Small-cell lung cancer

Nature Reviews Disease Primers, Journal Year: 2021, Volume and Issue: 7(1)

Published: Jan. 14, 2021

Language: Английский

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Notch signaling pathway: architecture, disease, and therapeutics

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: March 24, 2022

Abstract The NOTCH gene was identified approximately 110 years ago. Classical studies have revealed that signaling is an evolutionarily conserved pathway. receptors undergo three cleavages and translocate into the nucleus to regulate transcription of target genes. deeply participates in development homeostasis multiple tissues organs, aberration which results cancerous noncancerous diseases. However, recent indicate outcomes are changeable highly dependent on context. In terms cancers, can both promote inhibit tumor various types cancer. overall performance NOTCH-targeted therapies clinical trials has failed meet expectations. Additionally, mutation been proposed as a predictive biomarker for immune checkpoint blockade therapy many cancers. Collectively, pathway needs be integrally assessed with new perspectives inspire discoveries applications. this review, we focus classical latest findings related illustrate history, architecture, regulatory mechanisms, contributions physiological development, diseases, therapeutic applications microenvironment cancer immunotherapy also highlighted. We hope review will help not only beginners but experts systematically thoroughly understand

Language: Английский

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Targeting Notch in oncology: the path forward

Nature Reviews Drug Discovery, Journal Year: 2020, Volume and Issue: 20(2), P. 125 - 144

Published: Dec. 8, 2020

Language: Английский

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Clinical and Biological Features of Neuroendocrine Prostate Cancer

Current Oncology Reports, Journal Year: 2021, Volume and Issue: 23(2)

Published: Jan. 12, 2021

Language: Английский

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Precision medicine for human cancers with Notch signaling dysregulation (Review)

International Journal of Molecular Medicine, Journal Year: 2019, Volume and Issue: unknown

Published: Dec. 4, 2019

NOTCH1, NOTCH2, NOTCH3 and NOTCH4 are transmembrane receptors that transduce juxtacrine signals of the delta‑like canonical Notch ligand (DLL)1, DLL3, DLL4, jagged (JAG)1 JAG2. Canonical signaling activates transcription BMI1 proto‑oncogene polycomb ring finger, cyclin D1, CD44, dependent kinase inhibitor 1A, hes family bHLH factor 1, related with YRPW motif MYC, NOTCH3, RE1 silencing 7 in a cellular context‑dependent manner, while non‑canonical NF‑κB Rac small GTPase 1. is aberrantly activated breast cancer, non‑small‑cell lung cancer hematological malignancies, such as T‑cell acute lymphoblastic leukemia diffuse large B‑cell lymphoma. However, inactivated small‑cell squamous cell carcinomas. Loss‑of‑function NOTCH1 mutations early events during esophageal tumorigenesis, whereas gain‑of‑function late leukemogenesis lymphomagenesis. cascades crosstalk fibroblast growth WNT tumor microenvironment to maintain stem cells remodel microenvironment. The network exerts oncogenic tumor‑suppressive effects stage‑ or (sub)type‑dependent manner. Small‑molecule γ‑secretase inhibitors (AL101, MRK‑560, nirogacestat others) antibody‑based biologics targeting ligands [ABT‑165, AMG 119, rovalpituzumab tesirine (Rova‑T) others] have been developed investigational drugs. DLL3‑targeting antibody‑drug conjugate (ADC) Rova‑T, chimeric antigen receptor‑modified T (CAR‑Ts), promising anti‑cancer therapeutics, other ADCs CAR‑Ts necrosis receptor superfamily member 17, CD19, CD22, CD30, CD79B, CD205, Claudin 18.2, (FGFR)2, FGFR3, receptor‑type tyrosine‑protein FLT3, HER2, hepatocyte receptor, NECTIN4, inactive 7, ROR1 tumor‑associated calcium signal transducer 2. could alter therapeutic framework for refractory cancers, especially diffuse‑type gastric ovarian pancreatic peritoneal dissemination. Phase III clinical trials Rova‑T patients phase trial desmoid tumors ongoing. Integration human intelligence, cognitive computing explainable artificial intelligence necessary construct Notch‑related knowledge‑base optimize Notch‑targeted therapy cancer.

Language: Английский

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Clinical insights into small cell lung cancer: Tumor heterogeneity, diagnosis, therapy, and future directions

CA A Cancer Journal for Clinicians, Journal Year: 2023, Volume and Issue: 73(6), P. 620 - 652

Published: June 17, 2023

Abstract Small cell lung cancer (SCLC) is characterized by rapid growth and high metastatic capacity. It has strong epidemiologic biologic links to tobacco carcinogens. Although the majority of SCLCs exhibit neuroendocrine features, an important subset tumors lacks these properties. Genomic profiling SCLC reveals genetic instability, almost universal inactivation tumor suppressor genes TP53 RB1 , a mutation burden. Because early metastasis, only small fraction patients are amenable curative‐intent resection, individuals require adjuvant platinum‐etoposide chemotherapy. Therefore, vast currently being treated with chemoradiation or without immunotherapy. In disease confined chest, standard therapy includes thoracic radiotherapy concurrent Patients (extensive‐stage) combination chemotherapy plus immunotherapy anti‐programmed death‐ligand 1 monoclonal antibody. initially very responsive platinum‐based chemotherapy, responses transient because development drug resistance. recent years, authors have witnessed accelerating pace insights into disease, leading redefinition classification scheme. This emerging knowledge molecular subtypes potential define unique therapeutic vulnerabilities. Synthesizing new discoveries current biology clinical management may lead unprecedented advances in patient care. Here, present overview multimodal approaches SCLC, special focus on illuminating how advancements research could accelerate development.

Language: Английский

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AMG 757, a Half-Life Extended, DLL3-Targeted Bispecific T-Cell Engager, Shows High Potency and Sensitivity in Preclinical Models of Small-Cell Lung Cancer

Clinical Cancer Research, Journal Year: 2020, Volume and Issue: 27(5), P. 1526 - 1537

Published: Nov. 17, 2020

Small-cell lung cancer (SCLC) is an aggressive neuroendocrine tumor with a high relapse rate, limited therapeutic options, and poor prognosis. We investigated the antitumor activity of AMG 757, half-life extended bispecific T-cell engager molecule targeting delta-like ligand 3 (DLL3)-a target that selectively expressed in SCLC tumors, but minimal normal tissue expression.

Language: Английский

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Tarlatamab, a First-in-Class DLL3-Targeted Bispecific T-Cell Engager, in Recurrent Small-Cell Lung Cancer: An Open-Label, Phase I Study

Journal of Clinical Oncology, Journal Year: 2023, Volume and Issue: 41(16), P. 2893 - 2903

Published: Jan. 23, 2023

PURPOSE Small-cell lung cancer (SCLC) is an aggressive malignancy with limited treatments. Delta-like ligand 3 (DLL3) aberrantly expressed in most SCLC. Tarlatamab (AMG 757), a bispecific T-cell engager molecule, binds both DLL3 and CD3 leading to T-cellb–mediated tumor lysis. Herein, we report phase I results of tarlatamab patients PATIENTS AND METHODS This study evaluated relapsed/refractory The primary end point was safety. Secondary points included antitumor activity by modified RECIST 1.1, overall survival, pharmacokinetics. RESULTS By July 19, 2022, 107 received dose exploration (0.003 100 mg; n = 73) expansion (100 34) cohorts. Median prior lines anticancer therapy were 2 (range, 1-6); 49.5% antiprogrammed death-1/programmed death ligand-1 therapy. Any-grade treatment-related adverse events occurred 97 (90.7%) grade b % 33 (30.8%). One patient (1%) had 5 pneumonitis. Cytokine release syndrome the common event, occurring 56 (52%) including one (1%). Maximum tolerated not reached. Objective response rate 23.4% (95% CI, 15.7 32.5) two complete 23 partial responses. median duration 12.3 months 6.6 14.9). disease control 51.4% 41.5 61.2). progression-free survival 3.7 2.1 5.4) 13.2 10.5 reached), respectively. Exploratory analysis suggests that selecting for increased expression can result clinical benefit. CONCLUSION In heavily pretreated SCLC, demonstrated manageable safety encouraging durability. Further evaluation this promising molecule ongoing. [Media: see text]

Language: Английский

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SCLC: Epidemiology, Risk Factors, Genetic Susceptibility, Molecular Pathology, Screening, and Early Detection

Journal of Thoracic Oncology, Journal Year: 2022, Volume and Issue: 18(1), P. 31 - 46

Published: Oct. 12, 2022

Language: Английский

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Notch signaling pathway in cancer: from mechanistic insights to targeted therapies

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: May 27, 2024

Notch signaling, renowned for its role in regulating cell fate, organ development, and tissue homeostasis across metazoans, is highly conserved throughout evolution. The receptor ligands are transmembrane proteins containing epidermal growth factor-like repeat sequences, typically necessitating receptor-ligand interaction to initiate classical signaling transduction. Accumulating evidence indicates that the pathway serves as both an oncogenic factor a tumor suppressor various cancer types. Dysregulation of this promotes epithelial-mesenchymal transition angiogenesis malignancies, closely linked proliferation, invasion, metastasis. Furthermore, contributes maintaining stem-like properties cells, thereby enhancing invasiveness. regulatory metabolic reprogramming microenvironment suggests pivotal involvement balancing suppressive effects. Moreover, implicated conferring chemoresistance cells. Therefore, comprehensive understanding these biological processes crucial developing innovative therapeutic strategies targeting signaling. This review focuses on research progress cancers, providing in-depth insights into potential mechanisms regulation occurrence progression cancer. Additionally, summarizes pharmaceutical clinical trials therapy, aiming offer new human malignancies.

Language: Английский

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