern cell cycle progression (E2F targets, mitotic spindle, G2M checkpoint, MYC targets) and cell fate decisions (GATA2 networks), including the GATA2 master regulator gene. Silencing GATA2 recapitulates anti-leukemia phenotypes observed with HMGA1 deficiency whereas restoring GATA2 in MPN-AML cells with HMGA1 silencing partially rescues leukemia phenotypes, increasing clonogenicity and leukemic engraftment. Mechanistically, HMGA1 binds directly to AT-rich sequences near the GATA2 developmental enhancer (+9.5), enhances chromatin accessibility, and recruits active histone marks (H3K4me1/3) to induce GATA2 expression. HMGA1 depletion enhances responses to the JAK/STAT Inhibitor, ruxolitinib, delaying leukemic engraftment and prolonging survival in murine models of JAK2 V617F MPN-AML. Further, epigenetic drugs predicted to target HMGA1 transcriptional networks using CMAP synergize with JAK inhibitors to disrupt proliferation in human MPN-AML cells. HMGA1 and GATA2 are co-expressed and up-regulated with progression from MF to AML in matched patient samples. Moreover, HMGA1 transcriptional networks are activated in leukemic blasts, thus underscoring the role of HMGA1 in human MPN progression. Conclusions: We uncovered a previously unknown epigenetic program whereby HMGA1 enhances chromatin accessibility and recruits activating histone marks to induce transcriptional networks required for progression in MPN, including direct transactivation of GATA2. Further, HMGA1 networks can be targeted with epigenetic therapy and synergize with ruxolitinib. Together, our studies reveal a new paradigm whereby HMGA1 up-regulates GATA2 and proliferation networks to drive disease progression and illuminate HMGA1 as a novel therapeutic target in MPN. Figure 1 Figure 1. Disclosures Rampal: Jazz Pharmaceuticals: Consultancy; Incyte: Consultancy, Research Funding; Kartos: Consultancy; Constellation: Research Funding; Pharmaessentia: Consultancy; Blueprint: Consultancy; Disc Medicine: Consultancy; Stemline: Consultancy, Research Funding; BMS/Celgene: Consultancy; Novartis: Consultancy; Sierra Oncology: Consultancy; CTI: Consultancy; Abbvie: Consultancy; Memorial Sloan Kettering: Current Employment. Stubbs: Incyte Research Institute: Current Employment, Current holder of individual stocks in a privately-held company.


2021 ◽  
Author(s):  
Lingling Duan ◽  
Yu-An Chen ◽  
Yanping Liang ◽  
Zhenhua Chen ◽  
Jun Lu ◽  
...  

Abstract Background: Accumulating evidence points to epigenetic mechanisms as essential in tumorigenesis. Treatment that targets epigenetic regulators is becoming an attractive strategy for cancer therapy. The role of epigenetic therapy in prostate cancer (PCa) remains elusive. Previously we demonstrated a correlation of levels of histone lysine demethylase KDM4B with the appearance of castration resistant prostate cancer (CRPC) and identified a small molecular inhibitor of KDM4B, B3. In this study, we aim to define the role of KDM4B in promoting PCa progression and test the efficacy of B3 using clinically relevant PCa models. Methods: KDM4B was overexpressed in LNCaP cells or knocked down (KD) in 22Rv1 cells. The specificity of B3 was determined in vitro using recombinant KDM proteins and in vivo using 22Rv1 cell lysates. The efficacy of B3 monotherapy or in combination with androgen receptor (AR) antagonist enzalutamide or the mTOR inhibitor rapamycin was tested using xenograft models in castrated mice. Comparative transcriptomic analysis was performed on KDM4B KD and B3-treated 22Rv1 cells to determine the on-target (KDM4B-dependent) and off-target (non-KDM4B-associated) effects of B3.Results: Overexpression of KDM4B in LNCaP cells enhanced its tumorigenicity whereas knockdown of KDM4B in 22Rv1 cells reduced tumor growth in castrated mice. B3 suppressed the growth of both 22Rv1 and VCaP xenografts and sensitized 22Rv1 cells to enzalutamide inhibition. B3 also inhibited 22Rv1 tumor growth synergistically with rapamycin that resulted in cell apoptosis. Mechanistically, B3 inhibited expression of AR-V7 and genes involved in epithelial-to-mesenchymal transition. DNA replication stress marker gH2A.X was upregulated by B3, which is further increased when combined with rapamycin. Based on transcriptomic and biochemical analyses, B3 inhibits both H3K9me3 and H3K27me3 demethylase activity, which is believed to underlie its anti-tumor action. Conclusions: Our studies establish KDM4B as a potent target for CRPC and B3 as a potential therapeutic agent. B3 as monotherapy or in combination with other anti-PCa therapeutics offers proof of principle for the clinical translation of epigenetic therapy targeting KDMSs for CRPC patients.


2021 ◽  
pp. 1-16
Author(s):  
Ridhima Wadhwa ◽  
Keshav Raj Paudel ◽  
Shakti Shukla ◽  
Madhur Shastri ◽  
Gaurav Gupta ◽  
...  

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