Targeted therapy and immunotherapy for gastric cancer: rational strategies, novel advancements, challenges, and future perspectives

Molecular Medicine, Год журнала: 2025, Номер 31(1)

Опубликована: Фев. 8, 2025

Abstract Gastric cancer (GC) is one of the most common malignant tumors worldwide, and its treatment has been a focus medical research. Herein we systematically review current status advancements in targeted therapy immunotherapy for GC, which have emerged as important strategies recent years with great potential, summarize efficacy safety such treatments. Targeted therapies against key targets including epidermal growth factor receptor (EGFR), human 2 (HER2), vascular endothelial (VEGF)/VEGF (VEGFR), shown remarkable therapeutic efficacies by inhibiting tumor progression and/or blood supply. In particular, markable breakthroughs made HER2-targeting drugs HER2-positive GC patients. To address intrinsic acquired resistances to drugs, novel agents bispecific antibodies antibody–drug conjugates (ADC) targeting HER2 developed. Immunotherapy enhances recognition elimination cells activating body anticancer immune system. Programmed cell death protein 1 (PD-1) programmed death-ligand (PD-L1) are commonly used immunotherapeutic some success treatment. Innovative modalities, adoptive therapy, vaccines, non-specific immunomodulators oncolytic viruses promise early-stage clinical trials GC. Clinical supported that can significantly improve survival quality life However, effects need be further improved more personalized, advancement researches on microenvironment. Further studies remain needed issues drug resistance adverse events pertaining The combined application individualized should explored developed, provide effective treatments

Язык: Английский

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Effects of super-enhancers in cancer metastasis: mechanisms and therapeutic targets

Molecular Cancer, Год журнала: 2024, Номер 23(1)

Опубликована: Июнь 7, 2024

Abstract Metastasis remains the principal cause of cancer-related lethality despite advancements in cancer treatment. Dysfunctional epigenetic alterations are crucial metastatic cascade. Among these, super-enhancers (SEs), emerging as new regulators, consist large clusters regulatory elements that drive high-level expression genes essential for oncogenic process, upon which cells develop a profound dependency. These SE-driven oncogenes play an important role regulating various facets metastasis, including promotion tumor proliferation primary and distal organs, facilitating cellular migration invasion into vasculature, triggering epithelial-mesenchymal transition, enhancing stem cell-like properties, circumventing immune detection, adapting to heterogeneity niches. This heavy reliance on SE-mediated transcription delineates vulnerable target therapeutic intervention cells. In this article, we review current insights characteristics, identification methodologies, formation, activation mechanisms SEs. We also elaborate roles functions SEs context metastasis. Ultimately, discuss potential novel targets their implications clinical oncology, offering future directions innovative treatment strategies.

Язык: Английский

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High somatic mutations in circulating tumor DNA predict response of metastatic pancreatic ductal adenocarcinoma to first-line nab-paclitaxel plus S-1: prospective study

Journal of Translational Medicine, Год журнала: 2024, Номер 22(1)

Опубликована: Фев. 20, 2024

Abstract Aims We previously showed that the nab-paclitaxel plus S-1 (NPS) regimen had promising effects against metastatic pancreatic ducal adenocarcinoma (mPDAC), whose efficacy however could not be precisely predicted by routine biomarkers. This prospective study aimed to investigate values of mutations in circulating tumor DNA (ctDNA) and their dynamic changes predicting response mPDAC NPS chemotherapy. Methods Paired tissue blood samples were prospectively collected from patients with receiving first-line chemotherapy, underwent next-generation sequencing genomic profiling 425 genes for ctDNA. High mutation allelic frequency (MAF) was defined as ≥ 30% 5% blood, respectively. Kappa statistics used assess agreement between mutant Associations ctDNA response, overall survival (OS), progression-free (PFS) assessed using Kaplan–Meier method, multivariable-adjusted Cox proportional hazards regression, longitudinal data analysis. Results 147 43 paired specimens sequenced. The most common driver high MAF KRAS (tumor, 35%; ctDNA, 37%) TP53 37%; 33%). Mutation rates significantly higher liver metastasis, baseline CA19-9 2000 U/mL, and/or without an early response. κ 5 commonly mutated ranged 0.48 0.76. MAFs mostly decreased sequentially during subsequent measurements, which correlated objective increase indicating cancer progression. ARID1A both TP53, CDKN2A, SMAD4 but associated shorter survival. When 6-month OS, AUCs 0.59 0.84, larger than (0.56 0.71) clinicopathologic characteristics (0.51 0.68). Repeated measurements differentiated Among 31 2 tests, analysis gene progression 60 58 days ahead radiologic 48% 42% patients, Conclusions multiple driving effectively predict reliable predictive performance superior parameters. Inspiringly, tracking disease about months or evaluations, potential devise individualized therapeutic strategies mPDAC.

Язык: Английский

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Successful Management of Acquired von Willebrand Syndrome Associated with Monoclonal Gammopathy of Undetermined Significance After Sotorasib Treatment in a Patient with Non-Small-Cell Lung Carcinoma

Hematology Reports, Год журнала: 2025, Номер 17(2), С. 21 - 21

Опубликована: Апрель 16, 2025

Background: This case report investigates the effects of sotorasib treatment in a patient with acquired von Willebrand syndrome (AVWS) associated monoclonal gammopathy undetermined significance (MGUS), who subsequently developed non-small-cell lung carcinoma (NSCLC) KRAS G12C mutation. Case Presentation: The patient, 79-year-old male, presented prolonged history recurrent lower gastrointestinal bleeding attributed to digestive angiodysplasia, which had persisted for over 30 years. AVWS was suspected based on qualitative deficiency factor (VWF), abnormal results VIII activity (FVIII:C), VWF antigen (VWF:Ag), and ristocetin cofactor (VWF:Rco) (40%, 20%, <2.4%, respectively). Further evaluation revealed presence an IgM kappa spike, suggesting MGUS. In 2022, diagnosed NSCLC harboring mutation initiated second-line sotorasib. Notably, one year after initiation therapy, patient’s hemostasis normalized, accompanied by significant improvements levels. multimer electrophoresis demonstrated restoration high-molecular-weight multimers (HMWMs), serum protein no longer detected Conclusion: These were likely attributable indirect bone marrow microenvironment. By inhibiting stromal cells osteoclasts, may have disrupted supportive niche necessary malignant plasma cell survival, resulting reduction spike. Unfortunately, eventually succumbed carcinogenic pleurisy.

Язык: Английский

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Unveiling the Molecular Landscape of Pancreatic Ductal Adenocarcinoma: Insights into the Role of the COMPASS-like Complex

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(10), С. 5069 - 5069

Опубликована: Май 7, 2024

Pancreatic ductal adenocarcinoma (PDAC) is poised to become the second leading cause of cancer-related death by 2030, necessitating innovative therapeutic strategies. Genetic and epigenetic alterations, including those involving COMPASS-like complex genes, have emerged as critical drivers PDAC progression. This review explores genetic landscape PDAC, focusing on role in regulating chromatin accessibility gene expression. Specifically, we delve into functions key components such KDM6A, KMT2D, KMT2C, KMT2A, KMT2B, highlighting their significance potential targets. Furthermore, discuss implications these findings for developing novel treatment modalities PDAC.

Язык: Английский

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Global trends and topics in CDK7 inhibitor research: a bibliometric analysis

Frontiers in Pharmacology, Год журнала: 2024, Номер 15

Опубликована: Сен. 25, 2024

CDK7 has been demonstrated to play a crucial role in the initiation and progression of malignancy. Therefore, targeting CDK7, which regulates transcription process, emerged as new promising approach for treating cancer. Research on inhibitors significantly increased over past 2 decades, with almost 600 related papers Web Science Core Collection database. To effectively identify future research hotspots potential directions, it is systematically review visually present this topic from comprehensive viewpoint, ensuring scientific reliability.

Язык: Английский

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THZ1: Towards KRAS mutation‐based precision medicine against pancreatic ductal adenocarcinoma

Clinical and Translational Discovery, Год журнала: 2024, Номер 4(3)

Опубликована: Июнь 1, 2024

Pancreatic ductal adenocarcinoma (PDAC) remains a formidable global challenge, with grim prognosis and limited treatment options.1 Prior to the advent of molecular targeted therapies, patients PDAC typically received chemotherapy surgical resection, efficacies.2 Genetic analyses have revealed that KRAS mutation importantly drives pathogenesis PDAC, prompting an increasing number investigations into potential therapies addressing this genetic alteration.3, 4 Recent advances in particular Cyclin Dependent Kinase inhibitors, shown promise preclinical studies.5, 6 The recent study by Huang et al.7 presented compelling application for agent THZ1, small-molecule covalent CDK7/12/13 inhibitor, provided intriguing insights its efficacy. THZ1 demonstrated differential inhibitory effects based on specific mutant subtypes showed selective efficacy against harbouring KRAS-G12V compared cancer KRAS-G12D mutation. al.'s study7 employed combination vitro vivo models demonstrate was more effective inhibiting PDAC. importance PI3K/AKT/mTOR signalling pathway mutation-driven pancreatic has been previously highlighted.8 A previous study9 Ewing sarcoma, reduced phosphorylation RNA polymerase II (RNAPOLII) CDK7 activity, which attenuated transcriptional inhibited affecting binding H3K27ac PIK3CA, encodes catalytic subunit PI3K. present further explored how differentially cells pathway: through inhibition RNAPOLII phosphorylation, PIK3CA AKT mTOR enhanced PTEN expression, thus weakening proliferation cells. This specificity represents significant advance, as it paves way personalized management discovered discrepancies sensitivity different were related activity super-enhancers (SEs). significantly SEs marked H3K27ac, bound mutation, whereas had minor effect is interest, given critical role mutations responses cancers highlight profiling guiding therapeutic decisions. Concurrently, mechanistically elucidated SE thereby paving deeper comprehension precise potential. implications findings7 clinical practice are profound. They suggest profiling, particularly identification subtypes, should be integral part diagnostic decision-making processes By aligning profile clinicians can tailor treatments individual patients, potentially enhancing while minimizing toxicity. approach not only streamlines interventions but also underscores shift towards oncology Notably, scope studies needed explore efficacies PDACs wider range alterations. Inactivating genes including CDKN2A/p16, TP53 SMAD410 synergize mutations, subsequently leads aggressive growth. Future expand other therapies. It investigate long-term safety impact patient quality life. development liquid biopsy biomarkers predict response high necessary cancer,3 help regimens. understanding mechanism action molecular-level experiments, identify key proteins altered following treatment. field precision currently experiencing transformative phase. historically linked being challenged groundbreaking insights. highlights strategies tailored cancers. As intricate details PDAC's genetics uncovered, roles diagnostics therapeutics become increasingly significant. aberrations pivotal facilitating discovery bespoke integration tools poised markedly improve outcomes, offering new hope who long faced options. Together, research landmark ongoing endeavour therapy underpinnings each patient's marks step medicine provides blueprint future trials. lies ability precisely address aberrations, goal now closer realization thanks research.7 continues evolve, like hold transforming care. Conception design: Mancang Gu, Yan Shi Lei Huang. Writing, review, and/or revision manuscript: Yansong Qin, Administrative, technical, or material support (i.e. reporting organizing data constructing databases): Study supervision: All authors approved manuscript submission publication. funded grants from Start-up Fund Introduction High-Level Talents Ruijin Hospital, Shanghai Jiao Tong University School Medicine RC20210157. funder no design; collection, analysis, interpretation data; writing report; decision submit paper We appreciate great Public Platform Pharmaceutical Research Center, Academy Chinese Medical Sciences, Zhejiang University. declare conflict interest. Not applicable.

Язык: Английский

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Erratum for the research article “The suppressive efficacy of THZ1 depends on KRAS mutation subtype and is associated with super‐enhancer activity and the PI3K/AKT/mTOR signalling in pancreatic ductal adenocarcinoma: A hypothesis‐generating study” by Huang et al

Clinical and Translational Medicine, Год журнала: 2024, Номер 15(1)

Опубликована: Дек. 27, 2024

Some inadvertent mistake in our paper entitled "The suppressive efficacy of THZ1 depends on KRAS mutation subtype and is associated with super-enhancer activity the PI3K/AKT/mTOR signalling pancreatic ductal adenocarcinoma: A hypothesis-generating study" [1] published Clinical translational medicine came to attention recently: (1) There was an unintentional placement assembly representative individual bioluminescence images original Figure 2A, which does not impact statistical analysis, described findings, or conclusions. We would like correct image red block 2A as (Figure 1): (2) loading control band Western blot, influence findings GAPDH 1I 2). And 5C E 3): The corrections do have any conclusions, other part manuscript. sincerely apologize for inconvenience caused. n\a

Язык: Английский

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