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1.
Anticancer Res ; 40(2): 723-731, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32014914

RESUMO

BACKGROUND/AIM: MicroRNAs (miRNAs) play regulatory roles in pancreatic ductal adenocarcinoma (PDAC). However, it is still required to identify the function of miRNA-301-3p in pancreatic cancer cells. MATERIALS AND METHODS: Effects of luteolin on cell growth, TRAIL cytotoxicity, and miR-301-3p levels were evaluated. The role of miRNA-301-3p in regulating cell proliferation, target gene expression, and TRAIL cytotoxicity were studied. RESULTS: The levels of miR-301-3p were down-regulated in PANC-1 cells exposed to luteolin, which inhibits the growth of PANC-1 cells and sensitizes cells to TRAIL. The knockdown of miR-301-3p attenuates cell proliferation and enhances TRAIL cytotoxicity. In addition, caspase-8 was directly targeted by miR-301-3p. CONCLUSION: Our findings unveil a critical biological function of miR-301-3p in regulating cell proliferation and elevating an antiproliferative effect of TRAIL on cancer cells. Our observation of miR-301-3p/caspase-8 relationship can also serve to clarify the role of miR-301-3p in other cancer types and related diseases.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/metabolismo , Caspase 8/metabolismo , Luteolina/farmacologia , MicroRNAs/metabolismo , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/metabolismo , Ligante Indutor de Apoptose Relacionado a TNF/farmacologia , Carcinoma Ductal Pancreático/genética , Caspase 8/genética , Linhagem Celular Tumoral , Regulação para Baixo/efeitos dos fármacos , Sinergismo Farmacológico , Técnicas de Silenciamento de Genes , Humanos , Luteolina/administração & dosagem , MicroRNAs/genética , Neoplasias Pancreáticas/genética , Proteínas Recombinantes/farmacologia , Ligante Indutor de Apoptose Relacionado a TNF/administração & dosagem , Transfecção
2.
J Cancer Res Clin Oncol ; 146(2): 391-399, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31642961

RESUMO

PURPOSE: A prolonged time to treatment initiation (TTI) correlates with an adverse prognosis in different cancer types including resectable pancreatic cancer (PC). Only limited evidence on the correlation between TTI and prognosis in advanced PC exists. METHODS: Consecutive PC patients (n = 368) who were diagnosed or treated at our high-volume comprehensive cancer center were included in a prospectively maintained database. We retrospectively analyzed time from first imaging showing advanced PC to initiation of palliative first-line chemotherapy. Lead time bias and waiting time paradox were addressed by landmark analysis and correlation of tumor burden with TTI. RESULTS: Two hundred and ninety-seven patients met the pre-specified in- and exclusion criteria of our study. Median TTI was 29 days (range: 1-124 days). Most common reasons for prolonged TTI (> 21 days) were referral from an external treatment center (39%) and a second biopsy (31%). A TTI above the median-, 75th or 90th percentile (43 or 60 days, respectively) had no impact on overall survival. Furthermore, no correlation between levels of carbohydrate antigen 19-9 (CA 19-9) at time of treatment initiation and TTI was observed. CONCLUSION: While a timely work-up of advanced PC patients remains important, delays in treatment initiation due to repeated biopsies, inclusion in a clinical study or transfer to a specialized cancer center appear to be justified in light of the absence of a strong adverse effect of prolonged TTI on prognosis in advanced PC patients.


Assuntos
Carcinoma Ductal Pancreático/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Tempo para o Tratamento , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígeno CA-19-9/sangue , Carcinoma Ductal Pancreático/sangue , Carcinoma Ductal Pancreático/mortalidade , Estudos de Coortes , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Feminino , Fluoruracila/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Cuidados Paliativos , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/mortalidade , Prognóstico , Estudos Retrospectivos , Resultado do Tratamento
3.
Int J Cancer ; 146(6): 1618-1630, 2020 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-31291468

RESUMO

MALT1 is a key mediator of NF-κB signaling and a main driver of B-cell lymphomas. Remarkably, MALT1 is expressed in the majority of pancreatic ductal adenocarcinomas (PDACs) as well, but absent from normal exocrine pancreatic tissue. Following, MALT1 shows off to be a specific target in cancer cells of PDAC without affecting regular pancreatic cells. Therefore, we studied the impact of pharmacological MALT1 inhibition in pancreatic cancer and showed promising effects on tumor progression. Mepazine (Mep), a phenothiazine derivative, is a known potent MALT1 inhibitor. Newly, we described that biperiden (Bip) is a potent MALT1 inhibitor with even less pharmacological side effects. Thus, Bip is a promising drug leading to reduced proliferation and increased apoptosis in PDAC cells in vitro and in vivo. By compromising MALT1 activity, nuclear translocation of c-Rel is prevented. c-Rel is critical for NF-κB-dependent inhibition of apoptosis. Hence, off-label use of Bip or Mep represents a promising new therapeutic approach to PDAC treatment. Regularly, the Anticholinergicum Bip is used to treat neurological side effects of Phenothiazines, like extrapyramidal symptoms.


Assuntos
Biperideno/farmacologia , Carcinoma Ductal Pancreático/tratamento farmacológico , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/antagonistas & inibidores , Neoplasias Pancreáticas/tratamento farmacológico , Fenotiazinas/farmacologia , Animais , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Processos de Crescimento Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Camundongos , Camundongos Knockout , Modelos Moleculares , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/biossíntese , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/química , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/metabolismo , NF-kappa B/metabolismo , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Proteínas Proto-Oncogênicas c-rel/metabolismo , Distribuição Aleatória , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Gut ; 69(1): 122-132, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31076405

RESUMO

OBJECTIVE: We investigated how pancreatic cancer developed resistance to focal adhesion kinase (FAK) inhibition over time. DESIGN: Pancreatic ductal adenocarcinoma (PDAC) tumours from KPC mice (p48-CRE; LSL-KRasG12D/wt; p53flox/wt) treated with FAK inhibitor were analysed for the activation of a compensatory survival pathway in resistant tumours. We identified pathways involved in the regulation of signal transducer and activator of transcription 3 (STAT3) signalling on FAK inhibition by gene set enrichment analysis and verified these outcomes by RNA interference studies. We also tested combinatorial approaches targeting FAK and STAT3 in syngeneic transplantable mouse models of PDAC and KPC mice. RESULTS: In KPC mice, the expression levels of phosphorylated STAT3 (pSTAT3) were increased in PDAC cells as they progressed on FAK inhibitor therapy. This progression corresponded to decreased collagen density, lowered numbers of SMA+ fibroblasts and downregulation of the transforming growth factor beta (TGF-ß)/SMAD signalling pathway in FAK inhibitor-treated PDAC tumours. Furthermore, TGF-ß production by fibroblasts in vitro drives repression of STAT3 signalling and enhanced responsiveness to FAK inhibitor therapy. Knockdown of SMAD3 in pancreatic cancer cells abolished the inhibitory effects of TGF-ß on pSTAT3. We further found that tumour-intrinsic STAT3 regulates the durability of the antiproliferative activity of FAK inhibitor, and combinatorial targeting of FAK and Janus kinase/STAT3 act synergistically to suppress pancreatic cancer progression in mouse models. CONCLUSION: Stromal depletion by FAK inhibitor therapy leads to eventual treatment resistance through the activation of STAT3 signalling. These data suggest that, similar to tumour-targeted therapies, resistance mechanisms to therapies targeting stromal desmoplasia may be critical to treatment durability.


Assuntos
Aminopiridinas/uso terapêutico , Antineoplásicos/uso terapêutico , Carcinoma Ductal Pancreático/tratamento farmacológico , Proteína-Tirosina Quinases de Adesão Focal/antagonistas & inibidores , Neoplasias Pancreáticas/tratamento farmacológico , Aminopiridinas/farmacologia , Animais , Antineoplásicos/farmacologia , Carcinoma Ductal Pancreático/enzimologia , Carcinoma Ductal Pancreático/patologia , Colágeno/metabolismo , Regulação para Baixo/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/fisiologia , Feminino , Fibroblastos/efeitos dos fármacos , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Humanos , Camundongos Endogâmicos , Neoplasias Pancreáticas/enzimologia , Neoplasias Pancreáticas/patologia , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteína Smad3/metabolismo , Células Estromais/efeitos dos fármacos , Células Estromais/patologia , Fator de Crescimento Transformador beta/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Genes (Basel) ; 10(10)2019 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-31569425

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is the most common and aggressive type of pancreatic cancer. The five-year survival rate of PDAC is very low (less than 8%), which is associated with the late diagnosis, high metastatic potential, and resistance to therapeutic agents. The identification of better prognostic or therapeutic biomarker may have clinical benefits for PDAC treatment. SMAD4, a central mediator of transforming growth factor beta (TGFß) signaling pathway, is considered a tumor suppressor gene. SMAD4 inactivation is frequently found in PDAC. However, its role in prognosis and therapeutics of PDAC is still unclear. In this study, we applied bioinformatics approaches, and integrated publicly available resources, to investigate the role of SMAD4 gene deletion in PDAC. We found that SMAD4 deletion was associated with poorer disease-free, but not overall, survival in PDAC patients. Cancer hallmark enrichment and pathway analysis suggested that the upregulation of cell cycle-related genes in SMAD4-deleted PDAC. Chemotherapy response profiling of PDAC cell lines and patient-derived organoids revealed that SMAD4-deleted PDAC was sensitive to gemcitabine, the first-line treatment for PDAC, and specific cell cycle-targeting drugs. Taken together, our study provides an insight into the prognostic and therapeutic roles of SMAD4 gene deletion in PDAC, and SMAD4 gene copy numbers may be used as a therapeutic biomarker for PDAC treatment.


Assuntos
Antibióticos Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/genética , Carcinoma Ductal Pancreático/genética , Desoxicitidina/análogos & derivados , Resistencia a Medicamentos Antineoplásicos , Neoplasias Pancreáticas/genética , Proteína Smad4/genética , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/patologia , Ciclo Celular , Linhagem Celular Tumoral , Biologia Computacional/métodos , Desoxicitidina/uso terapêutico , Deleção de Genes , Humanos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Células Tumorais Cultivadas
6.
Anticancer Res ; 39(10): 5781-5787, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570482

RESUMO

BACKGROUND: Neoadjuvant chemotherapy (NAC) is established in the treatment of ductal pancreatic adenocarcinoma for downsizing borderline-resectable pancreatic cancer (BRPC) and may affect nodal positivity and rates of R0 resection. This study aimed to identify the impact of NAC on postoperative histopathological parameters with a prognostic relevance. PATIENTS AND METHODS: A one-to-three matched-pair analysis, including an overall total of 132 patients (25% treated with NAC and subsequent resection and 75% undergoing upfront surgery) was performed. Influence of NAC on nodal positivity, lymphatic, vascular and perineural invasion, as well as resection stage and grading, was examined. Furthermore, perioperative complications, in-hospital stay, re-admission rates, mortality, as well as preoperative body mass index and American Association of Anesthesiologist classification scores, were evaluated. RESULTS: Patients treated with NAC significantly less frequently had lymphatic tissue invasion (lymph node invasion: 51.5% vs. 72.7%; p=0.032, and lymphatic vessel invasion 9.4% vs. 55.3%; p=0.0004), whereas vascular and perineural invasion, as well as grading and resection state were not significantly different. Carbohydrate antigen 19-9 regression in correlation with nodal positivity also did not differ, and both groups showed comparable perioperative complication rates. Occurrence and severity of postoperative pancreatic fistula (18.2% vs. 24.3%; p=0.034) were significantly lower in patients who had undergone NAC. CONCLUSION: NAC significantly affects postoperative histopathological tumour stage in BRPC and appears to be a safe treatment option without increased perioperative complications, re-admission, in-hospital stay, or mortality. Further studies are mandatory to underline the suitability of NAC for ductal pancreatic adenocarcinoma subgroups in order to guide clinicians in their daily decision-making comprehensively.


Assuntos
Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Adenocarcinoma/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígeno CA-19-9/metabolismo , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/terapia , Quimioterapia Adjuvante/métodos , Feminino , Humanos , Masculino , Análise por Pareamento , Pessoa de Meia-Idade , Terapia Neoadjuvante/métodos , Estadiamento de Neoplasias/métodos , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/terapia , Período Pós-Operatório , Prognóstico , Estudos Retrospectivos
7.
Jpn J Clin Oncol ; 49(11): 1049-1054, 2019 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-31612916

RESUMO

Germline BRCA1 and BRCA2 mutations are the most common gene mutations in familial pancreatic adenocarcinoma. Several reports have demonstrated the utility of platinum-based chemotherapy for treating cancer patients who harbour a BRCA mutation. Here we discuss a 47-year-old Japanese female with no relevant past history who presented with epigastralgia and fever in September 2016. A computed tomography scan revealed a low-density, low-enhanced tumour 15 mm in diameter in the head of the pancreas. The pathological diagnosis was a ductal pancreatic carcinoma. A 6 mm low-enhanced metastatic tumour was also detected in segment 4 of the liver. Because she had early onset of the disease and a family history-her mother died of pancreatic adenocarcinoma at age 48-we considered a diagnosis of familial pancreatic adenocarcinoma. She received modified FOLFIRINOX. Two months after starting chemotherapy, she was diagnosed with an invasive ductal carcinoma in the right breast. FOLFIRINOX was continued for 8 cycles (4 months); the primary pancreatic adenocarcinoma shrank and the liver metastatic foci disappeared, but the size of the breast tumour increased. Total right breast excision and sentinel lymph node dissection were performed. FOLFIRINOX was continued and after 12 cycles (6 months), both her pancreatic adenocarcinoma and liver metastasis were no longer visible using imaging. Pancreatoduodenectomy was performed and the primary tumour had shrunk to 2.5 mm. Genetic testing revealed a germline BRCA2 mutation. The FOLFIRINOX regimen showed dramatic effects on the collision pancreatic but not on the breast cancer.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Ductal de Mama/tratamento farmacológico , Carcinoma Ductal Pancreático/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Proteína BRCA2/genética , Carcinoma Ductal de Mama/genética , Feminino , Fluoruracila/uso terapêutico , Testes Genéticos , Células Germinativas , Mutação em Linhagem Germinativa , Humanos , Irinotecano/uso terapêutico , Leucovorina/uso terapêutico , Neoplasias Hepáticas/secundário , Excisão de Linfonodo , Pessoa de Meia-Idade , Mutação , Oxaliplatina/uso terapêutico , Pancreaticoduodenectomia
8.
Cancer Treat Rev ; 80: 101895, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31542591

RESUMO

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers worldwide. Recent studies have shown that 4-20% of patients with PDAC have a germline BReast CAncer (gBRCA) genes 1 and 2 mutation (m). Because homologous recombination is impaired in patients with gBRCAm, some reports suggested that these tumors may be more sensitive to platinum compounds. Therefore, this systematic review and meta-analysis focused on benefit of patients with gBRCAm receiving a platinum-based chemotherapy (PtCh) compared with those treated with a non-platinum-based chemotherapy (NPtCh). MATERIAL AND METHODS: The following electronic databases were searched from inception to May 12, 2018: PubMed (MEDLINE), EMBASE, and Cochrane Library. Abstracts from conferences were also reviewed for inclusion. Cohort, case-control and randomized studies of patients with PDAC and gBRCAm were eligible for inclusion if they provided data to compare patients receiving PtCh vs NPtCh. The primary endpoint was overall survival (OS) in the PtCh group vs the NPtCh group in patients with clinical stage III (locally advanced) or IV (metastatic) (CS III-IV) PDAC. RESULTS: Of 112 studies identified, 6 were included (total of 108 patients); of these, 4 provided sufficient data for meta-analysis. Half of the patients were males, with a mean age ranging from 58 to 63 years. The OS in the 85 patients with CS III-IV PDAC was higher in the PtCh group (23.7 vs 12.2 months; mean difference of 10.21 months, 95% confidence interval [CI] 5.05-15.37; P < 0.001; very low quality of evidence). PtCh was associated with a lower mortality (62.3 vs 87.5%; relative risk of 0.80, 95%CI 0.66-0.97; P = 0.021; very low quality of evidence). CONCLUSION: Our study confirmed the hypothesis that patients with CS III-IV gBRCAm preferably benefit from a PtCh compared with NPtCh. However the very low quality of evidence should induce to be careful about the risk of potential biases. The generated hypothesis should be prospectively investigated in homogenous clinical settings.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/genética , Genes BRCA1 , Genes BRCA2 , Mutação em Linhagem Germinativa , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Proteína BRCA1/genética , Proteína BRCA2/genética , Humanos , Compostos Organoplatínicos/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto
9.
Anticancer Res ; 39(8): 4431-4440, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366541

RESUMO

BACKGROUND/AIM: To identify risk factors of early recurrence after neoadjuvant chemoradiation therapy (NACRT) and curative pancreatectomy in patients with borderline resectable (BR) pancreatic ductal adenocarcinoma (PDAC). PATIENTS AND METHODS: Sixty-one patients with BR-PDAC who underwent curative resection after NACRT during July 2009-June 2014 were included. Patients were divided into early recurrence (i.e., developed recurrence within 1 year after pancreatectomy; n=30) and late/non-recurrence groups (n=31). The patient characteristics, clinicopathological factors of early recurrence, and survival time were retrospectively compared between groups. RESULTS: In the univariate analysis, the maximum standardized uptake value (SUVmax), microvascular invasion, and lymph node metastasis were associated with early recurrence. In the multivariate analysis, the pre-NACRT SUVmax and microvascular invasion in the early recurrence group were significantly different from that in the late/non-recurrence group. A pre-NACRT SUVmax >4.1 was an independent predictor of poor recurrence-free and overall survival. CONCLUSION: SUVmax and microvascular invasion are independent predictors of poor recurrence-free and overall survival after NACRT for BR-PDAC. Although complete pancreatectomy after NACRT was performed, approximately half of the patients had recurrence within 1 year.


Assuntos
Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/radioterapia , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/radioterapia , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Idoso , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/cirurgia , Quimiorradioterapia , Intervalo Livre de Doença , Feminino , Humanos , Linfonodos/patologia , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/radioterapia , Prognóstico , Fatores de Risco
10.
J Surg Oncol ; 120(6): 976-984, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31452208

RESUMO

BACKGROUND AND OBJECTIVES: Conclusive evidence in favor of neoadjuvant therapy for those with non-metastatic pancreatic ductal adenocarcinoma (PDAC) is still lacking. The objective of this study was to evaluate the survival benefit of neoadjuvant therapy vs upfront surgery for patients with non-metastatic PDAC. METHODS: The study involved 565 patients undergoing neoadjuvant therapy or upfront surgery as the primary treatment for PDAC. Propensity score matching was performed between the neoadjuvant therapy group (NAT group) and the upfront surgery group (UFS group) using 20 clinical variables at diagnosis. Overall survival and surgical pathology were compared between the two treatment groups on an intent-to-treat basis. RESULTS: In the matched cohort, the NAT group (n = 91) had a longer median overall survival than the UFS group (n = 91) (23.1 months vs 18.5 months, P = .043). The rate of patients undergoing surgical resection was lower in the NAT group (58% vs 80%, P = .001). Regarding surgical pathology, the NAT group had smaller tumor size (2.8 cm vs 4.0 cm, P = .001), lower incidence of positive surgical margins (8% vs 30%, P < .002), and less lymph node metastasis (45% vs 78%, P < .001). CONCLUSIONS: The strategy of neoadjuvant therapy before surgical resection appears to offer pathologic effect and survival benefit for the patients presenting with non-metastatic PDAC.


Assuntos
Adenocarcinoma/mortalidade , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Ductal Pancreático/mortalidade , Análise de Intenção de Tratamento , Terapia Neoadjuvante/mortalidade , Pancreatectomia/mortalidade , Neoplasias Pancreáticas/mortalidade , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/cirurgia , Quimioterapia Adjuvante , Estudos de Coortes , Terapia Combinada , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/cirurgia , Prognóstico , Pontuação de Propensão , Taxa de Sobrevida , Adulto Jovem
11.
Carbohydr Polym ; 223: 115104, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31426957

RESUMO

Crude polysaccharides were obtained from fruits of Lycium ruthenicum Murr using hot water extraction followed by ethanol precipitation. A homogeneous polysaccharide, LRP3-S1 with a relative molecular weight of 114.8 kDa was purified by anion-exchange chromatography on DEAE Sepharose™Fast Flow and Sephacryl S-300 HR column. Monosaccharide composition analysis revealed that LRP3-S1 was composed of rhamnose, galacturonic acid, galactose, xylose and arabinose in a molar ratio of 14.4: 17.7: 26.6: 16.4: 24.9. LRP3-S1 contained a rhamnogalacturonan I (RG-I) backbone partially substituted at C-4 of rhamnose units by side chains, which included T-linked ß-D-Galp, 1,3-linked ß-D-Galp, 1,6-linked ß-D-Galp, 1,3,6-linked ß-D-Galp, 1,5-linked α-L-Araf, 1,3,5-linked α-L-Araf, T-linked α-L-Araf and T-linked ß-D-Xylp. Biological activity tests showed that LRP3-S1 could inhibit the growth of pancreatic cancer cells. In addition, LRP3-S1 could attenuate invasion ability of BxPC-3 cells and down-regulate protein expression of p-FAK, p-AKT, p-GSK-3ß and p-p38 MAP kinase.


Assuntos
Antineoplásicos/isolamento & purificação , Antineoplásicos/farmacologia , Carcinoma Ductal Pancreático/tratamento farmacológico , Lycium/química , Neoplasias Pancreáticas/tratamento farmacológico , Pectinas/isolamento & purificação , Pectinas/farmacologia , Antineoplásicos/química , Configuração de Carboidratos , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Pectinas/química , Relação Estrutura-Atividade
12.
Mol Carcinog ; 58(10): 1908-1918, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31313401

RESUMO

Gastrin signaling mediated through cholecystokinin-2 receptor (CCK2R) and its downstream molecules is altered in pancreatic cancer. CCK2R antagonists, YF476 (netazepide) and JNJ-26070109, were tested systematically for their effect on pancreatic intraepithelial neoplasia (PanIN) progression to pancreatic ductal adenocarcinoma (PDAC) in KrasG12D mice. After dose selection using wild-type mice, six-week-old p48Cre/+ -LSL-KrasG12D (22-24 per group) genetically engineered mice (GEM) were fed AIN-76A diets containing 0, 250, or 500 ppm JNJ-26070109 or YF-476 for 38 weeks. At termination, pancreata were collected, weighed, and evaluated for PanINs and PDAC. Results demonstrated that control-diet-fed mice showed 69% (males) and 33% (females) incidence of PDAC. Administration of low and high dose JNJ-26070109 inhibited the incidence of PDAC by 88% and 71% (P < .004) in male mice and by 100% and 24% (P > .05) in female mice, respectively. Low and high dose YF476 inhibited the incidence of PDAC by 74% (P < .02) and 69% (P < .02) in male mice and by 45% and 33% (P > .05) in female mice, respectively. Further, transcriptome analysis showed downregulation of Cldn1, Sstr1, Apod, Gkn1, Siglech, Cyp2c44, Bnc1, Fmo2, 623169, Kcne4, Slc27a6, Cma1, Rho GTPase activating protein 18, and Gpr85 genes in JNJ-26070109-treated mice compared with untreated mice. YF476-treated mouse pancreas showed downregulation of Riks, Zpbp, Ntf3, Lrrn4, Aass, Skint3, Kcnb1, Dgkb, Ddx60, and Aspn gene expressions compared with untreated mouse pancreas. Overall, JNJ-26070109 showed better chemopreventive efficacy than YF476. However, caution is recommended when selecting doses, as the agents appeared to exhibit gender-specific effects.


Assuntos
Adenocarcinoma/tratamento farmacológico , Carcinoma Ductal Pancreático/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Receptor de Colecistocinina B/genética , Adenocarcinoma/genética , Adenocarcinoma/patologia , Animais , Benzodiazepinonas/farmacologia , Carcinoma in Situ , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Quimioprevenção/métodos , Modelos Animais de Doenças , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Proteínas de Neoplasias/genética , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Compostos de Fenilureia/farmacologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Quinoxalinas/farmacologia , Receptor de Colecistocinina B/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Sulfonamidas/farmacologia
13.
Nat Commun ; 10(1): 3055, 2019 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-31296870

RESUMO

KRAS mutations are present in over 90% of pancreatic ductal adenocarcinomas (PDAC), and drive their poor outcomes and failure to respond to targeted therapies. Here we show that Leukemia Inhibitory Factor (LIF) expression is induced specifically by oncogenic KRAS in PDAC and that LIF depletion by genetic means or by neutralizing antibodies prevents engraftment in pancreatic xenograft models. Moreover, LIF-neutralizing antibodies synergize with gemcitabine to eradicate established pancreatic tumors in a syngeneic, KrasG12D-driven, PDAC mouse model. The related cytokine IL-6 cannot substitute for LIF, suggesting that LIF mediates KRAS-driven malignancies through a non-STAT-signaling pathway. Unlike IL-6, LIF inhibits the activity of the Hippo-signaling pathway in PDACs. Depletion of YAP inhibits the function of LIF in human PDAC cells. Our data suggest a crucial role of LIF in KRAS-driven pancreatic cancer and that blockade of LIF by neutralizing antibodies represents an attractive approach to improving therapeutic outcomes.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma Ductal Pancreático/tratamento farmacológico , Fator Inibidor de Leucemia/metabolismo , Neoplasias Pancreáticas/tratamento farmacológico , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Desoxicitidina/uso terapêutico , Feminino , Técnicas de Inativação de Genes , Humanos , Interleucina-6/genética , Interleucina-6/metabolismo , Fator Inibidor de Leucemia/antagonistas & inibidores , Fator Inibidor de Leucemia/genética , Camundongos , Mutação , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais/genética , Fatores de Transcrição , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Nagoya J Med Sci ; 81(2): 233-239, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31239592

RESUMO

The efficacy of nab-paclitaxel combined with gemcitabine (GnP) and of chemoradiotherapy (CRT) for unresectable locally advanced pancreatic ductal adenocarcinoma (UR-LA PDAC) is still unclear. We previously conducted a phase I study of CRT using GnP and determined the recommended dose and have now designed a phase II trial to evaluate the efficacy of CRT incorporating GnP for UR-LA PDAC. Eligibility criteria are chemotherapy-naïve patients with UR-LA PDAC as defined by the NCCN guidelines version 2. 2016. Study patients will receive 100 mg/m2 nab-paclitaxel and 800 mg/m2 gemcitabine on Days 1, 8, and 15 per 4-week cycle with concurrent radiation therapy (total dose of 50.4 Gy in 28 fractions of 1.8 Gy per day, 5 days per week). Treatment will be continued until disease progression or surgery, which is to be performed only for patients in whom the disease is well-controlled at 8 months from beginning the protocol treatment. Primary endpoint is 2-year overall survival rate and co-primary endpoint is resection rate. Secondary endpoints are overall survival, progression free survival, time to treatment failure, response rate, disease control rate, early tumor shrinkage, depth of response, reduction of SUV-max on PET-CT, serum tumor markers, relative dose intensity, safety, and Quality of life. This study will show the efficacy and safety of chemoradiotherapy combined with GnP.


Assuntos
Albuminas/uso terapêutico , Carcinoma Ductal Pancreático/tratamento farmacológico , Desoxicitidina/análogos & derivados , Paclitaxel/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Adulto , Idoso , Carcinoma Ductal Pancreático/mortalidade , Desoxicitidina/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/mortalidade , Taxa de Sobrevida , Resultado do Tratamento , Adulto Jovem
15.
Expert Opin Investig Drugs ; 28(7): 583-592, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31215251

RESUMO

Introduction: PDAC is a lethal malignancy with a clear unmet need; almost all patients fail 1st, 2nd, and 3rd line multi-agent cytotoxic chemotherapy. The mammalian target of rapamycin (mTOR) has been identified as a key signaling node enhancing tumor survival and drug resistance in PDAC; hence, it is considered a promising therapeutic target. Areas covered: We comprehensively reviewed the evidence from preclinical and phase I and II clinical trials, based on the authors'clinical experience and a PubMed, Cochrane library, Embase, and Google Scholar search everolimus + pancreatic cancer. Expert opinion: Everolimus has not demonstrated efficacy in PDAC; however, an mTOR inhibitor in combination with stroma-targeted therapies may be a promising area to explore in clinical trials.


Assuntos
Carcinoma Ductal Pancreático/tratamento farmacológico , Everolimo/administração & dosagem , Neoplasias Pancreáticas/tratamento farmacológico , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Carcinoma Ductal Pancreático/patologia , Resistencia a Medicamentos Antineoplásicos , Everolimo/farmacologia , Humanos , Terapia de Alvo Molecular , Neoplasias Pancreáticas/patologia , Sobrevida , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo
16.
BMC Cancer ; 19(1): 632, 2019 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-31242873

RESUMO

BACKGROUND: A key challenge in phase I trials is maintaining rapid escalation in order to avoid exposing too many patients to sub-therapeutic doses, while preserving safety by limiting the frequency of toxic events. Traditional rule-based designs require temporarily stopping recruitment whilst waiting to see whether enrolled patients develop toxicity. This can be both inefficient and introduces logistic challenges to recruitment in the clinic. We describe a novel two-stage dose assignment procedure designed for a phase I clinical trial (STARPAC), where a good estimation of prior was possible. METHODS: The STARPAC design uses rule-based design until the first patient has a dose limiting toxicity (DLT) and then switches to a modified CRM, with rules to handle patient recruitment during follow-up of earlier patients. STARPAC design is compared via simulations with the TITE-CRM and 3 + 3 methods in various toxicity estimate (T1-5), rate of recruitment (R1-2), and DLT events timing (DT1-4), scenarios using several metrics: accuracy of maximum tolerated dose (MTD), numbers of DLTs, number of patients enrolled and those missed; duration of trial; and proportion of patients treated at the therapeutic dose or MTD. RESULTS: The simulations suggest that STARPAC design performed well in MTD estimation and in treating patients at the highest possible therapeutic levels. STARPAC and TITE-CRM were comparable in the number of patients required and DLTs incurred. The 3 + 3 design often had fewer patients and DLTs although this is due to its low escalation rate leading to poor MTD estimation. For the numbers of declined patients and MTD estimation 3 + 3 is uniformly worse, with STARPAC being better in those metrics for high toxicity scenarios and TITE-CRM better with low toxicity. In situations including doses with toxicities both above and below 30%, the STARPAC design outperformed TITE-CRM with respect to every metric. CONCLUSION: When considering doses with toxicities both above and below the target of 30% toxicities, the two-stage STARPAC dose escalation design provides a more efficient phase I trial design than either the traditional 3 + 3 or the TITE-CRM design. Trialists should model various designs via simulation to adopt the most efficient design for their clinical scenario. TRIAL REGISTRATION: Clinical Trials NCT03307148 (11 October 2017).


Assuntos
Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma Ductal Pancreático/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Projetos de Pesquisa , Tretinoína/administração & dosagem , Albuminas/administração & dosagem , Albuminas/efeitos adversos , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Teorema de Bayes , Carcinoma Ductal Pancreático/patologia , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Reposicionamento de Medicamentos , Humanos , Dose Máxima Tolerável , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Pâncreas/patologia , Neoplasias Pancreáticas/patologia , Seleção de Pacientes , Critérios de Avaliação de Resposta em Tumores Sólidos , Tretinoína/efeitos adversos
17.
Intern Med ; 58(20): 2957-2962, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31243233

RESUMO

Gemcitabine plus nab-paclitaxel is the current standard chemotherapy for patients with metastatic pancreatic cancer. We conducted a phase I/II study in Japan, in which high response rates and manageable toxicity were observed. In this study, two patients were reported as experiencing pancreatitis due to chemotherapy. In general, pancreatitis is sometimes observed when the tumor involves the pancreatic duct, and the onset is observed before the diagnosis or at the initial stage. The onset of pancreatitis in these cases was unique and observed after the start of chemotherapy. Pancreatitis may be induced by the alleviation of stenosis of the pancreatic duct associated with tumor shrinkage.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/secundário , Neoplasias Pancreáticas/tratamento farmacológico , Pancreatite/induzido quimicamente , Doença Aguda , Idoso , Albuminas/administração & dosagem , Albuminas/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Ductal Pancreático/diagnóstico por imagem , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/análogos & derivados , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/patologia , Pancreatite/diagnóstico por imagem , Tomografia Computadorizada por Raios X
18.
Cancer Sci ; 110(8): 2442-2455, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31148345

RESUMO

The human prolyl isomerase PIN1, best known for its association with carcinogenesis, has recently been indicated in the disease of pancreatic ductal adenocarcinoma (PDAC). However, the functions of PIN1 and the feasibility of targeting PIN1 in PDAC remain elusive. For this purpose, we examined the expression of PIN1 in cancer, related paracarcinoma and metastatic cancer tissues by immunohistochemistry and analyzed the associations with the pathogenesis of PDAC in 173 patients. The functional roles of PIN1 in PDAC were explored in vitro and in vivo using both genetic and chemical PIN1 inhibition. We showed that PIN1 was upregulated in pancreatic cancer and metastatic tissues. High PIN1 expression is significantly association with poor clinicopathological features and shorter overall survival and disease-free survival. Further stratified analysis showed that PIN1 phenotypes refined prognostication in PDAC. Inhibition of PIN1 expression with RNA interference or with all trans retinoic acid decreased not only the growth but also the migration and invasion of PDAC cells through regulating the key molecules of multiple cancer-driving pathways, simultaneously resulting in cell cycle arrest and mesenchymal-epithelial transition in vitro. Furthermore, genetic and chemical PIN1 ablation showed dramatic inhibition of the tumorigenesis and metastatic spread and then reduced the tumor burden in vivo. We provided further evidence for the use of PIN1 as a promising therapeutic target in PDAC. Genetic and chemical PIN1 ablation exerted potent antitumor effects through blocking multiple cancer-driving pathways in PDAC. More potent and specific PIN1 targeted inhibitors could be exploited to treat this aggressive cancer.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/genética , Peptidilprolil Isomerase de Interação com NIMA/genética , Metástase Neoplásica/genética , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Animais , Carcinogênese/efeitos dos fármacos , Carcinogênese/genética , Carcinogênese/patologia , Carcinoma Ductal Pancreático/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/genética , Linhagem Celular , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Intervalo Livre de Doença , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/genética , Feminino , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Metástase Neoplásica/patologia , Neoplasias Pancreáticas/patologia , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética
19.
BMJ Case Rep ; 12(5)2019 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-31154349

RESUMO

Spontaneous cancer regression is a rare event, scarcely reported among gastrointestinal malignancies. Pancreatic adenocarcinoma regression has been documented in five previous cases, none of which included liver metastases, and the mechanism by which this occurs is not known. A 56-year-old woman with history of discoid lupus, homocysteinemia and peripheral vascular disease was diagnosed with stage IV pancreatic ductal adenocarcinoma (PDA) metastatic to the liver. She received palliative chemotherapy with 5-fluorouracil, leucovorin, irinotecan and oxaliplatin (FOLFIRINOX) for 6 months, complicated by mucositis, diarrhoea, vomiting and two Clostridium difficile colitis episodes. Cancer initially responded to chemotherapy. However, due to substantial toxicities, she decided to discontinue cytotoxic chemotherapy and focus on palliation alone. Thereafter, CT and carbohydrate antigen (CA) 19-9 showed further response and ultimately complete cancer regression that has persisted for 33 months after cessation of chemotherapy. This is the first report in the English literature showing spontaneous regression of a PDA with liver metastases. Two possible mechanisms are proposed: antitumoral autoimmunity and tumour hypoxia related to vascular disease.


Assuntos
Carcinoma Ductal Pancreático/diagnóstico , Neoplasias Hepáticas/diagnóstico , Lúpus Eritematoso Discoide , Neoplasias Pancreáticas/diagnóstico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/secundário , Feminino , Fluoruracila/uso terapêutico , Humanos , Irinotecano/administração & dosagem , Irinotecano/uso terapêutico , Leucovorina/uso terapêutico , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/secundário , Pessoa de Meia-Idade , Metástase Neoplásica , Regressão Neoplásica Espontânea , Oxaliplatina/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia
20.
Cells ; 8(6)2019 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-31181844

RESUMO

Background: Pancreatic ductal adenocarcinoma (PDAC) is highly resistant to standard chemo- and radiotherapy. Recently, a new class of non-platinum-based halogenated molecules (called FMD compounds) was discovered that selectively kills cancer cells. Here, we investigate the potential of 1,2-Diamino-4,5-dibromobenzene (2Br-DAB) in combination with standard chemotherapy and radiotherapy in murine and human PDAC. Methods: Cell viability and colony formation was performed in human (Panc1, BxPC3, PaTu8988t, MiaPaCa) and three murine LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre (KPC) pancreatic cancer cell lines. In vivo, preclinical experiments were conducted in LSL-KrasG12D/+;p48-Cre (KC) and KPC mice using 2Br-DAB (7 mg/kg, i.p.), +/- radiation (10 × 1.8 Gy), gemcitabine (100 mg/kg, i.p.), or a combination. Tumor growth and therapeutic response were assessed by high-resolution ultrasound and immunohistochemistry. Results: 2Br-DAB significantly reduced cell viability in human and murine pancreatic cancer cell lines in a dose-dependent manner. In particular, colony formation in human Panc1 cells was significantly decreased upon 25 µM 2Br-DAB + radiation treatment compared with vehicle control (p = 0.03). In vivo, 2Br-DAB reduced tumor frequency in KC mice. In the KPC model, 2Br-DAB or gemcitabine monotherapy had comparable therapeutic effects. Furthermore, the combination of gemcitabine and 2Br-DAB or 2Br-DAB and 18 Gy irradiation showed additional antineoplastic effects. Conclusions: 2Br-DAB is effective in killing pancreatic cancer cells in vitro. 2Br-DAB was not toxic in vivo, and additional antineoplastic effects were observed in combination with irradiation.


Assuntos
Antineoplásicos/uso terapêutico , Derivados de Benzeno/uso terapêutico , Carcinoma Ductal Pancreático/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Animais , Antineoplásicos/farmacologia , Derivados de Benzeno/farmacologia , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/radioterapia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Modelos Animais de Doenças , Progressão da Doença , Avaliação Pré-Clínica de Medicamentos , Raios gama , Engenharia Genética , Camundongos , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/radioterapia
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