Circulating microRNAs as dynamic biomarkers of response to treatment with FOLFIRINOX in advanced pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal and aggressive cancers with a less than 6% five-year survival rate. Circulating microRNAs (miRNAs) are emerging as a useful tool for non-invasive diagnosis and prognosis estimation in the various cancer types, including PDAC. Our study aimed to evaluate whether miRNAs in the pre-operative blood plasma specimen have the potential to predict the prognosis of PDAC patients. In total, 112 PDAC patients planned for surgical resection were enrolled in our prospective study. To identify prognostic miRNAs, we used small RNA sequencing in 24 plasma samples of PDAC patients with poor prognosis (overall survival (OS) < 16 months) and 24 plasma samples of PDAC patients with a good prognosis (OS > 20 months). qPCR validation of selected miRNA candidates was performed in the independent cohort of PDAC patients (n = 64). In the discovery phase of the study, we identified 44 miRNAs with significantly different levels in the plasma samples of the group of good and poor prognosis patients. Among these miRNAs, 23 showed lower levels, and 21 showed higher levels in plasma specimens from PDAC patients with poor prognosis. Eleven miRNAs were selected for the validation, but only miR-99a-5p and miR-365a-3p were confirmed to have significantly lower levels and miR-200c-3p higher levels in plasma samples of poor prognosis cases. Using the combination of these 3-miRNA levels, we were able to identify the patients with poor prognosis with sensitivity 85% and specificity 80% (Area Under the Curve = 0.890). Overall, 3-miRNA prognostic score associated with OS was identified in the pre-operative blood plasma samples of PDAC patients undergoing surgical resection. Following further independent validations, the detection of these miRNA may enable identification of PDAC patients who have no survival benefit from the surgical treatment, which is associated with the high morbidity rates.

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A Unique Set of Three Circulating Micrornas as Non-Invasive Biomarkers in Pancreatic Ductal Adenocarcinoma

Gastroenterology ◽

10.1016/s0016-5085(17)30943-5 ◽

2017 ◽

Vol 152 (5) ◽

pp. S189-S190

Author(s):

Safoora Rashid ◽

Sumaira Rashid ◽

Surabhi Gupta ◽

Nihar R. Dash ◽

Hem Chandra Sati ◽

...

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Ductal Adenocarcinoma ◽

Circulating Micrornas ◽

Non Invasive

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Pancreatic Ductal Adenocarcinoma: Relating Biomechanics and Prognosis

Journal of Clinical Medicine ◽

10.3390/jcm10122711 ◽

2021 ◽

Vol 10 (12) ◽

pp. 2711

Author(s):

Benjamin M. MacCurtain ◽

Ned P. Quirke ◽

Stephen D. Thorpe ◽

Tom K. Gallagher

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Cancer Progression ◽

Ex Vivo ◽

Neoadjuvant Treatment ◽

Response To Treatment ◽

Ductal Adenocarcinoma ◽

Borderline Resectable ◽

Dismal Prognosis ◽

Clinical Consequences

Pancreatic ductal adenocarcinoma (PDAC) is the most common form of pancreatic cancer and carries a dismal prognosis. Resectable patients are treated predominantly with surgery while borderline resectable patients may receive neoadjuvant treatment (NAT) to downstage their disease prior to possible resection. PDAC tissue is stiffer than healthy pancreas, and tissue stiffness is associated with cancer progression. Another feature of PDAC is increased tissue heterogeneity. We postulate that tumour stiffness and heterogeneity may be used alongside currently employed diagnostics to better predict prognosis and response to treatment. In this review we summarise the biomechanical changes observed in PDAC, explore the factors behind these changes and describe the clinical consequences. We identify methods available for assessing PDAC biomechanics ex vivo and in vivo, outlining the relative merits of each. Finally, we discuss the potential use of radiological imaging for prognostic use.

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Circulating micrornas as dynamic biomarkers of disease progression during folfirinox therapy in unresectable pancreatic ductal adenocarcinoma (pdac)

HPB ◽

10.1016/j.hpb.2016.02.109 ◽

2016 ◽

Vol 18 ◽

pp. e43-e44

Author(s):

L.L. Meijer ◽

I. Garajová ◽

C. Caparello ◽

T.Y.S. Le Large ◽

N. Funel ◽

...

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Disease Progression ◽

Ductal Adenocarcinoma ◽

Circulating Micrornas

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Multiplex Patient-Based Drug Response Assay in Pancreatic Ductal Adenocarcinoma

Biomedicines ◽

10.3390/biomedicines9070705 ◽

2021 ◽

Vol 9 (7) ◽

pp. 705

Author(s):

Andrew Armstrong ◽

Muhammad R. Haque ◽

Sina Mirbagheri ◽

Usman Barlass ◽

Douglas Z. Gilbert ◽

...

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Drug Response ◽

Ex Vivo ◽

Medical Center ◽

Treatment Success ◽

Area Under The Curve ◽

The Cancer Genome Atlas ◽

Response To Treatment ◽

Ductal Adenocarcinoma ◽

Cell Viability Assay

Pancreatic ductal adenocarcinoma (PDA) is an extremely lethal malignancy arising from the pancreas. The treatment of PDA is complicated by ineffective treatments and a lack of biomarkers predictive of treatment success. We have designed a patient-derived organoid (PDO) based high-throughput drug screening assay to model treatment response to a variety of conventional and investigational treatments for PDA. Consecutive patients undergoing endoscopic ultrasound-guided fine-needle biopsy for tissue diagnosis of PDA at Rush University Medical Center were offered to participate in the study. Biopsies were immediately processed to develop organoids. Fifteen PDOs were screened for sensitivity to 18 compounds, including conventional PDA chemotherapies and FDA-approved investigational targeted therapies in cancer using Cell-titer GLO 3D (Promega) cell viability assay. The area under the curve (AUC) was calculated and normalized to the maximum area under the curve to generate a normalized AUC between 0 and 1. Molecular profiling of PDOs was conducted using RNA-seq. Human PDA transcriptomic was extracted from The Cancer Genome Atlas (TCGA). The drug response curves were reproducible. We observed variation in response to conventional therapies overall as well as among individual patients. There were distinct transcriptome signatures associated with response to the conventional chemotherapeutics in PDA. The transcriptomic profile of overall resistance to conventional therapies in our study was associated with poor survival in PDA patients in TCGA. Our pathway analysis for targeted drugs revealed a number of predictors of response associated with the mechanism of action of the tested drug. The multiplex organoid-based drug assay could be used in preclinical to inform patient stratification and therapeutic selection in PDA. When combined with omics data, ex vivo response to treatment could help identify gene signatures associated with response to novel therapies.

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