RESUMO
Pancreatic cancer is one of the leading causes of cancer-associated mortality, with a poor treatment approach. Previous study has shown that inducing pyroptosis in pancreatic ductal adenocarcinoma (PDAC) slows the growth of PDACs, implying that pyroptosis inducers are potentially effective for PDAC therapy. Here, we found that Dronedarone hydrochloride (DH), an antiarrhythmic drug, induces pyroptosis in pancreatic cancer cells and inhibits PDAC development in mice. In PANC-1 cells, DH caused cell death in a dosage- and time-dependent manner, with only pyroptosis inhibitors and GSDMD silencing rescuing the cell death, indicating that DH triggered GSDMD-dependent pyroptosis. Further work revealed that DH increased mitochondrial stresses and caused mitochondrial DNA (mtDNA) leakage, activating the cytosolic STING-cGAS and pyroptosis pathways. Finally, we assessed the anti-cancer effects of DH in a pancreatic cancer mouse model and found that DH treatment suppressed pancreatic tumor development in vivo. Collectively, our investigation demonstrates that DH triggers pyroptosis in PDAC and proposes its potential effects on anti-PDAC growth.
Assuntos
DNA Mitocondrial , Dronedarona , Neoplasias Pancreáticas , Piroptose , Piroptose/efeitos dos fármacos , Animais , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/genética , Humanos , Dronedarona/farmacologia , DNA Mitocondrial/metabolismo , DNA Mitocondrial/genética , Camundongos , Linhagem Celular Tumoral , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/genética , Camundongos NusRESUMO
A spontaneously occurring temperature increase in solid tumors has been reported sporadically, but is largely overlooked in terms of cancer biology. Here we show that temperature is increased in tumors of patients with pancreatic ductal adenocarcinoma (PDAC) and explore how this could affect therapy response. By mimicking this observation in PDAC cell lines, we demonstrate that through adaptive changes in lipid metabolism, the temperature increase found in human PDAC confers protection to lipid peroxidation and contributes to gemcitabine resistance. Consistent with the recently uncovered role of p38 MAPK in ferroptotic cell death, we find that the reduction in lipid peroxidation potential following adaptation to tumoral temperature allows for p38 MAPK inhibition, conferring chemoresistance. As an increase in tumoral temperature is observed in several other tumor types, our findings warrant taking tumoral temperature into account in subsequent studies related to ferroptosis and therapy resistance. More broadly, our findings indicate that tumoral temperature affects cancer biology.
Assuntos
Carcinoma Ductal Pancreático , Desoxicitidina , Resistencia a Medicamentos Antineoplásicos , Ferroptose , Gencitabina , Metabolismo dos Lipídeos , Neoplasias Pancreáticas , Ferroptose/efeitos dos fármacos , Humanos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Resistencia a Medicamentos Antineoplásicos/genética , Linhagem Celular Tumoral , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/genética , Metabolismo dos Lipídeos/efeitos dos fármacos , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Desoxicitidina/uso terapêutico , Peroxidação de Lipídeos/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Temperatura , Animais , CamundongosRESUMO
This study integrates pharmacology databases with bulk RNA-seq and scRNA-seq to reveal the latent anti-PDAC capacities of BBR. Target genes of BBR were sifted through TargetNet, CTD, SwissTargetPrediction, and Binding Database. Based on the GSE183795 dataset, DEG analysis, GSEA, and WGCNA were sequentially run to build a disease network. Through sub-network filtration acquired PDAC-related hub genes. A PPI network was established using the shared genes. Degree algorithm from cytoHubba screened the key cluster in the network. Analysis of differential mRNA expression and ROC curves gauged the diagnostic performance of clustered genes. CYBERSORT uncovered the potential role of the key cluster on PDAC immunomodulation. ScRNA-seq analysis evaluated the distribution and expression profile of the key cluster at the single-cell level, assessing enrichment within annotated cell subpopulations to delineate the target distribution of BBR in PDAC. We identified 425 drug target genes and 771 disease target genes, using 57 intersecting genes to construct the PPI network. CytoHubba anchored the top 10 highest contributing genes to be the key cluster. mRNA expression levels and ROC curves confirmed that these genes showed good robustness for PDAC. CYBERSORT revealed that the key cluster influenced immune pathways predominantly associated with Macrophages M0, CD8 T cells, and naïve B cells. ScRNA-seq analysis clarified that BBR mainly acted on epithelial cells and macrophages in PDAC tissues. BBR potentially targets CDK1, CCNB1, CTNNB1, CDK2, TOP2A, MCM2, RUNX2, MYC, PLK1, and AURKA to exert therapeutic effects on PDAC. The mechanisms of action appear to significantly involve macrophage polarization-related immunological responses.
Assuntos
Berberina , Carcinoma Ductal Pancreático , Regulação Neoplásica da Expressão Gênica , Neoplasias Pancreáticas , Humanos , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Berberina/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Perfilação da Expressão Gênica , Mapas de Interação de Proteínas , Redes Reguladoras de Genes , MultiômicaRESUMO
Liposomal irinotecan has shown promising antitumor activity in patients with advanced or metastatic pancreatic ductal adenocarcinoma (PDAC) who have undergone prior gemcitabine-based therapies. This randomized, double-blind, parallel-controlled, multicenter phase 3 study (NCT05074589) assessed the efficacy and safety of liposomal irinotecan HR070803 combined with 5-fluorouracil (5-FU) and leucovorin (LV) in this patient population. Patients with unresectable, locally advanced, or metastatic PDAC who had previously received gemcitabine-based therapies were randomized 1:1 to receive either HR070803 (60 mg/m2 anhydrous irinotecan hydrochloride, equal to 56.5 mg/m2 free base) or placebo, both in combination with 5-FU (2000 mg/m2) and LV (200 mg/m2), all given intravenously every two weeks. The primary endpoint of the study was overall survival (OS). A total of 298 patients were enrolled and received HR070803 plus 5-FU/LV (HR070803 group, n = 149) or placebo plus 5-FU/LV (placebo group, n = 149). Median OS was significantly improved in the HR070803 group compared to the placebo group (7.4 months [95% CI 6.1-8.4] versus 5.0 months [95% CI 4.3-6.0]; HR 0.63 [95% CI 0.48-0.84]; two-sided p = 0.0019). The most common grade ≥ 3 adverse events in the HR070803 group were increased gamma-glutamyltransferase (19.0% versus 11.6% in placebo group) and decreased neutrophil count (12.9% versus 0 in placebo group). No treatment-related deaths occurred in the HR070803 group, while the placebo group reported one treatment-related death (abdominal infection). HR070803 in combination with 5-FU/LV has shown promising efficacy and manageable safety in advanced or metastatic PDAC in the second-line setting, representing a potential option in this patient population.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma Ductal Pancreático , Desoxicitidina , Fluoruracila , Gencitabina , Irinotecano , Leucovorina , Lipossomos , Neoplasias Pancreáticas , Humanos , Fluoruracila/administração & dosagem , Feminino , Masculino , Leucovorina/administração & dosagem , Leucovorina/uso terapêutico , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/patologia , Pessoa de Meia-Idade , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Irinotecano/administração & dosagem , Irinotecano/uso terapêutico , Desoxicitidina/análogos & derivados , Desoxicitidina/administração & dosagem , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Adulto , Método Duplo-Cego , Metástase NeoplásicaRESUMO
BACKGROUND: Metastatic pancreatic ductal adenocarcinoma (mPDAC) patients have very poor prognosis highlighting the urgent need of novel treatments. In this regard, repurposing non-oncology already-approved drugs might be an attractive strategy to offer more-effective treatment easily tested in clinical trials. Accumulating evidence suggests that epigenetic deregulation is a hallmark of cancer contributing to treatment resistance in several solid tumors, including PDAC. Histone deacetylase inhibitors (HDACi) are epigenetic drugs we have investigated preclinically and clinically as anticancer agents. Valproic acid (VPA) is a generic low-cost anticonvulsant and mood stabilizer with HDAC inhibitory activity, and anticancer properties also demonstrated in PDAC models. Statins use was reported to be associated with lower mortality risk in patients with pancreatic cancer and statins have been shown to have a direct antitumor effect when used alone or in combination therapy. We recently showed capability of VPA/Simvastatin (SIM) combination to potentiate the antitumor activity of gemcitabine/nab-paclitaxel in vitro and in vivo PDAC preclinical models. METHODS/DESIGN: VESPA is a patient-centric open label randomized multicenter phase-II investigator-initiated trial, evaluating the feasibility, safety, and efficacy of VPA/SIM plus first line gemcitabine/nab-paclitaxel-based regimens (AG or PAXG) (experimental arm) versus chemotherapy alone (standard arm) in mPDAC patients. The study involves Italian and Spanish oncology centers and includes an initial 6-patients safety run-in-phase. A sample size of 240 patients (120 for each arm) was calculated under the hypothesis that the addition of VPA/SIM to gemcitabine and nab-paclitaxel-based regimens may extend progression free survival from 6 to 9 months in the experimental arm. Secondary endpoints are overall survival, response rate, disease control rate, duration of response, CA 19.9 reduction, toxicity, and quality of life. The study includes a patient engagement plan and complementary biomarkers studies on tumor and blood samples. CONCLUSIONS: VESPA is the first trial evaluating efficacy and safety of two repurposed drugs in oncology such as VPA and SIM, in combination with standard chemotherapy, with the aim of improving mPDAC survival. The study is ongoing. Enrollment started in June 2023 and a total of 63 patients have been enrolled as of June 2024. TRIAL REGISTRATION: EudraCT number: 2022-004154-63; ClinicalTrials.gov identifier NCT05821556, posted 2023/04/20.
Assuntos
Albuminas , Protocolos de Quimioterapia Combinada Antineoplásica , Desoxicitidina , Gencitabina , Paclitaxel , Neoplasias Pancreáticas , Sinvastatina , Ácido Valproico , Humanos , Ácido Valproico/uso terapêutico , Ácido Valproico/administração & dosagem , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Sinvastatina/administração & dosagem , Sinvastatina/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Desoxicitidina/análogos & derivados , Desoxicitidina/administração & dosagem , Desoxicitidina/uso terapêutico , Paclitaxel/administração & dosagem , Paclitaxel/uso terapêutico , Albuminas/administração & dosagem , Albuminas/uso terapêutico , Feminino , Masculino , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/patologia , Pessoa de Meia-Idade , Idoso , Reposicionamento de Medicamentos/métodos , AdultoRESUMO
The Nab-paclitaxel combined with gemcitabine (AG) regimen is the main chemotherapy regimen for pancreatic cancer, but drug resistance often occurs. Currently, the ability to promote sensitization in drug-resistant cases is an important clinical issue, and the strategy of repurposing conventional drugs is a promising strategy. This study aimed to identify a classic drug that targets chemotherapy resistance's core signaling pathways and combine it with the AG regimen to enhance chemosensitivity. We also aimed to find reliable predictive biomarkers of drug combination sensitivity. Using RNA sequencing, we found that abnormal PI3K/Akt pathway activation plays a central role in mediating resistance to the AG regimen. Subsequently, through internal and external verification of randomly selected AG-resistant patient-derived organoid (PDO) and PDO xenograft models, we discovered for the first time that the classic anti-inflammatory drug sulindac K-80003, an inhibitor of the PI3K/Akt pathway that we focused on, promoted sensitization in half (14/28) of AG-resistant pancreatic ductal adenocarcinoma cases. Through RNA-sequencing, multiplex immunofluorescent staining, and immunohistochemistry experiments, we identified cFAM124A as a novel biomarker through which sulindac K-80003 promotes AG sensitization. Its role as a sensitization marker is explained via the following mechanism: cFAM124A enhances both the mRNA expression of cathepsin L and the activity of the cathepsin L enzyme. This dual effect stimulates the cleavage of RXRα, leading to large amounts of truncated RXRα, which serves as a direct target of K-80003. Consequently, this process results in the pathological activation of the PI3K/Akt pathway. In summary, our study provides a new treatment strategy and novel biological target for patients with drug-resistant pancreatic cancer.
Assuntos
Albuminas , Protocolos de Quimioterapia Combinada Antineoplásica , Desoxicitidina , Resistencia a Medicamentos Antineoplásicos , Gencitabina , Paclitaxel , Neoplasias Pancreáticas , Sulindaco , Ensaios Antitumorais Modelo de Xenoenxerto , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Humanos , Paclitaxel/farmacologia , Paclitaxel/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Animais , Camundongos , Albuminas/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Sulindaco/farmacologia , Sulindaco/análogos & derivados , Linhagem Celular Tumoral , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Feminino , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/metabolismo , Masculino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacosRESUMO
Less than half of all patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) respond to chemotherapy, and the prognosis of PDAC is poor, which may be mediated by the gut microbiota. We investigated the clinical improvement effects of 1-kestose, a fructooligosaccharide, on PDAC chemotherapy in this single-center, randomized, controlled pilot trial conducted at Fujita Health University Hospital, which enrolled patients with PDAC. The trial included 1-kestose administration and non-administration groups. The 1-kestose group received 9 g of 1-kestose daily for 12 weeks, and their blood markers, imaging studies, physical findings, and gut microbiota were evaluated. In the 1-kestose administration group, the cancer marker CA19-9 significantly decreased, and there was a reduction in the neutrophil-to-lymphocyte ratio (NLR). There was also suppression of the reduction of albumin levels and of an increase in C-reactive protein. Additionally, Escherichia coli, which typically increases in PDAC, significantly decreased in the 1-kestose group. Thus, 1-kestose altered the gut microbiota and improved the prognostic factors for PDAC. Large-scale, long-term trials of 1-kestose interventions for PDAC are thus warranted to improve the prognosis of PDAC.
Assuntos
Carcinoma Ductal Pancreático , Microbioma Gastrointestinal , Neoplasias Pancreáticas , Humanos , Projetos Piloto , Carcinoma Ductal Pancreático/tratamento farmacológico , Masculino , Feminino , Neoplasias Pancreáticas/tratamento farmacológico , Microbioma Gastrointestinal/efeitos dos fármacos , Idoso , Pessoa de Meia-Idade , Suplementos Nutricionais , Biomarcadores Tumorais/sangue , Prognóstico , Antígeno CA-19-9/sangue , Proteína C-Reativa/análise , Proteína C-Reativa/metabolismo , Escherichia coli/efeitos dos fármacos , Resultado do Tratamento , Neutrófilos , Oligossacarídeos/administração & dosagem , Oligossacarídeos/farmacologiaRESUMO
Pancreatic ductal adenocarcinoma (PDAC) is an invasive and rapidly progressive malignancy. A major challenge in patient management is the lack of a reliable imaging tool to monitor tumor response to treatment. Tumor-associated fibrosis characterized by high type I collagen is a hallmark of PDAC, and fibrosis further increases in response to neoadjuvant chemoradiotherapy (CRT). We hypothesized that molecular positron emission tomography (PET) using a type I collagen-specific imaging probe, 68Ga-CBP8 can detect and measure changes in tumor fibrosis in response to standard treatment in mouse models and patients with PDAC. Methods: We evaluated the specificity of 68Ga-CBP8 PET to tumor collagen and its ability to differentiate responders from non-responders based on the dynamic changes of fibrosis in nude mouse models of human PDAC including FOLFIRNOX-sensitive (PANC-1 and PDAC6) and FOLFIRINOX-resistant (SU.86.86). Next, we demonstrated the specificity and sensitivity of 68Ga-CBP8 to the deposited collagen in resected human PDAC and pancreas tissues. Eight male participant (49-65 y) with newly diagnosed PDAC underwent dynamic 68Ga-CBP8 PET/MRI, and five underwent follow up 68Ga-CBP8 PET/MRI after completing standard CRT. PET parameters were correlated with tumor collagen content and markers of response on histology. Results: 68Ga-CBP8 showed specific binding to PDAC compared to non-binding 68Ga-CNBP probe in two mouse models of PDAC using PET imaging and to resected human PDAC using autoradiography (P < 0.05 for all comparisons). 68Ga-CBP8 PET showed 2-fold higher tumor signal in mouse models following FOLFIRINOX treatment in PANC-1 and PDAC6 models (P < 0.01), but no significant increase after treatment in FOLFIRINOX resistant SU.86.86 model. 68Ga-CBP8 binding to resected human PDAC was significantly higher (P < 0.0001) in treated versus untreated tissue. PET/MRI of PDAC patients prior to CRT showed significantly higher 68Ga-CBP8 uptake in tumor compared to pancreas (SUVmean: 2.35 ± 0.36 vs. 1.99 ± 0.25, P = 0.036, n = 8). PET tumor values significantly increased following CRT compared to untreated tumors (SUVmean: 2.83 ± 0.30 vs. 2.25 ± 0.41, P = 0.01, n = 5). Collagen deposition significantly increased in response to CRT (59 ± 9% vs. 30 ± 9%, P=0.0005 in treated vs. untreated tumors). Tumor and pancreas collagen content showed a positive direct correlation with SUVmean (R2 = 0.54, P = 0.0007). Conclusions: This study demonstrates the specificity of 68Ga-CBP8 PET to tumor type I collagen and its ability to differentiate responders from non-responders based on the dynamic changes of fibrosis in PDAC. The results highlight the potential use of collagen PET as a non-invasive tool for monitoring response to treatment in patients with PDAC.
Assuntos
Carcinoma Ductal Pancreático , Colágeno Tipo I , Radioisótopos de Gálio , Irinotecano , Imageamento por Ressonância Magnética , Neoplasias Pancreáticas , Tomografia por Emissão de Pósitrons , Animais , Humanos , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/terapia , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Tomografia por Emissão de Pósitrons/métodos , Camundongos , Carcinoma Ductal Pancreático/diagnóstico por imagem , Carcinoma Ductal Pancreático/terapia , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/patologia , Pessoa de Meia-Idade , Masculino , Imageamento por Ressonância Magnética/métodos , Colágeno Tipo I/metabolismo , Idoso , Irinotecano/uso terapêutico , Irinotecano/farmacologia , Camundongos Nus , Fluoruracila/uso terapêutico , Fluoruracila/farmacologia , Oxaliplatina/uso terapêutico , Oxaliplatina/farmacologia , Linhagem Celular Tumoral , Leucovorina/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Pesquisa Translacional Biomédica , Resultado do Tratamento , Fibrose/diagnóstico por imagem , Compostos RadiofarmacêuticosRESUMO
INTRODUCTION: Refractory pain is a major clinical problem in patients with pancreatic ductal adenocarcinoma (PDAC) and chronic pancreatitis (CP). New, effective therapies to reduce pain are urgently needed. Intravenous lidocaine is used in clinical practice in patients with PDAC and CP, but its efficacy has not been studied prospectively. METHODS: Multicenter prospective nonrandomized pilot study included patients with moderate or severe pain (Numeric Rating Scale ≥ 4) associated with PDAC or CP in 5 Dutch centers. An intravenous lidocaine bolus of 1.5 mg/kg was followed by continuous infusion at 1.5 mg/kg/hr. The dose was raised every 15 minutes until treatment response (up to a maximum 2 mg/kg/hr) and consecutively administered for 2 hours. Primary outcome was the mean difference in pain severity, preinfusion, and the first day after (Brief Pain Inventory [BPI] scale 1-10). A BPI decrease ≥1.3 points was considered clinically relevant. RESULTS: Overall, 30 patients were included, 19 with PDAC (63%) and 11 with CP (37%). The mean difference in BPI at day 1 was 1.1 (SD ± 1.3) points for patients with PDAC and 0.5 (SD ± 1.7) for patients with CP. A clinically relevant decrease in BPI on day 1 was reported in 9 of 29 patients (31%), and this response lasted up to 1 month. No serious complications were reported, and only 3 minor complications (vertigo, nausea, and tingling of mouth). Treatment with lidocaine did not impact quality of life. DISCUSSION: Intravenous lidocaine in patients with painful PDAC and CP did not show an overall clinically relevant reduction of pain. However, this pilot study shows that the treatment is feasible in this patient group and had a positive effect in a third of patients which lasted up to a month with only minor side effects. To prove or exclude the efficacy of intravenous lidocaine, the study should be performed in a study with a greater sample size and less heterogeneous patient group.
Assuntos
Anestésicos Locais , Carcinoma Ductal Pancreático , Lidocaína , Medição da Dor , Dor Intratável , Neoplasias Pancreáticas , Pancreatite Crônica , Humanos , Projetos Piloto , Lidocaína/administração & dosagem , Masculino , Feminino , Pessoa de Meia-Idade , Pancreatite Crônica/complicações , Pancreatite Crônica/tratamento farmacológico , Estudos Prospectivos , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/complicações , Neoplasias Pancreáticas/complicações , Neoplasias Pancreáticas/tratamento farmacológico , Idoso , Anestésicos Locais/administração & dosagem , Infusões Intravenosas , Dor Intratável/tratamento farmacológico , Dor Intratável/etiologia , Resultado do Tratamento , Adulto , Países BaixosRESUMO
Pancreatic ductal adenocarcinoma (PDAC) is a significant cause of cancer-associated mortality, with a rising global incidence. A paucity of strong predictive risk factors mean screening programmes are difficult to implement. Historically, a lack of identifiable and actionable driver mutations, coupled with a relatively immunosuppressed tumour microenvironment, has led to a reliance on cytotoxic chemotherapy. The NAPOLI-3 trial has reported data supporting consideration of NALIRIFOX as a new first-line standard of care. Kirsten Rat Sarcoma Virus (KRAS) G12D mutations are present in >90% of all PDAC's; exciting breakthroughs in small molecule inhibitors targeting KRAS G12D may open new modalities of treatment, and therapies targeting multiple KRAS mutations are also in early clinical trials. Although immunotherapy strategies to date have been disappointing, combination with chemotherapy and/or small molecule inhibitors hold promise and warrant further exploration.
Assuntos
Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/tratamento farmacológico , Metástase Neoplásica , Carcinoma Ductal Pancreático/tratamento farmacológico , Imunoterapia/métodosRESUMO
PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is among the most aggressive malignancies. Our previous work revealed Chitinase 3-like 1 (CHI3L1) involvement in PDAC resistance to gemcitabine, identifying it as a promising therapeutic target. Here, we aimed to identify putative CHI3L1 inhibitors and to investigate their chemosensitizing potential in PDAC. METHODS: Docking analysis for CHI3L1 identified promising CHI3L1 inhibitors, including darifenacin (muscarinic receptor antagonist). PDAC cell lines (BxPC-3, PANC-1) and primary PDAC cells were used to evaluate darifenacin's effects on cell growth (Sulforhodamine B, SRB), alone or in combination with gemcitabine or gemcitabine plus paclitaxel. Cytotoxicity against normal immortalized pancreatic ductal cells (HPNE) was assessed. Recombinant protein was used to confirm the impact of darifenacin on CHI3L1-induced PDAC cellular resistance to therapy (SRB assay). Darifenacin's effect on Akt activation was analysed by ELISA. The association between cholinergic receptor muscarinic 3 (CHRM3) expression and therapeutic response was evaluated by immunohistochemistry of paraffin-embedded tissues from surgical resections of a 68 patients' cohort. RESULTS: In silico screening revealed the ability of darifenacin to target CHI3L1 with high efficiency. Darifenacin inhibited PDAC cell growth, with a GI50 of 26 and 13.6 µM in BxPC-3 and PANC-1 cells, respectively. These results were confirmed in primary PDAC-3 cells, while darifenacin showed no cytotoxicity against HPNE cells. Importantly, darifenacin sensitized PDAC cells to standard chemotherapies, reverted CHI3L1-induced PDAC cellular resistance to therapy, and decreased Akt phosphorylation. Additionally, high CHMR3 expression was associated with low therapeutic response to gemcitabine. CONCLUSION: This work highlights the potential of darifenacin as a chemosensitizer for PDAC treatment.
Assuntos
Benzofuranos , Carcinoma Ductal Pancreático , Resistencia a Medicamentos Antineoplásicos , Neoplasias Pancreáticas , Pirrolidinas , Receptor Muscarínico M3 , Humanos , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/patologia , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Benzofuranos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Pirrolidinas/farmacologia , Pirrolidinas/administração & dosagem , Receptor Muscarínico M3/antagonistas & inibidores , Receptor Muscarínico M3/genética , Linhagem Celular Tumoral , Gencitabina , Proliferação de Células/efeitos dos fármacos , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Simulação de Acoplamento Molecular , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteína 1 Semelhante à Quitinase-3RESUMO
Liposomes are applied to various anticancer treatments as representative drug delivery carriers. However, liposomes do not have their own targeting properties; therefore, there are limitations in drug delivery to specific tissues or cells. High targetability in drug delivery is an important factor in improving bioavailability and drug efficacy and reducing side effects; recent research has been actively investigated to modify the surface of liposomes to give them specific functions. In this study, we studied a drug delivery system for anticancer treatment that enhances targeting ability through fusion with exosomes on the surface of liposomes. We designed exosome-liposome hybrid nanoparticles loaded with a gemcitabine prodrug as a treatment for pancreatic ductal adenocarcinoma (PDAC). Membrane fusion with exosomes shows excellent targeting ability to pancreatic cancer cells due to intrinsic targeting ability and expansion of the macropinocytosis pathway.
Assuntos
Carcinoma Ductal Pancreático , Desoxicitidina , Ensaios de Seleção de Medicamentos Antitumorais , Vesículas Extracelulares , Gencitabina , Lipossomos , Nanopartículas , Neoplasias Pancreáticas , Tamanho da Partícula , Pró-Fármacos , Desoxicitidina/análogos & derivados , Desoxicitidina/química , Desoxicitidina/farmacologia , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Humanos , Lipossomos/química , Nanopartículas/química , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/metabolismo , Vesículas Extracelulares/química , Vesículas Extracelulares/metabolismo , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/metabolismo , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacologia , Proliferação de Células/efeitos dos fármacos , Teste de Materiais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sistemas de Liberação de Medicamentos , Antineoplásicos/química , Antineoplásicos/farmacologiaRESUMO
Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease that is almost entirely resistant to conventional chemotherapy and radiation therapy. A significant factor in this resistance appears to be the dense desmoplastic stroma, which contains various cancer-associated fibroblast (CAF) populations. However, our understanding of the communication between tumor cells and CAFs that contributes to this aggressive malignancy is still developing. Recently, we used an advanced three-dimensional heterospecies, heterospheroid co-culture model to investigate the signaling between human pancreatic tumor Panc1 cells and mouse pancreatic stellate cells (mPSCs) through global expression profiling. Upon discovering that CCN1 was significantly upregulated in Panc1 cells during co-culture, we decided to explore the role of CCN1 using CRISPR-Cas9 knockout technology. Panc1 cells lacking CCN1 showed reduced differentiation and decreased sensitivity to gemcitabine, primarily due to lower expression of genes involved in gemcitabine transport and metabolism. Additionally, we observed that stimulation with TGF-ß1 and lysophosphatidic acid increased CCN1 expression in Panc1 cells and induced a shift in mPSCs towards a more myofibroblastic CAF-like phenotype.
Assuntos
Técnicas de Cocultura , Proteína Rica em Cisteína 61 , Desoxicitidina , Gencitabina , Neoplasias Pancreáticas , Células Estreladas do Pâncreas , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Proteína Rica em Cisteína 61/metabolismo , Proteína Rica em Cisteína 61/genética , Humanos , Células Estreladas do Pâncreas/metabolismo , Células Estreladas do Pâncreas/efeitos dos fármacos , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/tratamento farmacológico , Camundongos , Animais , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/tratamento farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Lisofosfolipídeos/metabolismo , Lisofosfolipídeos/farmacologia , Fator de Crescimento Transformador beta1/metabolismo , Fator de Crescimento Transformador beta1/farmacologia , Fibroblastos Associados a Câncer/metabolismo , Fibroblastos Associados a Câncer/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacosRESUMO
OBJECTIVES: Although systemic chemotherapy for pancreatic ductal adenocarcinoma (PDAC) has made progress, ensuring long-term survival remains difficult. There are several reports on the usefulness of neutrophil-to-lymphocyte ratio (NLR) in predicting the prognosis of PDAC, but few reports in systemic chemotherapy. We hereby investigated the usefulness of NLR in systemic chemotherapy for PDAC. MATERIALS AND METHODS: A retrospective study was conducted on patients with advanced PDAC treated with first-line systemic chemotherapy. Cox regression hazards models were performed to analyze the association between baseline patient characteristics and the initial treatment response, and overall survival (OS). RESULTS: A total of 60 patients with PDAC were enrolled. At baseline, there were significant differences in NLR and carbohydrate antigen 19-9 (CA19-9), as well as the selection rate of combination chemotherapy, between patients with partial response or stable disease and those with progressive disease. Univariate and multivariate analysis showed that NLR < 3.10, combination chemotherapy, and CA19-9 < 1011 U/mL were significant and independent predictive factors of the initial treatment response. Meanwhile, NLR < 3.10 and combination chemotherapy were independently associated with longer OS. Moreover, OS was significantly prolonged in patients with NLR < 3.10, regardless of whether combination chemotherapy or monotherapy. Patients with NLR < 3.10 at baseline had a significantly higher conversion rate to third-line chemotherapy and a longer duration of total chemotherapy. CONCLUSIONS: This study suggests that NLR may be a useful marker for predicting the initial treatment response to first-line chemotherapy and the prognosis for patients with advanced PDAC.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma Ductal Pancreático , Linfócitos , Neutrófilos , Neoplasias Pancreáticas , Humanos , Feminino , Masculino , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/sangue , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/patologia , Estudos Retrospectivos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Pessoa de Meia-Idade , Idoso , Prognóstico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Adulto , Antígeno CA-19-9/sangue , Contagem de Linfócitos , Fluoruracila/uso terapêutico , Fluoruracila/administração & dosagem , Modelos de Riscos Proporcionais , Idoso de 80 Anos ou mais , Gencitabina , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Desoxicitidina/administração & dosagem , Resultado do TratamentoRESUMO
KRAS is the most frequently altered oncogene in pancreatic ductal adenocarcinoma, in which the aberrantly activated RAS signaling pathway plays pleiotropic roles in tumor initiation and maintenance. Nearly four decades after the discovery of the RAS oncoprotein, a multitude of pharmacologic inhibitors are now available that directly target mutant KRAS. This In Focus commentary, published simultaneously with the 2024 AACR Special Conference on Pancreatic Cancer, summarizes the current state of this rapidly changing field, including preclinical data and emerging clinical trends with respect to therapeutic efficacy, mechanisms of resistance, and potential combinations to maximize clinical benefit from this promising class of therapies.
Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Proteínas Proto-Oncogênicas p21(ras) , Humanos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/antagonistas & inibidores , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/metabolismo , Mutação , Terapia de Alvo Molecular/métodos , Animais , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêuticoRESUMO
BACKGROUND: Immune checkpoint inhibitors (ICIs) are rarely used to treat advanced pancreatic ductal adenocarcinoma (PDAC) due to marginal efficacy. PATIENTS AND METHODS: This study included 92 consecutive patients diagnosed with advanced or recurrent PDAC who received nivolumab-based treatment. Univariate and multivariate analyses were used to identify prognostic factors. A control group of 301 patients with PDAC who achieved disease control with palliative chemotherapy but without ICIs was selected for comparison using propensity score matching (PSM). RESULTS: The median overall survival (OS) since nivolumab treatment was 15.8 (95% confidence interval [CI], 12.5-19.0), 2.4 (95% CI 1.2-3.6), and 1.1 (95% CI 1.0-1.2) months in patients who received add-on nivolumab after achieving disease control with chemotherapy, in those who received concomitant nivolumab and chemotherapy without prerequisite confirmation of disease control, and in those who received nivolumab without concomitant chemotherapy, respectively (P < 0.001). After PSM, the median overall survival (OS) since initiation of the concomitant chemotherapy that achieved disease control was significantly longer (P = 0.026) in patients who received add-on nivolumab (19.8 months; 95% CI 14.5-25.1) than in those who received chemotherapy alone (13.8 months; 95% CI 10.8-16.9). The immune profiling of the tumors in resected patients revealed higher scores of CD8+ T cells to Tregs in patients with add-on nivolumab comparing to those who received chemotherapy alone. CONCLUSION: Adding-on nivolumab was associated with improved OS in patients with advanced PDAC who achieved disease control following chemotherapy.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma Ductal Pancreático , Nivolumabe , Neoplasias Pancreáticas , Humanos , Masculino , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/patologia , Nivolumabe/uso terapêutico , Nivolumabe/administração & dosagem , Feminino , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/mortalidade , Idoso , Pessoa de Meia-Idade , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Prognóstico , Inibidores de Checkpoint Imunológico/uso terapêutico , Adulto , Idoso de 80 Anos ou mais , Estudos RetrospectivosRESUMO
Pancreatic ductal adenocarcinoma (PDAC) presents significant challenges for targeted clinical interventions due to prevalent KRAS mutations, rendering PDAC resistant to RAF and MEK inhibitors (RAFi and MEKi). In addition, responses to targeted therapies vary between patients. Here, we explored the differential sensitivities of PDAC cell lines to RAFi and MEKi and developed an isogenic pair comprising the most sensitive and resistant PDAC cells. To simulate patient- or tumor-specific variations, we constructed cell-line-specific mechanistic models based on protein expression profiling and differential properties of KRAS mutants. These models predicted synergy between two RAFi with different conformation specificity (type I½ and type II RAFi) in inhibiting phospho-ERK (ppERK) and reducing PDAC cell viability. This synergy was experimentally validated across all four studied PDAC cell lines. Our findings underscore the need for combination approaches to inhibit the ERK pathway in PDAC.
Assuntos
Carcinoma Ductal Pancreático , Sistema de Sinalização das MAP Quinases , Neoplasias Pancreáticas , Inibidores de Proteínas Quinases , Humanos , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/metabolismo , Linhagem Celular Tumoral , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/metabolismo , Sinergismo Farmacológico , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , Quinases raf/metabolismo , Quinases raf/antagonistas & inibidoresRESUMO
Immunotherapy has revolutionized the cancer treatment paradigm, yet efficient immunotherapeutic responses against immune-cold/desert cancers remain challenging. Herein, we report that photoactivatable nanoagonists yield a potent antitumor synergy of photoimmunotherapy against pancreatic ductal adenocarcinoma (PDAC). The nanoagonist was fabricated by assembling an amphiphilic boron dipyrromethene-derived polymer conjugated with a Toll-like receptor agonist via a photocleavable linker and stimulator of interferon genes agonist. The nanoagonist enables light-induced generation of reactive oxygen species and on-demand release of the agonists to yield synergistic photoimmunotherapy. The produced tumor antigens promote dendritic cell maturation, which is further amplified by these agonists for eliciting adaptive immunity, accompanied by apparently abscopal and long-term memory effects. The nanoagonist further alleviates the fibrosis of tumor stroma and the immunosuppressive microenvironment, leading to the deep infiltrations of clinically used therapeutics and immune cells to yield preferable combinational treatments against PDAC models. These results provide valuable insights into activatable nanoparticles for cancer therapy against immune-desert cancers.
Assuntos
Carcinoma Ductal Pancreático , Imunoterapia , Nanopartículas , Neoplasias Pancreáticas , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/terapia , Humanos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/terapia , Animais , Camundongos , Nanopartículas/química , Nanopartículas/uso terapêutico , Linhagem Celular Tumoral , Microambiente Tumoral/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologiaRESUMO
Pancreatic ductal adenocarcinoma (PDAC) is associated with significant morbidity and mortality and is projected to be the second leading cause of cancer-related deaths by 2030. Mutations in KRAS are found in the vast majority of PDAC cases and plays an important role in the development of the disease. KRAS drives tumor cell proliferation and survival through activating the MAPK pathway to drive cell cycle progression and to lead to MYC-driven cellular programs. Moreover, activated KRAS promotes a protumorigenic microenvironment through forming a desmoplastic stroma and by impairing antitumor immunity. Secretion of granulocyte-macrophage colony-stimulating factor and recruitment of myeloid-derived suppressor cells and protumorigenic macrophages results in an immunosuppressive environment while secretion of secrete sonic hedgehog and TGFß drive fibroblastic features characteristic of PDAC. Recent development of several small molecules to directly target KRAS marks an important milestone in precision medicine. Many molecules show promise in preclinical models of PDAC and in early phase clinical trials. In this review, we discuss the underlying cell intrinsic and extrinsic roles of KRAS in PDAC tumorigenesis, the pharmacologic development of KRAS inhibition, and therapeutic strategies to target KRAS in PDAC.
Assuntos
Neoplasias Pancreáticas , Proteínas Proto-Oncogênicas p21(ras) , Humanos , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/metabolismo , Animais , Terapia de Alvo Molecular , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/metabolismo , Carcinogênese/genética , Microambiente Tumoral , Adenocarcinoma/genética , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Adenocarcinoma/metabolismo , MutaçãoRESUMO
BACKGROUND: A standardised dose-reduction strategy has not been established for the widely used gemcitabine plus nab-paclitaxel regimen in patients with metastatic pancreatic ductal adenocarcinoma. We aimed to investigate the efficacy and tolerability of alternating treatment cycles of nab-paclitaxel-gemcitabine combination therapy and gemcitabine alone versus continuous treatment with the nab-paclitaxel-gemcitabine combination. METHODS: ALPACA was a randomised, open-label, phase 2 trial conducted at 29 study centres across Germany. Patients aged 18 years or older with a histologically or cytologically confirmed diagnosis of metastatic pancreatic ductal adenocarcinoma who had not been previously treated for advanced disease were enrolled. After an induction phase with three cycles of nab-paclitaxel-gemcitabine combination therapy (nab-paclitaxel 125 mg/m2 and gemcitabine 1000 mg/m2 administered intravenously on days 1, 8, and 15 of each 28-day cycle), patients were randomly assigned (1:1) by stratified permuted block randomisation either to continue treatment with standard nab-paclitaxel-gemcitabine or to receive alternating cycles of nab-paclitaxel-gemcitabine and gemcitabine alone. Patients and investigators were not masked to treatment allocation. Randomisation was done centrally by the study statistician using a computer-generated randomisation list, and was stratified by Karnofsky Performance Status and presence of liver metastases. The primary endpoint was the derivation of an unbiased point estimate and an associated confidence interval with a confidence coefficient of 80% for the hazard ratio (HR) for overall survival after randomisation, without testing a specific hypothesis, analysed by intention to treat in all patients who started randomised treatment. Safety was analysed according to treatment received. This trial is registered with ClinicalTrials.gov, NCT02564146, and is completed. FINDINGS: Between May 27, 2016, and May 27, 2021, 325 patients were enrolled. Following three cycles of induction treatment, 174 patients were randomly assigned: 85 to continue receiving standard nab-paclitaxel-gemcitabine, of whom 79 started treatment, and 89 to the alternating treatment schedule, of whom 88 started treatment. Of the 167 patients who started randomised treatment, 88 (53%) were female and 79 (47%) were male. Median overall survival after randomisation was 10·4 months (80% CI 9·2-12·0) in the group that received standard treatment and 10·5 months (10·2-11·1) in the group that received alternating treatment (HR 0·90, 80% CI 0·72-1·13; p=0·56). The most common adverse events of any grade were peripheral neuropathy (59 [74%] of 80 patients in the continuous treatment group vs 53 [62%] of 85 patients in the alternating treatment group) and fatigue (43 [54%] vs 44 [52%]). Treatment-emergent serious adverse events after randomisation occurred in 40 (50%) patients in the continuous treatment group and in 28 (33%) in the alternating treatment group. Fewer treatment-emergent adverse events of grade 3 or higher occurred in patients treated with alternating cycles compared with those receiving standard therapy, especially for peripheral neuropathy (17 [21%] patients in the continuous treatment group vs 12 [14%] in the alternating treatment group) and infections (16 [20%] vs nine [11%]). There were two treatment-related deaths after randomisation, both in the continuous treatment group (one multiple organ dysfunction syndrome, not treated after randomisation, and one interstitial lung disease). INTERPRETATION: Our findings suggest that a dose-reduced regimen with alternating cycles of nab-paclitaxel-gemcitabine and gemcitabine alone after three induction cycles is associated with similar overall survival to that for standard treatment with nab-paclitaxel-gemcitabine, but with improved tolerability. We therefore propose that a switch to the alternating schedule could be considered in a clinical setting for patients with metastatic pancreatic cancer who have at least stable disease after three cycles of nab-paclitaxel-gemcitabine treatment. FUNDING: Celgene/Bristol Myers Squibb.