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1.
Phys Rev Lett ; 125(12): 128103, 2020 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-33016731

RESUMO

While many cellular mechanisms leading to chemotherapeutic resistance have been identified, there is an increasing realization that tumor-stroma interactions also play an important role. In particular, mechanical alterations are inherent to solid cancer progression and profoundly impact cell physiology. Here, we explore the influence of compressive stress on the efficacy of chemotherapeutics in pancreatic cancer spheroids. We find that increased compressive stress leads to decreased drug efficacy. Theoretical modeling and experiments suggest that mechanical stress decreases cell proliferation which in turn reduces the efficacy of chemotherapeutics that target proliferating cells. Our work highlights a mechanical form of drug resistance and suggests new strategies for therapy.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/patologia , Modelos Biológicos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/fisiologia , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Resistencia a Medicamentos Antineoplásicos , Humanos , Estresse Mecânico
2.
J Cancer Res Ther ; 16(4): 950-954, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32930150

RESUMO

Despite recent advances in treatment with multidrug chemotherapy regimens, outcomes of patients with advanced pancreatic ductal adenocarcinoma (PDAC) remain very poor. Treatment with targeted therapies has shown marginal benefits due to intrinsic or acquired resistance. Actionable mutations, while detected infrequently in patients with PDAC, are becoming increasingly used in personalized medicine. Here, we describe an epidermal growth factor receptor (EGFR)-activating mutation (E746_T751>VP) to erlotinib, a first-generation tyrosine kinase inhibitor (TKI), in a patient with metastatic PDAC. After an initial partial response to erlotinib for 12 months, the patient's disease progressed with emergence of the EGFR A647T mutation. Certainly, the patient also progressed after switching therapy to a third-generation EGFR TKI (osimertinib). This case illustrates the posttreatment evolution of EGFR A647T-mediated resistance to the first- and third-generation TKIs. To our knowledge, this is the first case to report the aforementioned activating and resistance-mediated mutations. In summary, genomic analysis performed in this patient with PDAC on the tumor biopsy and peripheral blood provided tools to understand mechanisms of response and resistance to targeted therapy with EFGR TKIs.


Assuntos
Carcinoma Ductal Pancreático/tratamento farmacológico , Cloridrato de Erlotinib/uso terapêutico , Mutação , Neoplasias Pancreáticas/tratamento farmacológico , Idoso , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Receptores ErbB/genética , Feminino , Humanos , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Prognóstico , Inibidores de Proteínas Quinases/uso terapêutico
3.
Am J Clin Oncol ; 43(9): 654-659, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32889836

RESUMO

OBJECTIVE: By using the Korean Pancreatic Cancer (K-PaC) registry, we compared the clinical outcomes of FOLFIRINOX (FFX) and gemcitabine plus nab-paclitaxel (GNP) in patients with metastatic pancreatic cancer (MPC). METHODS: We constructed a web-based database of 3748 anonymized patients diagnosed with pancreatic ductal adenocarcinoma. MPC patients who received first-line FFX or GNP were enrolled. Overall survival (OS), progression-free survival, grade III to IV toxicity, and cross-over treatment were analyzed. RESULTS: A total of 413 patients (232 vs. 181, FFX vs. GNP; all data are presented in this sequence) were eligible. Median age was 63 years (60 vs. 69 y) with 43% (39% vs. 47%) comprising female individuals. The major metastatic sites were the liver (64%), peritoneum (25%), and distant lymph nodes (18%). The median OS was 11.5 versus 12.7 months (hazard ratio [HR]=0.87, 95% confidence interval [CI]: 0.68-1.12, P=0.286), and median progression-free survival was 7.5 versus 8.1 months (HR=0.92, 95% CI: 0.70-1.20, P=0.517), respectively. The frequency of grade III to IV febrile neutropenia was higher in the FFX group (18% vs. 11%, P=0.040), and that of peripheral neuropathy was higher in the GNP group (8% vs. 14%, P=0.046). The chance to receive second-line chemotherapy was higher in the GNP group (45% vs. 56%, P=0.036). In the cross-over treatment, the median OS of the FFX-GNP group (n=43) and the GNP-FFX group (n=47) was 16.8 versus 17.7 months (HR=0.79, 95% CI: 0.44-1.41, P=0.425). CONCLUSIONS: FFX and GNP showed similar efficacy and comparable toxicity in MPC patients. Although the GNP group had a higher chance to receive second-line chemotherapy, they did not have improved overall survival.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Ductal Pancreático/tratamento farmacológico , Neoplasias Hepáticas/secundário , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Peritoneais/secundário , Idoso , Albuminas/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma Ductal Pancreático/secundário , Estudos Cross-Over , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Neutropenia Febril/induzido quimicamente , Feminino , Fluoruracila/efeitos adversos , Fluoruracila/uso terapêutico , Humanos , Irinotecano/efeitos adversos , Irinotecano/uso terapêutico , Leucovorina/efeitos adversos , Leucovorina/uso terapêutico , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Oxaliplatina/efeitos adversos , Oxaliplatina/uso terapêutico , Paclitaxel/administração & dosagem , Neoplasias Pancreáticas/patologia , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Intervalo Livre de Progressão , Sistema de Registros , República da Coreia , Taxa de Sobrevida , Resultado do Tratamento
5.
Anticancer Res ; 40(9): 5181-5189, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878806

RESUMO

BACKGROUND/AIM: Mathematical models have long been considered as important tools in cancer biology and therapy. Herein, we present an advanced non-linear mathematical model that can predict accurately the effect of an anticancer agent on the growth of a solid tumor. MATERIALS AND METHODS: Advanced non-linear mathematical optimization techniques and human-to-mouse experimental data were used to develop a tumor growth inhibition (TGI) estimation model. RESULTS: Using this mathematical model, we could accurately predict the tumor mass in a human-to-mouse pancreatic ductal adenocarcinoma (PDAC) xenograft under gemcitabine treatment up to five time periods (points) ahead of the last treatment. CONCLUSION: The ability of the identified TGI dynamic model to perform satisfactory short-term predictions of the tumor growth for up to five time periods ahead was investigated, evaluated and validated for the first time. Such a prediction model could not only assist the pre-clinical testing of putative anticancer agents, but also the early modification of a chemotherapy schedule towards increased efficacy.


Assuntos
Antineoplásicos/farmacologia , Modelos Teóricos , Dinâmica não Linear , Ensaios Antitumorais Modelo de Xenoenxerto , Algoritmos , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/patologia , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Humanos , Camundongos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia
6.
Anticancer Res ; 40(10): 5765-5776, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988904

RESUMO

BACKGROUND/AIM: We evaluated the safety, feasibility, and preliminary efficacy of Wilms tumor gene 1 (WT1) peptide and Mucin 1 (MUC1)-pulsed dendritic cell (DC) (WT1/MUC1-DC) vaccination as an adjuvant immunotherapy for surgically resectable pancreatic ductal adenocarcinoma (PDA) patients. PATIENTS AND METHODS: Eligible patients were administered WT1/MUC1-DC vaccination at least seven times every 2 weeks with concomitant adjuvant chemotherapy after surgical resection of PDA. RESULTS: Ten patients were enrolled and no Grade 2 or higher toxicities were associated with DC vaccination. The estimated overall survival (OS) and relapse-free survival (RFS) at 3-years from the time of surgical resection were 77.8% and 35.0%, respectively. Immunohistochemical analysis suggested a possible relationship between induction of WT1-specific cytotoxic T lymphocyte after DC vaccination and higher infiltration of CD3/CD4/CD8 lymphocytes in tumor tissues. CONCLUSION: WT1/MUC1-DC vaccination in the adjuvant setting was safe and well-tolerated in PDA patients after tumor resection. A large-scale prospective study is warranted to evaluate the clinical benefit of this modality.


Assuntos
Adenocarcinoma/tratamento farmacológico , Carcinoma Ductal Pancreático/tratamento farmacológico , Mucina-1/genética , Proteínas WT1/genética , Adenocarcinoma/genética , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Idoso , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/imunologia , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/cirurgia , Quimioterapia Adjuvante/métodos , Células Dendríticas/imunologia , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Intervalo Livre de Doença , Feminino , Humanos , Imunoterapia/métodos , Masculino , Pessoa de Meia-Idade , Mucina-1/uso terapêutico , Proteínas WT1/uso terapêutico
7.
Nat Commun ; 11(1): 4841, 2020 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-32973176

RESUMO

Pre-clinical models have shown that targeting pancreatic stellate cells with all-trans-retinoic-acid (ATRA) reprograms pancreatic stroma to suppress pancreatic ductal adenocarcinoma (PDAC) growth. Here, in a phase Ib, dose escalation and expansion, trial for patients with advanced, unresectable PDAC (n = 27), ATRA is re-purposed as a stromal-targeting agent in combination with gemcitabine-nab-paclitaxel chemotherapy using a two-step adaptive continual re-assessment method trial design. The maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D, primary outcome) is the FDA/EMEA approved dose of gemcitabine-nab-paclitaxel along-with ATRA (45 mg/m2 orally, days 1-15/cycle). Dose limiting toxicity (DLT) is grade 4 thrombocytopenia (n = 2). Secondary outcomes show no detriment to ATRA pharmacokinetics.. Median overall survival for RP2D treated evaluable population, is 11.7 months (95%CI 8.6-15.7 m, n = 15, locally advanced (2) and metastatic (13)). Exploratory pharmacodynamics studies including changes in diffusion-weighted (DW)-MRI measured apparent diffusion coefficient after one cycle, and, modulation of cycle-specific serum pentraxin 3 levels over various cycles indicate stromal modulation. Baseline stromal-specific retinoid transport protein (FABP5, CRABP2) expression may be predicitve of response. Re-purposing ATRA as a stromal-targeting agent with gemcitabine-nab-paclitaxel is safe and tolerable. This combination will be evaluated in a phase II randomized controlled trial for locally advanced PDAC. Clinical trial numbers: EudraCT: 2015-002662-23; NCT03307148. Trial acronym: STARPAC.


Assuntos
Carcinoma Ductal Pancreático/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Tretinoína/uso terapêutico , Biomarcadores Tumorais , Proteínas de Ligação a Ácido Graxo/metabolismo , Humanos , Dose Máxima Tolerável , Neoplasias Pancreáticas/diagnóstico por imagem , Receptores do Ácido Retinoico/metabolismo , Resultado do Tratamento , Tretinoína/efeitos adversos , Tretinoína/farmacocinética
8.
Life Sci ; 260: 118302, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32827543

RESUMO

AIMS: The roles of estrogen receptors (ERs) and the efficacy of anti-estrogen (E2) therapies in pancreatic cancer stay controversial. The main objectives of this study were to investigate the potential roles of ERs in tumor progression and endocrine therapies. MAIN METHODS: The ER expression status in PANC-1 and SW1990 pancreatic cancer cell lines was determined. SRB assay, colony formation assay and proliferation assay were used to investigate the responses of these cells to E2. ERα-selective agonist propylpyrazoletriol (PPT), ERß-selective agonist diarylpropionitrile (DPN), ERα over-expressed SW1990 cells, ERα knock-out PANC-1 cells and patient-derived xenografts (PDX) were applied to investigate the potential roles of ERα in pancreatic cancer. The phosphorylation of ERα-related signaling molecules extracellular regulated protein kinases (ERK1/2) and protein kinase B (AKT) were investigated. The in vivo anti-tumor efficacy and safety of letrozole (LTZ) combined with leuprorelin acetate (LA) and gemcitabine (GEM) were also preliminarily studied. KEY FINDINGS: PANC-1 cells expressed much more ERα than SW1990 cells, and ERß level was with less diversity. Accordingly, the proliferation of PANC-1 rather than SW1990 cells could be stimulated by E2, and only PANC-1 could respond to LTZ endocrine therapy in female but not male mice. The phosphorylation of ERK1/2 but not AKT was altered by over-expressed or knocking out of ERα with or without the addition of E2 and LTZ. The combination therapy of LTZ and GEM showed acceptable efficacy and safety. SIGNIFICANCE: This study showed the important roles of ERα in tumor progression and endocrine therapies of pancreatic cancer in women.


Assuntos
Adenocarcinoma/tratamento farmacológico , Carcinoma Ductal Pancreático/tratamento farmacológico , Moduladores de Receptor Estrogênico/uso terapêutico , Receptor alfa de Estrogênio/fisiologia , Neoplasias Pancreáticas/tratamento farmacológico , Adenocarcinoma/patologia , Adenocarcinoma/fisiopatologia , Animais , Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/fisiopatologia , Linhagem Celular Tumoral , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Estradiol/farmacologia , Receptor alfa de Estrogênio/genética , Feminino , Expressão Gênica , Técnicas de Inativação de Genes , Humanos , Letrozol/administração & dosagem , Leuprolida/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/fisiopatologia , Ensaios Antitumorais Modelo de Xenoenxerto
9.
AJR Am J Roentgenol ; 215(3): 610-616, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32755156

RESUMO

OBJECTIVE. The purpose of this study was to investigate the association between primary pancreatic ductal adenocarcinoma fractional extracellular space (fECS) estimated from pretreatment CT and tumor response to chemotherapy and patient outcome. MATERIALS AND METHODS. A database search identified the records of patients with locally advanced or metastatic pancreatic ductal adenocarcinoma treated with systemic therapies who had undergone pretreatment CT that included both unenhanced and equilibrium phase images. An ROI was placed on the primary tumor and aorta, and the tumor fECS was calculated as follows: (tumor attenuation in the equilibrium phase - tumor attenuation in the unenhanced phase) / (aortic attenuation in the equilibrium phase - aortic attenuation in the unenhanced phase) × (1 - hematocrit). Response to therapy was assessed in subsequent CT examinations according to the Response Evaluation Criteria in Solid Tumors version 1.1. Relevant clinical variables, including carbohydrate antigen 19-9 level, chemotherapy regimen, and survival were recorded. Multivariate analyses were performed to determine the predictors of treatment response and patient survival. RESULTS. The median primary tumor fECS was 0.41 (range, 0.02-0.69). When dichotomized to high (> 0.41) versus low fECS (≤ 0.41) values, a larger proportion of patients with high tumor fECS values achieved disease control after chemotherapy than did those with low tumor fECS values: full cohort, 27 of 30 versus 19 of 30 (p = 0.030); cohort with locally advanced disease, 23 of 24 versus 10 of 15 (p = 0.024). The mean progression-free survival among patients with high primary tumor fECS values was significantly longer than that among those with low fECS values (191 versus 115 days, p = < 0.0001). Primary tumor fECS was an independent predictor of progression-free survival (p = 0.003) in multivariate analysis. CONCLUSION. High primary tumor fECS value estimated from staging CT was associated with chemotherapy response and progression-free survival of patients with advanced pancreatic ductal adenocarcinoma.


Assuntos
Carcinoma Ductal Pancreático/diagnóstico por imagem , Espaço Extracelular/diagnóstico por imagem , Neoplasias Pancreáticas/diagnóstico por imagem , Tomografia Computadorizada por Raios X/métodos , Idoso , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/patologia , Feminino , Humanos , Masculino , Estadiamento de Neoplasias , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Interpretação de Imagem Radiográfica Assistida por Computador , Critérios de Avaliação de Resposta em Tumores Sólidos , Estudos Retrospectivos , Taxa de Sobrevida
10.
Nat Commun ; 11(1): 4249, 2020 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-32843618

RESUMO

Aberrant cell cycle machinery and loss of the CDKN2A tumor suppressor locus make CDK4/6 a potential target in pancreatic ductal adenocarcinoma (PDAC). However, a vast majority of PDAC cases do not harbor a durable response to monotherapy of CDK4/6 inhibitor. Utilizing remote loading to co-encapsulate CDK4/6 inhibitor palbociclib (PAL) and an autophagy inhibitor hydroxychloroquine (HCQ), we demonstrate a ratiometrically designed mesoporous silica nanoformulation with synergistic efficacy in subcutaneous and orthotopic PDAC mouse models. The synergism is attributed to the effective intratumoral buildup of PAL/HCQ, which otherwise exhibit distinctly different circulatory and biodistribution profile. PAL/HCQ co-delivery nanoparticles lead to the most effective shrinkage of PDAC compared to various controls, including free drug mixture. Immunohistochemistry reveals that PAL/HCQ co-delivery nanoparticles trigger anti-apoptotic pathway after repetitive intravenous administrations in mice. When combined with a Bcl inhibitor, the performance of co-delivery nanoparticles is further improved, leading to a long-lasting anti-PDAC effect in vivo.


Assuntos
Autofagia/efeitos dos fármacos , Carcinoma Ductal Pancreático/tratamento farmacológico , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Sistemas de Liberação de Medicamentos , Neoplasias Pancreáticas/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Modelos Animais de Doenças , Sinergismo Farmacológico , Humanos , Hidroxicloroquina/administração & dosagem , Hidroxicloroquina/química , Hidroxicloroquina/farmacologia , Camundongos , Nanopartículas/administração & dosagem , Nanopartículas/química , Piperazinas/administração & dosagem , Piperazinas/química , Piperazinas/farmacologia , Piridinas/administração & dosagem , Piridinas/química , Piridinas/farmacologia , Dióxido de Silício/administração & dosagem , Dióxido de Silício/química , Dióxido de Silício/farmacologia , Resultado do Tratamento
11.
Mol Carcinog ; 59(10): 1227-1240, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32816368

RESUMO

Chemoresistance to gemcitabine (GEM)-a frontline chemotherapeutic, resulting from its dysfunctional uptake and metabolism in cancer cells, is a major contributing factor for failed therapy in pancreatic cancer (PanC) patients. Therefore, there is an urgent need for agents that could reverse GEM resistance and allow continued chemosensitivity to the drug. We employed natural nontoxic agent (with anti-PanC potential) bitter melon juice (BMJ) and GEM to examine their combinatorial benefits against tumorigenesis of PanC patient-derived xenograft (PDX)-pancreatic ductal adenocarcinomas explants PDX272 (wild-type KRAS), PDX271 (mutant KRAS and SMAD4), and PDX266 (mutant KRAS). Anti-PanC efficacy of single agents vs combination in the three tumor explants, both at the end of active dosing regimen and following a drug-washout phase were compared. In animal studies, GEM alone treatment significantly inhibited PDX tumor growth, but effects were not sustained, as GEM-treated tumors exhibited regrowth posttreatment termination. However, combination-regimen displayed enhanced and sustained efficacy. Mechanistic assessments revealed that overcoming GEM resistance by coadministration with BMJ was possibly due to modulation of GEM transport/metabolism pathway molecules (ribonucleotide reductase regulatory subunit M1, human equilibrative nucleoside transporter 1, and deoxycytidine kinase). Study outcomes, highlighting significantly higher and sustained efficacy of GEM in combination with BMJ, make a compelling case for a clinical trial in PanC patients, wherein BMJ could be combined with GEM to target and overcome GEM resistance. In addition, given their specific effectiveness against KRAS-mutant tumors, this combination could be potentially beneficial to a broader PanC patient population.


Assuntos
Carcinoma Ductal Pancreático/tratamento farmacológico , Desoxicitidina/análogos & derivados , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Momordica charantia/química , Neoplasias Pancreáticas/tratamento farmacológico , Extratos Vegetais/farmacologia , Animais , Antimetabólitos Antineoplásicos/farmacologia , Apoptose , Carcinoma Ductal Pancreático/patologia , Proliferação de Células , Desoxicitidina/farmacologia , Feminino , Humanos , Camundongos , Camundongos Nus , Invasividade Neoplásica , Neoplasias Pancreáticas/patologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
12.
AAPS PharmSciTech ; 21(6): 231, 2020 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-32778980

RESUMO

The classically used nontargeted chemotherapeutic approach to pancreatic cancer has a dual drawback of suboptimal drug delivery at the target site and the systemic side effects produced by the unfettered exposure of the drug to healthy tissue. This study has the objective of developing novel poly(2-ethyl-2-oxazoline) (PETOX)-based long circulating liposomes loaded with gemcitabine and irinotecan for the treatment of pancreatic ductal adenocarcinoma, with a juxtaposition to PEGylated and uncoated liposomes. A PETOX-cholesteryl chloroformate lipopolymer conjugate (PETOX-ChC) with a carbonate linkage was prepared and characterized by 1H NMR, FTIR, and DSC. Liposomes were prepared using the thin film hydration technique followed by freeze-thaw and membrane extrusion methods. Liposome characterization includes particle size determination, zeta potential determination using a zetameter, and structural elucidation using 31P NMR and cryo-TEM. The PETOXylated liposomes showed a particle size of 180.1 ± 2.2 nm and a zeta potential of - 33.63 ± 1.23 mV. The liposomal combination therapy of gemcitabine and irinotecan was found to have an IC50 value 39 times lower in comparison to the drug combination in solution, while the PEGylated and PETOXylated liposomes showed IC50 values 1.6 times lower and 2 times lower than that of uncoated liposomes, respectively, against Mia PaCa II pancreatic cancer cell line. The PEGylated and PETOXylated liposomes showed 4.1 and 5.4 times slower macrophagial uptake in vitro in comparison to the uncoated liposomes respectively. The PEGylated liposomes showed 11% higher in vitro macrophagial uptake in comparison to PETOXylated liposomes.


Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma Ductal Pancreático/tratamento farmacológico , Desoxicitidina/análogos & derivados , Irinotecano/administração & dosagem , Lipossomos , Neoplasias Pancreáticas/tratamento farmacológico , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Desoxicitidina/administração & dosagem , Sistemas de Liberação de Medicamentos , Humanos , Neoplasias Pancreáticas/patologia , Tamanho da Partícula , Polietilenoglicóis/química
13.
Surgery ; 168(3): 448-456, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32620306

RESUMO

BACKGROUND: We describe the use of pancreatic retrograde venous infusion in an orthotopic murine model of pancreatic ductal adenocarcinoma and hypothesize that pancreatic retrograde venous infusion delivery of gemcitabine will increase concentrations of gemcitabine in the tumor and the subsequent tumor response to treatment. METHODS: Murine pancreatic ductal adenocarcinoma (KPC4580P) was transplanted onto the pancreatic tail of C57BL/6J mice. Groups (n = 15) of mice were assigned to sham laparotomy and 100 mg/kg intraperitoneal infusion of gemcitabine (systemic gemcitabine), pancreatic venous isolation with pancreatic retrograde venous infusion of 100 mg/kg gemcitabine, or pancreatic retrograde venous infusion with saline infusion. Tumor pressures were recorded during pancreatic retrograde venous infusion. Mice were killed at 1 hour or 7 days after infusion. RESULTS: Baseline tumor pressures were 45 ± 8 mm Hg, and pancreatic retrograde venous infusion increased tumor pressures by 29 ± 6 mm Hg (P < .01). Pancreatic retrograde venous infusion gemcitabine mice had greater tumor gemcitabine concentrations compared with systemic gemcitabine (127 vs 19 ng/mg; P < .01) and lesser tumor volumes compared with both systemic gem and pancreatic retrograde venous infusion with saline (274 vs 857 vs 629 mm3; P < .01). CONCLUSION: Pancreatic retrograde venous infusion increased tumor pressures greater than baseline, improved gemcitabine delivery, and increased the treatment response. These findings suggest that pressurized, regional delivery overcomes the increased pressure barrier in pancreatic ductal adenocarcinoma. Additional preclinical studies with cytotoxic and immunotherapeutic agents and clinical trials using pressure-enabled drug delivery with pancreatic retrograde venous infusion devices are underway.


Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Carcinoma Ductal Pancreático/tratamento farmacológico , Desoxicitidina/análogos & derivados , Infusões Intralesionais/métodos , Neoplasias Pancreáticas/tratamento farmacológico , Animais , Antimetabólitos Antineoplásicos/farmacocinética , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral/transplante , Desoxicitidina/administração & dosagem , Desoxicitidina/farmacocinética , Modelos Animais de Doenças , Humanos , Infusões Intravenosas/métodos , Masculino , Camundongos , Pâncreas/irrigação sanguínea , Pâncreas/patologia , Neoplasias Pancreáticas/patologia , Pressão , Distribuição Tecidual
14.
Anticancer Res ; 40(8): 4445-4455, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32727774

RESUMO

BACKGROUND/AIM: To examine interferon (IFN) signaling pathways in human pancreatic cancer cells and their therapeutic application for pancreatic ductal adenocarcinoma (PDAC). MATERIALS AND METHODS: We examined the effects of IFNα on cytotoxicity, migration, as well as on the levels of toll-like receptor (TLR) signaling pathway-associated genes expression in pancreatic cancer cells. We also examined the additive effects of IFNα and poly(I-C) on tyrosine kinase inhibitor (TKI)-induced cytotoxicity. We performed transcriptome analysis (RNA-Seq) of clinical samples and compared the profile between pancreatic intraepithelial neoplasias (PanINs) and PDACs. RESULTS: IFNα suppressed cell viability and cell migration, and affected TLR signaling pathways, in pancreatic cancer cells. TLR3 is one of the potential genes involved in IFN-treated pancreatic cancer cells. Furthermore, similar to IFN, extracellular addition of poly(I-C) enhanced TKI-induced cytotoxicity in pancreatic cancer cells. RNA-Seq analysis demonstrated that IFN signaling is one of the potential pathways involved in the progression of PanIN to PDAC. CONCLUSION: IFN signaling may be involved in the development of PDAC. Treatments that target the IFN and TLR3 signaling pathways may be therapeutic options against PDAC.


Assuntos
Carcinoma in Situ/genética , Carcinoma Ductal Pancreático/genética , Perfilação da Expressão Gênica/métodos , Interferons/metabolismo , Neoplasias Pancreáticas/genética , Poli I-C/farmacologia , Receptores Toll-Like/genética , Idoso , Carcinoma in Situ/tratamento farmacológico , Carcinoma in Situ/metabolismo , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Análise de Sequência de RNA , Transdução de Sinais/efeitos dos fármacos
15.
Anticancer Res ; 40(7): 3659-3667, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32620605

RESUMO

BACKGROUND/AIM: FOLFIRINOX [fluorouracil (5-FU), irinotecan, oxaliplatin] and gemcitabine plus nab-paclitaxel are standard treatments for patients with pancreatic ductal adenocarcinoma (PDAC). Despite efficacy rates of less than 32%, evidence is lacking to guide the use of one drug over the other. Herein, we compared the sensitivity of patient-derived PDAC cell lines to each of these regimens. MATERIALS AND METHODS: Changes in the growth of 19 low-passage patient-derived PDAC cell lines were evaluated in response to treatment with FOLFIRINOX and gemcitabine plus paclitaxel (Gem-Pac). RESULTS: Six cell lines exhibited optimal sensitivity (high EMax and low GI50) to FOLFIRINOX and three cell lines exhibited optimal sensitivity to Gem-Pac. Several cell lines that were optimally sensitive to one drug regimen exhibited very poor response to the other. CONCLUSION: Further characterization of cancer cells exhibiting preferential sensitivity to each of these regimens may allow the identification of biomarkers to guide the selection of appropriate chemotherapy for a given patient.


Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Ductal Pancreático/tratamento farmacológico , Desoxicitidina/análogos & derivados , Neoplasias Pancreáticas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Linhagem Celular Tumoral , Desoxicitidina/uso terapêutico , Feminino , Fluoruracila/uso terapêutico , Humanos , Irinotecano/uso terapêutico , Leucovorina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Oxaliplatina/uso terapêutico
16.
Crit Rev Oncol Hematol ; 153: 103060, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32707435

RESUMO

BACKGROUND: Current research that combines radiation with targeted therapy may dramatically improve prognosis of pancreatic ductal adenocarcinoma (PDAC). We investigated preclinical outcomes of DNA repair inhibitor targeted therapy associated with radiotherapy. METHODS: We searched Pubmed database to identify publications assessing DNA damage targeted therapies in preclinical models of PDACin vitro and in vivo. Standard enhancement ratio, median survival and growth delay were extracted. RESULTS: We identified fourteen publications using DNA repair targeted therapies in preclinical models of PDAC. Ten publications comprising twenty-eight experiments evaluated radiosensitization with different DNA repair inhibitors in vitro and displayed cell killing by a factor of 1.35 ±â€¯0.047. Moreover, 86 % (24/28) of in vitro experiments showed radiosensitization with DNA damage response inhibitor. However, only 60 % (9/15) of the in vivo experiments presented radiosensitization effects. CONCLUSION: DNA repair targeted therapies use promising radiosensitizers for PDAC and could successfully be translated into clinical trials.


Assuntos
Carcinoma Ductal Pancreático/tratamento farmacológico , Neoplasias Pancreáticas/radioterapia , Radiossensibilizantes/uso terapêutico , Dano ao DNA , Reparo do DNA , Humanos
17.
Nat Commun ; 11(1): 3303, 2020 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-32620742

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) lethality is due to metastatic dissemination. Characterization of rare, heterogeneous circulating tumor cells (CTCs) can provide insight into metastasis and guide development of novel therapies. Using the CTC-iChip to purify CTCs from PDAC patients for RNA-seq characterization, we identify three major correlated gene sets, with stemness genes LIN28B/KLF4, WNT5A, and LGALS3 enriched in each correlated gene set; only LIN28B CTC expression was prognostic. CRISPR knockout of LIN28B-an oncofetal RNA-binding protein exerting diverse effects via negative regulation of let-7 miRNAs and other RNA targets-in cell and animal models confers a less aggressive/metastatic phenotype. This correlates with de-repression of let-7 miRNAs and is mimicked by silencing of downstream let-7 target HMGA2 or chemical inhibition of LIN28B/let-7 binding. Molecular characterization of CTCs provides a unique opportunity to correlated gene set metastatic profiles, identify drivers of dissemination, and develop therapies targeting the "seeds" of metastasis.


Assuntos
Carcinoma Ductal Pancreático/genética , Proteína HMGA2/genética , MicroRNAs/genética , Células Neoplásicas Circulantes/metabolismo , Neoplasias Pancreáticas/genética , Proteínas de Ligação a RNA/genética , Adulto , Idoso , Animais , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/metabolismo , Linhagem Celular Tumoral , Movimento Celular/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Proteína HMGA2/metabolismo , Humanos , Estimativa de Kaplan-Meier , Masculino , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Pessoa de Meia-Idade , Metástase Neoplásica , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/metabolismo , Proteínas de Ligação a RNA/metabolismo
18.
Nat Chem Biol ; 16(9): 979-987, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32483379

RESUMO

Peptidyl-prolyl cis/trans isomerase NIMA-interacting 1 (Pin1) is commonly overexpressed in human cancers, including pancreatic ductal adenocarcinoma (PDAC). While Pin1 is dispensable for viability in mice, it is required for activated Ras to induce tumorigenesis, suggesting a role for Pin1 inhibitors in Ras-driven tumors, such as PDAC. We report the development of rationally designed peptide inhibitors that covalently target Cys113, a highly conserved cysteine located in the Pin1 active site. The inhibitors were iteratively optimized for potency, selectivity and cell permeability to give BJP-06-005-3, a versatile tool compound with which to probe Pin1 biology and interrogate its role in cancer. In parallel to inhibitor development, we employed genetic and chemical-genetic strategies to assess the consequences of Pin1 loss in human PDAC cell lines. We demonstrate that Pin1 cooperates with mutant KRAS to promote transformation in PDAC, and that Pin1 inhibition impairs cell viability over time in PDAC cell lines.


Assuntos
Antineoplásicos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Peptidilprolil Isomerase de Interação com NIMA/antagonistas & inibidores , Peptidilprolil Isomerase de Interação com NIMA/metabolismo , Animais , Antineoplásicos/química , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Transformação Celular Neoplásica/genética , Cristalografia por Raios X , Cisteína/metabolismo , Desenho de Fármacos , Inibidores Enzimáticos/metabolismo , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Humanos , Camundongos , Células NIH 3T3 , Peptidilprolil Isomerase de Interação com NIMA/química , Peptidilprolil Isomerase de Interação com NIMA/genética , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Conformação Proteica , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo
20.
Eur J Cancer ; 132: 112-121, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32361265

RESUMO

BACKGROUND: Necuparanib, a rationally engineered low-molecular-weight heparin, combined with gemcitabine/nab-paclitaxel showed an encouraging safety and oncologic signal in a phase Ib trial. This randomised multicentre phase II trial evaluates the addition of necuparanib or placebo to gemcitabine/nab-paclitaxel in untreated metastatic pancreatic ductal adenocarcinoma (PDAC). PATIENTS AND METHODS: Eligibility included 18 years, histologically or cytologically confirmed metastatic PDAC, measurable disease and Eastern Co-Operative Oncology Group performance status of 0-1. Patients were randomly assigned to necuparanib (5 mg/kg subcutaneous injection once daily) or placebo (subcutaneous injection once daily) and gemcitabine/nab-paclitaxel on days 1, 8 and 15 of 28-day cycles. The primary end-point was median overall survival (OS), and secondary end-points included median progression-free survival, response rates and safety. RESULTS: One-hundred ten patients were randomised, 62 to necuparanib arm and 58 to placebo arm. The futility boundary was crossed at a planned interim analysis, and the study was terminated by the Data Safety Monitoring Board. The median OS was 10.71 months (95% confidence interval [CI]: 7.95-11.96) for necuparanib arm and 9.99 months (95% CI: 7.85-12.85) for placebo arm (hazard ratio: 1.12, 95% CI: 0.66-1.89, P-value: 0.671). The necuparanib arm had a higher incidence of haematologic toxicity relative to placebo patients (83% and 70%). CONCLUSION: The addition of necuparanib to standard of care treatment for advanced PDAC did not improve OS. Safety was acceptable. No further development of necuparanib is planned although targeting the coagulation cascade pathway remains relevant in PDAC. NCT01621243.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Ductal Pancreático/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Albuminas/administração & dosagem , Carcinoma Ductal Pancreático/secundário , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Método Duplo-Cego , Feminino , Seguimentos , Heparitina Sulfato/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Neoplasias Pancreáticas/patologia , Prognóstico , Taxa de Sobrevida
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