The Role of Chronic Inflammation in Pediatric Cancer DOI Open Access

Christine Mella,

Panogiotis Tsarouhas,

Maximillian Brockwell

et al.

Cancers, Journal Year: 2025, Volume and Issue: 17(1), P. 154 - 154

Published: Jan. 6, 2025

Inflammation plays a crucial role in wound healing and the host immune response following pathogenic invasion. However, unresolved chronic inflammation can result tissue fibrosis genetic alterations that contribute to pathogenesis of human diseases such as cancer. Recent scientific advancements exploring underlying mechanisms malignant cellular transformations cancer progression have exposed significant disparities between pediatric adult-onset cancers. For instance, cancers tend lower mutational burdens arise actively developing tissues, where cell-cycle dysregulation leads gene, chromosomal, fusion gene development not seen counterparts. As such, findings adult cannot be directly applied cancers, unique mutations inherent etiologies remain poorly understood. Here, we review processes chromosomal instability, tumor microenvironment, tumorigenesis transformation explore current therapeutic interventions maintain and/or restore inflammatory homeostasis.

Language: Английский

Targeting MAPK Signaling in Cancer: Mechanisms of Drug Resistance and Sensitivity DOI Open Access
Shannon Lee, Jens Rauch, Walter Kölch

et al.

International Journal of Molecular Sciences, Journal Year: 2020, Volume and Issue: 21(3), P. 1102 - 1102

Published: Feb. 7, 2020

Mitogen-activated protein kinase (MAPK) pathways represent ubiquitous signal transduction that regulate all aspects of life and are frequently altered in disease. Here, we focus on the role MAPK modulating drug sensitivity resistance cancer. We briefly discuss new findings extracellular signaling-regulated (ERK) pathway, but mainly mechanisms how stress activated pathways, such as p38 Jun N-terminal kinases (JNK), impact response cancer cells to chemotherapies targeted therapies. In this context, also metabolic epigenetic aberrations therapeutic opportunities arising from these changes.

Language: Английский

Citations

639
Thirty Years of HDAC Inhibitors: 2020 Insight and Hindsight DOI

Terence C. S. Ho,

Alex H. Y. Chan, A. Ganesan

et al.

Journal of Medicinal Chemistry, Journal Year: 2020, Volume and Issue: 63(21), P. 12460 - 12484

Published: July 1, 2020

It is now 30 years since the first report of a potent zinc-dependent histone deacetylase (HDAC) inhibitor appeared. Since then, five HDAC inhibitors have received regulatory approval for cancer chemotherapy while many others are in clinical development oncology as well other therapeutic indications. This Perspective reviews biological and medicinal chemistry advances over past 3 decades with an emphasis on design selective that discriminate between 11 human isoforms.

Language: Английский

Citations

574
Epigenetic mechanisms in breast cancer therapy and resistance DOI Creative Commons
Liliana Garcia-Martinez, Yusheng Zhang,

Yuichiro Nakata

et al.

Nature Communications, Journal Year: 2021, Volume and Issue: 12(1)

Published: March 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.

Language: Английский

Citations

336
Rational combinations of targeted cancer therapies: background, advances and challenges DOI
Haojie Jin, Liqin Wang, René Bernards

et al.

Nature Reviews Drug Discovery, Journal Year: 2022, Volume and Issue: 22(3), P. 213 - 234

Published: Dec. 12, 2022

Language: Английский

Citations

249
Apoptosis Deregulation and the Development of Cancer Multi-Drug Resistance DOI Open Access
Christiana M. Neophytou, Ioannis P. Trougakos, Nuray Erin

et al.

Cancers, Journal Year: 2021, Volume and Issue: 13(17), P. 4363 - 4363

Published: Aug. 28, 2021

The ability of tumor cells to evade apoptosis is established as one the hallmarks cancer. deregulation apoptotic pathways conveys a survival advantage enabling cancer develop multi-drug resistance (MDR), complex phenotype referring concurrent toward agents with different function and/or structure. Proteins implicated in intrinsic pathway apoptosis, including Bcl-2 superfamily and Inhibitors Apoptosis (IAP) family members, well their regulator, suppressor p53, have been development MDR many types. PI3K/AKT pivotal promoting proliferation often overactive tumors. In addition, microenvironment, particularly factors secreted by cancer-associated fibroblasts, can inhibit reduce effectiveness anti-cancer drugs. this review, we describe main alterations that occur apoptosis-and related promote MDR. We also summarize therapeutic approaches against resistant tumors, targeting small molecule inhibitors IAPs or AKT natural origin may be used monotherapy combination conventional therapeutics. Finally, highlight potential exploitation epigenetic modifications reverse phenotype.

Language: Английский

Citations

246
Epigenetic modulation of antitumor immunity for improved cancer immunotherapy DOI Creative Commons
Enyong Dai, Zhi Zhu,

Shudipto Wahed

et al.

Molecular Cancer, Journal Year: 2021, Volume and Issue: 20(1)

Published: Dec. 20, 2021

Abstract Epigenetic mechanisms play vital roles not only in cancer initiation and progression, but also the activation, differentiation effector function(s) of immune cells. In this review, we summarize current literature related to epigenomic dynamics cells impacting cell fate functionality, immunogenicity Some important immune-associated genes, such as granzyme B, IFN-γ, IL-2, IL-12, FoxP3 STING, are regulated via epigenetic or/and cells, checkpoint molecules (PD-1, CTLA-4, TIM-3, LAG-3, TIGIT) expressed by tumor-associated stromal Thus, therapeutic strategies implementing modulating drugs expected significantly impact tumor microenvironment (TME) promoting transcriptional metabolic reprogramming local populations, resulting inhibition immunosuppressive (MDSCs Treg) activation anti-tumor T professional antigen presenting (APC), well which can serve non-professional APC. latter instance, agents may coordinately promote inducing de novo expression transcriptionally repressed antigens, increasing neoantigens MHC processing/presentation machinery, activating immunogenic death (ICD). ICD provides a rich source immunogens for cross-priming sensitizing interventional immunotherapy. way, modulators be envisioned effective components combination immunotherapy approaches capable mediating superior efficacy.

Language: Английский

Citations

194
Cancer epigenetics in clinical practice DOI Open Access
Verónica Dávalos, Manel Esteller

CA A Cancer Journal for Clinicians, Journal Year: 2022, Volume and Issue: 73(4), P. 376 - 424

Published: Dec. 13, 2022

Abstract Cancer development is driven by the accumulation of alterations affecting structure and function genome. Whereas genetic changes disrupt DNA sequence, epigenetic contribute to acquisition hallmark tumor capabilities regulating gene expression programs that promote tumorigenesis. Shifts in methylation histone mark patterns, two main modifications, orchestrate progression metastasis. These cancer‐specific events have been exploited as useful tools for diagnosis, monitoring, treatment choice aid clinical decision making. Moreover, reversibility contrast irreversibility changes, has made machinery an attractive target drug development. This review summarizes most advanced applications biomarkers drugs setting, highlighting commercially available methylation‐based assays already approved US Food Drug Administration.

Language: Английский

Citations

158
Triple negative breast cancer (TNBC): Non-genetic tumor heterogeneity and immune microenvironment: Emerging treatment options DOI Creative Commons
Jae Young So, Joyce E. Ohm,

Stan Lipkowitz

et al.

Pharmacology & Therapeutics, Journal Year: 2022, Volume and Issue: 237, P. 108253 - 108253

Published: July 21, 2022

Triple-negative breast cancer (TNBC) is an aggressive subtype characterized by extensive intra-tumoral heterogeneity, and frequently develops resistance to therapies. Tumor heterogeneity lack of biomarkers are thought be some the most difficult challenges driving therapeutic relapse. This review will summarize current therapy for TNBC, studies in treatment relapse, including data from recent single cell sequencing. We discuss changes both transcriptome epigenome we mechanisms regulating immune microenvironment. Lastly, provide new perspective patient stratification, options targeting dysregulation microenvironment TNBC patients.

Language: Английский

Citations

137
Small-molecule inhibitors, immune checkpoint inhibitors, and more: FDA-approved novel therapeutic drugs for solid tumors from 1991 to 2021 DOI Creative Commons
Qing Wu, Wei Qian,

Xiaoli Sun

et al.

Journal of Hematology & Oncology, Journal Year: 2022, Volume and Issue: 15(1)

Published: Oct. 8, 2022

Abstract The United States Food and Drug Administration (US FDA) has always been a forerunner in drug evaluation supervision. Over the past 31 years, 1050 drugs (excluding vaccines, cell-based therapies, gene therapy products) have approved as new molecular entities (NMEs) or biologics license applications (BLAs). A total of 228 these were identified cancer therapeutics cancer-related drugs, 120 them classified therapeutic for solid tumors according to their initial indications. These evolved from small molecules with broad-spectrum antitumor properties early stage monoclonal antibodies (mAbs) antibody‒drug conjugates (ADCs) more precise targeting effect during most recent decade. extended indications other malignancies, constituting treatment system monotherapy combined therapy. However, available targets are still mainly limited receptor tyrosine kinases (RTKs), restricting development drugs. In this review, summarized indications, characteristics, functions. Additionally, RTK-targeted therapies immune checkpoint-based immunotherapies also discussed. Our analysis existing challenges potential opportunities may advance tumor future.

Language: Английский

Citations

137
A Dual PI3K/HDAC Inhibitor Induces Immunogenic Ferroptosis to Potentiate Cancer Immune Checkpoint Therapy DOI Open Access

Fushun Fan,

Pei Liu,

Rudi Bao

et al.

Cancer Research, Journal Year: 2021, Volume and Issue: 81(24), P. 6233 - 6245

Published: Oct. 28, 2021

The capacity of targeted anticancer agents to exert immunomodulatory effects provides a strong rationale develop novel suitable for combinatorial regimens with immunotherapy improve clinical outcomes. In this study, we developed dual-targeting PI3K and HDAC inhibitor BEBT-908 that potently inhibits tumor cell growth potentiates anti-PD1 therapy in mice by inducing immunogenic ferroptosis cancer cells. Treatment promoted ferroptotic death cells hyperacetylating p53 facilitating the expression signaling. Furthermore, proinflammatory microenvironment activated host antitumor immune responses potentiated checkpoint blockade therapy. Mechanistically, BEBT-908-induced led upregulation MHC class I activation endogenous IFNγ signaling via STAT1 pathway. dual PI3K/HDAC is promising therapeutic agent against multiple types promotes enhances efficacy immunotherapy. SIGNIFICANCE: elicits potent responses, effectively potentiating

Language: Английский

Citations

128