scholarly journals OncoSNIPE® Study Protocol, a study of molecular profiles associated with development of resistance in solid cancer patients

BMC Cancer ◽  
2022 ◽  
Vol 22 (1) ◽  
Author(s):  
Sébastien Vachenc ◽  
Jessica Gobbo ◽  
Sarah El Moujarrebe ◽  
Isabelle Desmoulins ◽  
Marine Gilabert ◽  
...  
Keyword(s):  
Clinical Data ◽  
Molecular Mechanisms ◽  
Locally Advanced ◽  
Ductal Adenocarcinoma ◽  
Rapid Progression ◽  
Case Report Form ◽  
Solid Cancer ◽  
Mechanisms Of Resistance ◽  
Resistance To Treatment

Abstract Background Nowadays, evaluation of the efficacy and the duration of treatment, in context of monitoring patients with solid tumors, is based on the RECIST methodology. With these criteria, resistance and/or insensitivity are defined as tumor non-response which does not allow a good understanding of the diversity of the underlying mechanisms. The main objective of the OncoSNIPE® collaborative clinical research program is to identify early and late markers of resistance to treatment. Methods Multicentric, interventional study with the primary objective to identify early and / or late markers of resistance to treatment, in 600 adult patients with locally advanced or metastatic triple negative or Luminal B breast cancer, non-small-cell lung cancer or pancreatic ductal adenocarcinoma. Patients targeted in this study have all rapid progression of their pathology, making it possible to obtain models for evaluating markers of early and / or late responses over the 2-year period of follow-up, and thus provide the information necessary to understand resistance mechanisms. To explore the phenomena of resistance, during therapeutic response and / or progression of the pathology, we will use a multidisciplinary approach including high-throughput sequencing (Exome-seq and RNAseq), clinical data, medical images and immunological profile by ELISA. Patients will have long-term follow-up with different biological samples, at baseline (blood and biopsy) and at each tumoral evaluation or tumoral progression evaluated by medical imaging. Clinical data will be collected through a dedicated Case Report Form (CRF) and enriched by semantic extraction based on the French ConSoRe (Continuum Soins Recherche) initiative, a dedicated Semantic Clinical Data Warehouse (SCDW) to cancer. The study is sponsored by Oncodesign (Dijon, France) and is currently ongoing. Discussion The great diversity of intrinsic or acquired molecular mechanisms involved in resistance to treatment constitutes a real therapeutic issue. Improving understanding of mechanisms of resistance of cancer cells to anti-tumor treatments is therefore a major challenge. The OncoSNIPE cohort will lead to a better understanding of the mechanisms of resistance and will allow to explore new mechanisms of actions and to discover new therapeutic targets or strategies making it possible to circumvent the escape in different types of cancer. Trial registration Clinicaltrial.gov. Registered 16 September 2020, https://clinicaltrials.gov/ct2/show/NCT04548960?term=oncosnipe&draw=2&rank=1 and ANSM ID RCB 2017-A02018-45.

scholarly journals “Open Sesame?”: Biomarker Status of the Human Equilibrative Nucleoside Transporter-1 and Molecular Mechanisms Influencing its Expression and Activity in the Uptake and Cytotoxicity of Gemcitabine in Pancreatic Cancer

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3206
Author(s):  
Ornella Randazzo ◽  
Filippo Papini ◽  
Giulia Mantini ◽  
Alessandro Gregori ◽  
Barbara Parrino ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Ductal Adenocarcinoma ◽  
Rapid Progression ◽  
Nucleoside Transporter ◽  
Equilibrative Nucleoside Transporter ◽  
Multimodal Analysis ◽  
Predictive Role ◽  
Aggressive Tumor ◽  
Disease Free ◽  
Free Status

Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive tumor characterized by early invasiveness, rapid progression and resistance to treatment. For more than twenty years, gemcitabine has been the main therapy for PDAC both in the palliative and adjuvant setting. After the introduction of FOLFIRINOX as an upfront treatment for metastatic disease, gemcitabine is still commonly used in combination with nab-paclitaxel as an alternative first-line regimen, as well as a monotherapy in elderly patients unfit for combination chemotherapy. As a hydrophilic nucleoside analogue, gemcitabine requires nucleoside transporters to permeate the plasma membrane, and a major role in the uptake of this drug is played by human equilibrative nucleoside transporter 1 (hENT-1). Several studies have proposed hENT-1 as a biomarker for gemcitabine efficacy in PDAC. A recent comprehensive multimodal analysis of hENT-1 status evaluated its predictive role by both immunohistochemistry (with five different antibodies), and quantitative-PCR, supporting the use of the 10D7G2 antibody. High hENT-1 levels observed with this antibody were associated with prolonged disease-free status and overall-survival in patients receiving gemcitabine adjuvant chemotherapy. This commentary aims to critically discuss this analysis and lists molecular factors influencing hENT-1 expression. Improved knowledge on these factors should help the identification of subgroups of patients who may benefit from specific therapies and overcome the limitations of traditional biomarker studies.

Efficacy and safety of nab-paclitaxel plus S-1(nab-P/S-1) versus nab-paclitaxel plus gemcitabine (nab-P/Gem) for first-line chemotherapy in advanced pancreatic ductal adenocarcinoma (aPDAC): A randomized study.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 717-717 ◽  
Author(s):  
Yuan Zong ◽  
Zhi Peng ◽  
Xicheng Wang ◽  
Lin Shen ◽  
Jun Zhou
Keyword(s):  
Phase Ii ◽  
Randomized Study ◽  
Locally Advanced ◽  
Primary Lesion ◽  
Ductal Adenocarcinoma ◽  
Hematologic Toxicity ◽  
Phase Ii Trials ◽  
Duration Of Treatment ◽  
Significant Difference

717 Background: Nab-P/Gem significantly improved survival compared with gem in patients (pts) with metastatic PDAC, but the ORR was limited to 23% with increased myelosuppression. Two phase II trials demonstrated high ORR of 50.0-53.1% with nab-P/S-1 and showed less hematologic toxicity. Methods: A randomized (1:1) phase II trial was conducted. Eligibility required treatment-naïve pts with unresectable PDAC. Pts received nab-P 125mg/m2on day 1 + S-1 80-120mg orally per day on day 1-7 every 2 weeks or nab-P 125mg/m2+ Gem 1000mg/m2 on days 1,8 every 3 weeks. With an increase of ORR from 25% to 50%, 100 pts were required for 90% power at a two-sided significance level of 0.05. We enrolled 40 pts for a pilot study. Primary endpoints were ORR and 6-month PFS rate. Secondary endpoints were ORR of primary lesion, DCR, PFS, OS and safety. Results: 40 pts were enrolled between 06/2018 and 06/2019, including locally advanced (27.5%) and metastatic (72.5%) PDACs. 42.5% were male and the median age was 61 (range, 36-75) years old. The median duration of treatment was 2.3 months in nab-P/S-1 (n = 20) and 2.7 months in nab-P/Gem (n = 20). In the intention-to-treat (ITT) population, the ORR and DCR were 35.0% vs 25.0% ( P= 0.49) and 70.0% vs 70.0%, respectively.The ORR of primary lesion was 30.0% vs 25.0% ( P= 0.72). In the evaluable pts (nab-P/S-1 n = 18, nab-P/Gem n = 18), the ORR, DCR and the ORR of primary lesion were 38.9% vs 27.8%, 77.8% vs 77.8% and 35.3% vs 29.4%, respectively.With the median follow-up of 5.0 (range 0.3-11.4) months, the median PFS and 6-month PFS rate was 6.3 vs 5.7 months and 56.1% vs 36.2%( P= 0.61) for nab-P/S-1 and nab-P/Gem, respectively. The median OS have not reached. Grade 3/4 toxicities occurred in 30.0% nab-P/S-1 and 30.0% nab-P/Gem: leukopenia/neutropenia(15.0% vs 25.0%), febrile neutropenia (0 vs 5.0%), rash (0 vs 5.0%) and diarrhea (10.0% vs 0). Conclusions: Compared with nab-P/Gem, nab-P/S-1 had higher ORR, ORR of primary lesion and longer PFS without significant difference. Nab-P/S-1 developed a trend towards less hematologic toxicity. Follow up for survival is ongoing. Clinical trial information: 03636308.

scholarly journals ELK3 Mediated by ZEB1 Facilitates the Growth and Metastasis of Pancreatic Carcinoma by Activating the Wnt/β-Catenin Pathway

2021 ◽  
Vol 9 ◽  
Author(s):  
Qiuyan Zhao ◽  
Yingchun Ren ◽  
Haoran Xie ◽  
Lanting Yu ◽  
Jiawei Lu ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Ductal Adenocarcinoma ◽  
Migration And Invasion ◽  
Rapid Progression ◽  
Normal Tissues ◽  
Online Databases ◽  
Ternary Complex Factor

Rapid progression and metastasis are the major causes of death in patients with pancreatic ductal adenocarcinoma (PDAC). ELK3, a member of the ternary complex factor (TCF), has been associated with the initiation and progression of various cancers. However, the role of ELK3 in PDAC is not yet fully understood. Online databases and immunohistochemistry were used to analyze the ELK3 levels in PDAC tissues. The function of ELK3 was confirmed by a series of in vivo and in vitro studies. Western blotting and immunofluorescence were used to detect the molecular mechanisms of PDAC. ChIP-qPCR was used to study the mechanism responsible for the elevation of ELK3 expression in PDAC. The ELK3 levels were higher in PDAC tissues than in adjacent normal tissues. Functionally, we demonstrated that ELK3 acted as an oncogene to promote PDAC tumorigenesis and metastasis. Further study suggested that ELK3 promoted PDAC cell migration and invasion by activating the Wnt/β-catenin pathway, and proved that ZEB1 could directly bind to the promoter of ELK3 to increase its transcription. Finally, both were associated with the patients’ clinicopathological features and worse overall survival. Conclusively, our findings enrich the role of ELK3 in PDAC, and provide potential avenues for exploring more effective biomarkers and therapeutic strategies for the treatment of PDAC.

scholarly journals ELK3 Mediated by ZEB1 Facilitates the Growth and Metastasis of Pancreatic Carcinoma by Activating the Wnt/Β-Catenin Pathway

2021 ◽  
Author(s):  
Qiuyan Zhao ◽  
Yingchun Ren ◽  
Haoran Xie ◽  
Lanting Yu ◽  
Jiawei Lu ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Ductal Adenocarcinoma ◽  
Migration And Invasion ◽  
Rapid Progression ◽  
Normal Tissues ◽  
Online Databases ◽  
Ternary Complex Factor

Abstract BackgroundRapid progression and metastasis are the major cause of death of pancreatic ductal adenocarcinoma (PDAC) patients. ELK3, a member of ternary complex factor (TCF), has been associated with the initiation and progression of various cancers. However, the role of ELK3 in PDAC need to be further elucidated.MethodsOnline databases and immunohistochemistry were used to analyze ELK3 level in PDAC tissues. The function of ELK3 was confirmed by a series of in vivo and in vitro studies. Western blot and immunofluorescence were used to detect the molecular mechanisms in PDAC. ChIP-qPCR was used to study the mechanism responsible for elevation of ELK3 in PDAC. ResultsELK3 level was higher in PDAC tissues than that in adjacent normal tissues. Functionally, we demonstrated that ELK3 acted as an oncogene to promote PDAC tumorigenesis and metastasis. Further investigations suggested that ELK3 could promote PDAC cells migration and invasion by activating Wnt/β-catenin pathway. Then we proved that ZEB1 could directly bind to the promoter of ELK3 to increase its transcription. Finally, both of them were associated with patients’ clinicopathological features and worse overall survival. ConclusionsOur findings enrich the role of ELK3 in PDAC, and provide potential avenues for exploring more effective biomarkers and therapeutic strategies in the treatment of PDAC.

Molecular mechanisms of resistance to anti-angiogenic drugs

2020 ◽  
Author(s):  
Arianna Filippelli ◽  
Valerio Ciccone ◽  
Sandra Donnini ◽  
Lucia Morbidelli
Keyword(s):  
Molecular Mechanisms ◽  
Mechanisms Of Resistance

Assessment of parental knowledge, attitude and practice towards antibiotic use in children

2020 ◽  
Vol 10 (2) ◽  
pp. 25-41
Author(s):  
Thejaswini Karanth ◽  
Someswar Deb ◽  
Lal Ruatpuii Zadeng ◽  
Rajeswari Ramasamy ◽  
Teena Nazeem ◽  
...  
Keyword(s):  
Parental Knowledge ◽  
Antibiotic Use ◽  
Case Report Form ◽  
Standard Case ◽  
Attitude And Practice ◽  
Validated Questionnaire ◽  
Antibiotics Use ◽  
The Impact ◽  
Knowledge Attitude And Practice

Objective to assess the impact of pharmacist assisted counselling in improving Parental Knowledge, Attitude and Practice [KAP] towards antibiotic use in children. A Prospective, Educational Interventional Study was conducted in 200 subjects, from the randomly chosen communities in Bangalore. The investigators did door to door visit. The primary demographics data of parents and their children were collected using standard Case Report Form (CRF), and the baseline towards antibiotic use in Children was obtained from parents using validated Questionnaire. In the presence of both parents, only one was supposed to answer the Questionnaire. Pharmacist assisted parent centred interventional counselling was provided with the help of Patient Information Leaflet1s (PIL). Follow-up and post interventional KAP assessment were done after two months from the baseline measurement. The changes in parental KAP towards antibiotics use in children were being assessed by comparing the Pretest and Posttest responses using statistical analysis. The knowledge of parents towards antibiotic use in children was medium to good in the baseline KAP assessment; however, in the majority of the participating parents it was not satisfactory in attitude and practice domains. A statistically significant improvement was seen in the KAP of parents towards antibiotic use in children after the pharmacist assisted interventional counselling. Thus, Investigators could bring excellent changes in the knowledge part; whereas the result for changes in the Attitude and Practice was good to medium respectively.

Molecular Processes Involved in Pancreatic Cancer and Therapeutics

2020 ◽  
Vol 14 ◽  
Author(s):  
Subhajit Makar ◽  
Abhrajyoti Ghosh ◽  
Divya ◽  
Shalini Shivhare ◽  
Ashok Kumar ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Molecular Mechanisms ◽  
Early Stage ◽  
Locally Advanced ◽  
Therapeutic Strategies ◽  
Screening Methods ◽  
Pancreatic Cancer Cells ◽  
Systemic Treatments ◽  
Cancer Initiation ◽  
Novel Therapeutic Strategies

: Despite advances in the development of cytotoxic and targeted therapies, pancreatic adenocarcinoma (PAC) remains a significant cause of cancer mortality worldwide. It is also difficult to detect it at an early stage due to numbers of factors. Most of the patients are present with locally advanced or metastatic disease, which precludes curative resection. In the absence of effective screening methods, considerable efforts have been made to identify better systemic treatments during the past decade. This review describes the recent advances in molecular mechanisms involved in pancreatic cancer initiation, progression, and metastasis. Additionally, the importance of deregulated cellular signalling pathways and various cellular proteins as potential targets for developing novel therapeutic strategies against incurable forms of pancreatic cancer is reported. The emphasis is on the critical functions associated with growth factors and their receptors viz. c-MET/HGF, CTHRC1, TGF-β, JAK-STAT, cyclooxygenase pathway, WNT, CCK, MAPK-RAS-RAF, PI3K-AKT, Notch, src, IGF-1R, CDK2NA and chromatin regulation for the sustained growth, survival, and metastasis of pancreatic cancer cells. It also includes various therapeutic strategies viz. immunotherapy, surgical therapy, radiation therapy and chemotherapy.

scholarly journals Brain atrophy and clinical characteristics predicting SDMT performance in multiple sclerosis: A 10-year follow-up study

2021 ◽  
Vol 7 (1) ◽  
pp. 205521732199239
Author(s):  
Cecilie Jacobsen ◽  
Robert Zivadinov ◽  
Kjell-Morten Myhr ◽  
Turi O Dalaker ◽  
Ingvild Dalen ◽  
...  
Keyword(s):  
Clinical Data ◽  
Grey Matter Volume ◽  
Lesion Volume ◽  
Information Processing Speed ◽  
Disability Status ◽  
Mri Scans ◽  
Patients At Risk ◽  
Magnetic Resonance Imaging Mri ◽  
Specific Volumes

Objectives To identify Magnetic Resonance Imaging (MRI), clinical and demographic biomarkers predictive of worsening information processing speed (IPS) as measured by Symbol Digit Modalities Test (SDMT). Methods Demographic, clinical data and 1.5 T MRI scans were collected in 76 patients at time of inclusion, and after 5 and 10 years. Global and tissue-specific volumes were calculated at each time point. For the primary outcome of analysis, SDMT was used. Results Worsening SDMT at 5-year follow-up was predicted by baseline age, Expanded Disability Status Scale (EDSS), SDMT, whole brain volume (WBV) and T2 lesion volume (LV), explaining 30.2% of the variance of SDMT. At 10-year follow-up, age, EDSS, grey matter volume (GMV) and T1 LV explained 39.4% of the variance of SDMT change. Conclusion This longitudinal study shows that baseline MRI-markers, demographic and clinical data can help predict worsening IPS. Identification of patients at risk of IPS decline is of importance as follow-up, treatment and rehabilitation can be optimized.

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