Exploring the next generation of antibody–drug conjugates

Nature Reviews Clinical Oncology, Год журнала: 2024, Номер 21(3), С. 203 - 223

Опубликована: Янв. 8, 2024

Язык: Английский

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Amivantamab plus Lazertinib in Previously Untreated EGFR -Mutated Advanced NSCLC

New England Journal of Medicine, Год журнала: 2024, Номер 391(16), С. 1486 - 1498

Опубликована: Июнь 26, 2024

BackgroundAmivantamab plus lazertinib (amivantamab–lazertinib) has shown clinically meaningful and durable antitumor activity in patients with previously untreated or osimertinib-pretreated EGFR (epidermal growth factor receptor)–mutated advanced non–small-cell lung cancer (NSCLC).MethodsIn a phase 3, international, randomized trial, we assigned, 2:2:1 ratio, EGFR-mutated (exon 19 deletion L858R), locally metastatic NSCLC to receive amivantamab–lazertinib (in an open-label fashion), osimertinib blinded fashion, assess the contribution of treatment components). The primary end point was progression-free survival group as compared group, assessed by independent central review.ResultsOverall, 1074 underwent randomization (429 amivantamab–lazertinib, 429 osimertinib, 216 lazertinib). median significantly longer than (23.7 vs. 16.6 months; hazard ratio for disease progression death, 0.70; 95% confidence interval [CI], 0.58 0.85; P<0.001). An objective response observed 86% (95% CI, 83 89) 85% those 81 88) group; among confirmed (336 314 group), duration 25.8 months 20.1 could not be estimated) 16.8 14.8 18.5), respectively. In planned interim overall analysis death 0.80 0.61 1.05). Predominant adverse events were EGFR-related toxic effects. incidence discontinuation all agents due treatment-related 10% 3% osimertinib.ConclusionsAmivantamab–lazertinib showed superior efficacy first-line NSCLC. (Funded Janssen Research Development; MARIPOSA ClinicalTrials.gov number, NCT04487080.)

Язык: Английский

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Recent Advances in Pyrimidine-Based Drugs

Pharmaceuticals, Год журнала: 2024, Номер 17(1), С. 104 - 104

Опубликована: Янв. 11, 2024

Pyrimidines have become an increasingly important core structure in many drug molecules over the past 60 years. This article surveys recent areas which pyrimidines had a major impact discovery therapeutics, including anti-infectives, anticancer, immunology, immuno-oncology, neurological disorders, chronic pain, and diabetes mellitus. The presents synthesis of medicinal agents highlights role biological target with respect to disease model. Additionally, potency, ADME properties pharmacokinetics/pharmacodynamics (if available) are discussed. survey attempts demonstrate versatility pyrimidine-based drugs, not only for their potency affinity but also improved chemistry pyrimidine as bioisostere phenyl other aromatic π systems. It is hoped that this will provide insight researchers considering scaffold chemotype future candidates order counteract medical conditions previously deemed untreatable.

Язык: Английский

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Therapeutic advances of targeting receptor tyrosine kinases in cancer

Signal Transduction and Targeted Therapy, Год журнала: 2024, Номер 9(1)

Опубликована: Авг. 14, 2024

Abstract Receptor tyrosine kinases (RTKs), a category of transmembrane receptors, have gained significant clinical attention in oncology due to their central role cancer pathogenesis. Genetic alterations, including mutations, amplifications, and overexpression certain RTKs, are critical creating environments conducive tumor development. Following discovery, extensive research has revealed how RTK dysregulation contributes oncogenesis, with many subtypes showing dependency on aberrant signaling for proliferation, survival progression. These findings paved the way targeted therapies that aim inhibit crucial biological pathways cancer. As result, RTKs emerged as primary targets anticancer therapeutic Over past two decades, this led synthesis validation numerous small molecule kinase inhibitors (TKIs), now effectively utilized treating various types. In manuscript we provide comprehensive understanding context We explored alterations specific receptors across different malignancies, special dedicated examination current inhibitors, highlighting potential therapies. By integrating latest evidence, seek elucidate pivotal biology efficacy inhibition promising treatment outcomes.

Язык: Английский

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Results from a phase 1b study of telisotuzumab vedotin in combination with osimertinib in patients with c-Met protein–overexpressing, EGFR-mutated locally advanced/metastatic non-small cell lung cancer (NSCLC) after progression on prior osimertinib

Annals of Oncology, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

Язык: Английский

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Pyrimidine scaffold dual‐target kinase inhibitors for cancer diseases: A review on design strategies, synthetic approaches, and structure–activity relationship (2018‒2023)

Archiv der Pharmazie, Год журнала: 2025, Номер 358(1)

Опубликована: Янв. 1, 2025

Abstract Cancer, the second leading cause of death globally, causes a significant threat to life. Despite advancements in treatment cancer, persistent challenges include severe side effects and emergence acquired drug resistance. Additionally, many traditional chemotherapy drugs show restricted efficacy high toxicity, primarily attributed their lack selectivity. Thus, development targeting protein kinases has emerged as noteworthy priority for addressing human cancers. Medicinal chemists have shown considerable interest dual candidates strategy create medicines that are safer, more efficient, cost‐effective. Furthermore, Food Drug Administration (FDA) approved several dual‐target anticancer treatment, emphasizing lower risks interactions improved pharmacokinetics safety profiles. This review focuses on synthetic efforts, design strategies, structure–activity relationship pyrimidine scaffold‐based kinase inhibitors developed with potential within recent 6 years (2018‒2023). Collectively, these strategies expected offer fresh perspectives future directions pyrimidine‐based design, potentially advancing cancer therapeutics.

Язык: Английский

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Integrating network pharmacology and experimental validation to explore the potential mechanism by which resveratrol acts on osimertinib resistance in lung cancer

Oncology Letters, Год журнала: 2025, Номер 29(4), С. 1 - 9

Опубликована: Фев. 20, 2025

Globally, osimertinib resistance has been a long-term challenge. Resveratrol, naturally occurring polyphenolic compound found in various plants, the potential to modulate multidrug mechanisms. However, specific role of resveratrol delaying lung cancer is still unclear. The present study aimed investigate therapeutic effects and underlying mechanisms resistance. Accordingly, corresponding targets were screened through Traditional Chinese Medicine Systems Pharmacology database. Similarly, for mined from GeneCards A protein-protein interaction network was subsequently constructed pinpoint key hub genes that may target delay Molecular docking analysis then employed assess binding energy between predicted resveratrol. Finally, vitro experiments performed validate results. Ultimately, 13 related identified. Kyoto Encyclopedia Genes Genomes suggested be associated with apoptotic pathway. revealed good affinities MCL1 BCL2L11. In confirmed inhibited proliferation osimertinib-resistant cells upregulated expression conclusion, promote apoptosis by targeting BCL2L11

Язык: Английский

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DNA topoisomerase II inhibition potentiates osimertinib’s therapeutic efficacy in EGFR-mutant non–small cell lung cancer models

Journal of Clinical Investigation, Год журнала: 2024, Номер 134(10)

Опубликована: Март 7, 2024

Development of effective strategies to manage the inevitable acquired resistance osimertinib, an approved 3rd generation EGFR inhibitor for treatment mutant (EGFRm) non-small cell lung cancer (NSCLC), is urgently needed. This study reported that DNA topoisomerase II (Topo II) inhibitors, doxorubicin and etoposide (VP-16) synergistically decreased survival with enhanced induction damage apoptosis in osimertinib-resistant cells, suppressed growth tumors, delayed emergence osimertinib resistance. Mechanistically, Topo IIα levels EGFRm NSCLC cells by facilitating FBXW7-mediated proteasomal degradation, resulting damage; these effects were lost lines possessing elevated IIα. elevation was also detected majority tissues relapsed from EGFR-TKI treatment. Enforced expression ectopic TOP2A gene sensitive conferred whereas knockdown restored their response undergo osimertinib-induced apoptosis. Together, results reveal essential role inhibition mediating therapeutic efficacy against NSCLC, providing scientific rationale targeting osimertinib.

Язык: Английский

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Digital counting of tissue cells for molecular analysis: the QuANTUM pipeline

Virchows Archiv, Год журнала: 2024, Номер unknown

Опубликована: Март 26, 2024

Abstract The estimation of tumor cellular fraction (TCF) is a crucial step in predictive molecular pathology, representing an entry adequacy criterion also the next-generation sequencing (NGS) era. However, heterogeneity quantification practices and inter-pathologist variability hamper robustness its evaluation, stressing need for more reliable results. Here, 121 routine histological samples from non-small cell lung cancer (NSCLC) cases with complete NGS profiling were used to evaluate TCF interobserver among three different pathologists (pTCF), developing computational tool (cTCF) assessing reliability vs ground truth (GT) cellularity potential impact on final Inter-pathologist reproducibility was fair good, overall W k ranging between 0.46 0.83 (avg. 0.59). obtained cTCF comparable GT ( p = 0.129, 0.502, 0.130 surgical, biopsies, block, respectively) demonstrated good if elaborated by (W 0.9). Overall lower as compared pTCF (30 ± 10 52 19, < 0.001), 20% (17, 14%, 0.690), but none containing 100 cells algorithm. Similarities noted area (36 29, partly explaining human assessment cellularity. Finally, allowed reduction copy number variations (CNVs) called (27 − 6.9%) increase effective CNVs detection (13 7, + 85.7%), some clinical previously undetected pTCF. An automated pipeline (Qupath Analysis Nuclei Tumor Uniform Molecular tests, QuANTUM) has been created freely available QuPath extension. method this study improve efficacy NSCLC,

Язык: Английский

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Design, synthesis, and antitumor activity evaluation of potent fourth-generation EGFR inhibitors for treatment of Osimertinib resistant non-small cell lung cancer (NSCLC)

Bioorganic Chemistry, Год журнала: 2024, Номер 147, С. 107394 - 107394

Опубликована: Апрель 26, 2024

Язык: Английский

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