Reprogramming of cancer-associated fibroblasts combined with immune checkpoint inhibitors: A potential therapeutic strategy for cancers

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, Год журнала: 2023, Номер 1878(5), С. 188945 - 188945

Опубликована: Июнь 24, 2023

Язык: Английский

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BCL2L1 is regulated by the lncRNA MIR4435-2HG-miR-513a-5p-BCL2L1 ceRNA axis and serves as a biomarker for pancreatic adenocarcinoma treatment and prognosis

Gene, Год журнала: 2024, Номер 925, С. 148615 - 148615

Опубликована: Май 23, 2024

Язык: Английский

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Stereotactic Radiotherapy Plus Nivolumab in Patients with Locally Advanced Pancreatic Cancer: Results from Phase 1/2 Clinical CA209-9KH Trial

Oncology and Therapy, Год журнала: 2024, Номер 12(4), С. 817 - 831

Опубликована: Окт. 23, 2024

The dismal prognosis of pancreatic ductal adenocarcinoma (PDAC) highlights the urgent need for novel therapeutic strategies. Immune checkpoint inhibitors (ICIs) seem to be ineffective in most PDAC studies. Therefore, we conducted an open-label, multicenter phase 1/2 study (CA209-9KH) evaluate safety stereotactic radiotherapy (SRT) and sequential ICI therapy PDAC, as well validate efficacy this regimen a potential activator antitumor immunity. Patients aged ≥ 18 years with unresectable non-metastatic following four FOLFIRINOX induction cycles were included. Treatment comprised SRT (4 × 8 Gy) nivolumab administration until disease progression or unacceptable toxicity. primary endpoints toxicity assessment. Secondary included progression-free survival (PFS), overall (OS), biomarker evaluation, quality life (QoL) analysis. Twenty-two patients screened, 15 enrolled. Eleven (median) administered. demonstrated low clinically nonsignificant toxicity, whereas aligned prior profiles, without grade 4–5 events observed. Three discontinued owing Median PFS OS 8.1 13.0 months, respectively, 12-month rates 0% 66.7%, 24-month rate 8.9%. Biomarker levels correlated clinical radiological control. Patient-reported QoL remained acceptable, deteriorating progression. exhibited manageable profiles consistent previous findings; however, long-term treatment responses not achieved locally advanced PDAC. Another strategy trigger immunity needs sought. EudraCT: 2017–003404-52; ClinicalTrials.gov: NCT04098432.

Язык: Английский

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The application of pancreatic cancer organoids for novel drug discovery

Expert Opinion on Drug Discovery, Год журнала: 2023, Номер 18(4), С. 429 - 444

Опубликована: Март 22, 2023

Introduction Pancreatic ductal adenocarcinoma presents with a dismal prognosis. Personalized therapy is urgently warranted to overcome the treatment limitations of 'one-size-fits-all' scheme. Organoids have emerged as fundamental novel tools study tumor biology and heterogeneity, hence overcoming other model systems by better-reflecting tissue heterogeneity recapitulating in-vivo processes. Besides their crucial role in basic research, they evolved for translational drug discovery patient stratification.Areas covered This review highlights achievements an organoid-based investigation discovery. The authors present overview studies using organoids testing. Further, pinpoint correlating vitro prediction actual patient`s response. Furthermore, describe take thorough overlook microfluidic chips, synthetic matrices, multicellular systems, bioprinting, stem cell-derived pancreatic organoid systemsExpert opinion Organoid promise great potential future clinical applications. Indeed, may be implemented into informed decision-making guiding therapies. However, validation randomized trials mandatory. Additionally, combination cellular compartments exploited studying niche-tumor interaction. Yet, several precautions must kept mind, such standardization reproducibility.

Язык: Английский

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CARD9 deficiency promotes pancreatic cancer growth by blocking dendritic cell maturation via SLC6A8-mediated creatine transport

OncoImmunology, Год журнала: 2023, Номер 12(1)

Опубликована: Апрель 19, 2023

Pancreatic cancer (PC) is featured with low survival rate and poor outcomes. Herein, we found that the expression of caspase-recruitment domain-containing protein 9 (CARD9), predominantly expressed in innate immune cells, was positively related to prognosis PC patients. CARD9-deficient mice exhibited rapider progression poorer rate. CARD9 knockout decreased dendritic cell (DC) maturation impaired DC ability activate T cells vivo vitro. Adoptive transfer confirmed role deficiency relied on DCs. Creatine identified as most significant differential metabolite between WT DCs CARD9−/− wherein it played an essential maintaining function. led creatine levels by inhibiting transcription creatine-specific transporter, solute carrier family 6 member 8 (SLC6A8). Furtherly, deletion blocked p65 activation abolishing formation CARD9-BCL10-MALT1 complex, which prevented binding SLC6A8 promoter. These events transport into DCs, immaturity impairment antitumor immunity, consequently promoting progression.

Язык: Английский

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