Epigenetic mechanisms in breast cancer therapy and resistance

Nature Communications, Год журнала: 2021, Номер 12(1)

Опубликована: Март 19, 2021

The majority of breast cancers express the estrogen receptor (ERα) and agents targeting this pathway represent main treatment modality. Endocrine therapy has proven successful in hormone-responsive cancer since its early adoption 1940s as an ablative therapy. Unfortunately, therapeutic resistance arises, leading to disease recurrence relapse. Recent studies increased our understanding how changes chromatin landscape deregulation epigenetic factors orchestrate resistant phenotype. Here, we will discuss epigenome is integral determinant hormone response why are promising targets for overcoming clinical resistance.

Язык: Английский

---

The Roles of Histone Deacetylases and Their Inhibitors in Cancer Therapy

Frontiers in Cell and Developmental Biology, Год журнала: 2020, Номер 8

Опубликована: Сен. 29, 2020

Genetic mutations and abnormal gene regulation are key mechanisms underlying tumorigenesis. Nucleosomes, which consist of DNA wrapped around histone cores, represent the basic units chromatin. The fifth amino group (Nε) lysine residues is a common site for post-translational modifications (PTMs), these, acetylation second most common. Histone modulated by acetyltransferases (HATs) deacetylases (HDACs), involved in expression. Over past two decades, numerous studies characterizing HDACs HDAC inhibitors (HDACi) have provided novel exciting insights concerning their biological potential anti-cancer treatments. In this review, we detail diverse structures functions, including transcriptional regulation, metabolism, angiogenesis, damage response, cell cycle, apoptosis, protein degradation, immunity other several physiological processes. We also highlight avenues to use HDACi as novel, precision cancer

Язык: Английский

---

The Glioma Stem Cell Model in the Era of Single-Cell Genomics

Cancer Cell, Год журнала: 2020, Номер 37(5), С. 630 - 636

Опубликована: Май 1, 2020

Язык: Английский

---

Clinical Efficacy of ONC201 in H3K27M-Mutant Diffuse Midline Gliomas Is Driven by Disruption of Integrated Metabolic and Epigenetic Pathways

Cancer Discovery, Год журнала: 2023, Номер 13(11), С. 2370 - 2393

Опубликована: Авг. 11, 2023

Abstract Patients with H3K27M-mutant diffuse midline glioma (DMG) have no proven effective therapies. ONC201 has recently demonstrated efficacy in these patients, but the mechanism behind this finding remains unknown. We assessed clinical outcomes, tumor sequencing, and tissue/cerebrospinal fluid (CSF) correlate samples from patients treated two completed multisite studies. following initial radiation prior to recurrence a median overall survival of 21.7 months, whereas those after had 9.3 months. Radiographic response was associated increased expression key tricarboxylic acid cycle–related genes baseline sequencing. treatment 2-hydroxyglutarate levels cultured H3K27M-DMG cells patient CSF samples. This corresponded increases repressive H3K27me3 vitro human tumors accompanied by epigenetic downregulation cell cycle regulation neuroglial differentiation genes. Overall, demonstrates disrupting integrated metabolic pathways reversing pathognomonic reduction. Significance: The clinical, radiographic, molecular analyses included study demonstrate DMG support as first monotherapy improve outcomes beyond radiation. Mechanistically, disrupts reverses article is featured Selected Articles Issue, p. 2293

Язык: Английский

---

LSD1 inhibitors for cancer treatment: Focus on multi-target agents and compounds in clinical trials

Frontiers in Pharmacology, Год журнала: 2023, Номер 14

Опубликована: Фев. 2, 2023

Histone lysine-specific demethylase 1 (LSD1/KDM1A) was first identified in 2004 as an epigenetic enzyme able to demethylate specific lysine residues of histone H3, namely H3K4me1/2 and H3K9me1/2, using FAD the cofactor. It is ubiquitously overexpressed many types cancers (breast, gastric, prostate, hepatocellular, esophageal cancer, acute myeloid leukemia, others) leading block differentiation increase proliferation, migration invasiveness at cellular level. LSD1 inhibitors can be grouped covalent non-covalent agents. Each group includes some hybrid compounds, inhibit addition other target(s) same time (dual or multitargeting compounds). To date, 9 have entered clinical trials, for hematological and/or solid cancers. Seven them (tranylcypromine, iadademstat (ORY-1001), bomedemstat (IMG-7289), GSK-2879552, INCB059872, JBI-802, Phenelzine) covalently bind cofactor, two are [pulrodemstat (CC-90011) seclidemstat (SP-2577)]. Another TCP-based LSD1/MAO-B dual inhibitor, vafidemstat (ORY-2001), trial Alzheimer’s diseases personality disorders. The present review summarizes structure functions LSD1, its pathological implications cancer non-cancer diseases, identification with different chemical scaffolds, including those involved highlighting their potential potent selective anticancer

Язык: Английский

---

Signaling pathways in brain tumors and therapeutic interventions

Signal Transduction and Targeted Therapy, Год журнала: 2023, Номер 8(1)

Опубликована: Янв. 4, 2023

Abstract Brain tumors, although rare, contribute to distinct mortality and morbidity at all ages. Although there are few therapeutic options for brain enhanced biological understanding unexampled innovations in targeted therapies immunotherapies have considerably improved patients’ prognoses. Nonetheless, the reduced response rates unavoidable drug resistance of currently available treatment approaches become a barrier further improvement tumor (glioma, meningioma, CNS germ cell lymphoma) treatment. Previous literature data revealed that several different signaling pathways dysregulated tumor. Importantly, better targeting influences malignant behavior cells might open way development novel therapies. Thus, is an urgent need more comprehensive pathogenesis these which result greater progress approaches. This paper began with brief description epidemiology, incidence, risk factors, as well survival tumors. Next, major underlying tumors’ current therapies, including clinical trials, immunotherapies, system been systemically reviewed discussed. Finally, future perspective challenges strategies were emphasized.

Язык: Английский

---

Integrated Metabolic and Epigenomic Reprograming by H3K27M Mutations in Diffuse Intrinsic Pontine Gliomas

Cancer Cell, Год журнала: 2020, Номер 38(3), С. 334 - 349.e9

Опубликована: Авг. 13, 2020

Язык: Английский

---

The Chemical Biology of Reversible Lysine Post-translational Modifications

Cell chemical biology, Год журнала: 2020, Номер 27(8), С. 953 - 969

Опубликована: Июль 21, 2020

Язык: Английский

---

H3 K27M and EZHIP Impede H3K27-Methylation Spreading by Inhibiting Allosterically Stimulated PRC2

Molecular Cell, Год журнала: 2020, Номер 80(4), С. 726 - 735.e7

Опубликована: Окт. 12, 2020

Язык: Английский

---

LSD1/KDM1A, a Gate-Keeper of Cancer Stemness and a Promising Therapeutic Target

Cancers, Год журнала: 2019, Номер 11(12), С. 1821 - 1821

Опубликована: Ноя. 20, 2019

A new exciting area in cancer research is the study of stem cells (CSCs) and translational implications for putative epigenetic therapies targeted against them. Accumulating evidence effects modulating agents has revealed their dramatic consequences on cellular reprogramming and, particularly, reversing stemness characteristics, such as self-renewal chemoresistance. Lysine specific demethylase 1 (LSD1/KDM1A) plays a well-established role normal hematopoietic neuronal cells. Overexpression LSD1 been documented variety cancers, where enzyme is, usually, associated with more aggressive types disease. Interestingly, recent studies have implicated regulation pool CSCs different leukemias solid tumors. However, precise mechanisms that uses to mediate its are largely unknown. Herein, we review literature LSD1's cells, highlighting analogies mode action two biological settings. Given potential pharmacological target, we, also, discuss current advances design novel therapeutic regimes incorporate inhibitors, well future perspectives.

Язык: Английский

---