Focal Adhesion Kinase: A promising therapeutic target in pancreatic adenocarcinoma

Decaup, Emilie; Rochotte, Julia; Pyronnet, Stéphane; Bousquet, Corinne; Jean, Christine

doi:10.1016/j.clinre.2016.10.010

Cited by 4 publications

(5 citation statements)

References 7 publications

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“…36 Other novel strategies are also aimed at potentiating immune checkpoint blockade in PDAC. [38][39][40][41] With the exception of data regarding increased CTLA-4 expression on CD8-positive T cells, which is associated with shorter OS in treatment-naive patients, 42 data to derive an association between the expression of immune checkpoint markers and survival in patients with mPDAC are lacking to date. Meaningful evaluation of response and PD-L1 expression in this study was constrained by the low DCR and ORR, which also limited additional biomarker analyses (eg, microsatellite instability status, tumor mutation burden, and breast cancer gene mutations); thus, no conclusions about biomarkers, including tumor mutation burden or microsatellite instability, could be drawn.…”

Section: Discussionmentioning

confidence: 99%

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Durvalumab With or Without Tremelimumab for Patients With Metastatic Pancreatic Ductal Adenocarcinoma

et al. 2019

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IMPORTANCE New therapeutic options for patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) are needed. This study evaluated dual checkpoint combination therapy in patients with mPDAC. OBJECTIVE To evaluate the safety and efficacy of the anti-PD-L1 (programmed death-ligand 1) antibody using either durvalumab monotherapy or in combination with the anticytotoxic T-lymphocyte antigen 4 antibody using durvalumab plus tremelimumab therapy in patients with mPDAC. DESIGN, SETTING, AND PARTICIPANTS Part A of this multicenter, 2-part, phase 2 randomized clinical trial was a lead-in safety, open-label study with planned expansion to part B pending an efficacy signal from part A. Between November 26, 2015, and March 23, 2017, 65 patients with mPDAC who had previously received only 1 first-line fluorouracil-based or gemcitabine-based treatment were enrolled at 21 sites in 6 countries. Efficacy analysis included the intent-to-treat population; safety analysis included patients who received at least 1 dose of study treatment and for whom any postdose data were available. INTERVENTIONS Patients received durvalumab (1500 mg every 4 weeks) plus tremelimumab (75 mg every 4 weeks) combination therapy for 4 cycles followed by durvalumab therapy (1500 mg every 4 weeks) or durvalumab monotherapy (1500 mg every 4 weeks) for up to 12 months or until the onset of progressive disease or unacceptable toxic effects. MAIN OUTCOMES AND MEASURES Safety and efficacy were measured by objective response rate, which was used to determine study expansion to part B. The threshold for expansion was an objective response rate of 10% for either treatment arm. RESULTS Among 65 randomized patients, 34 (52%) were men and median age was 61 (95% CI, 37-81) years. Grade 3 or higher treatment-related adverse events occurred in 7 of 32 patients (22%) receiving combination therapy and in 2 of 32 patients (6%) receiving monotherapy; 1 patient randomized to the monotherapy arm did not receive treatment owing to worsened disease. Fatigue, diarrhea, and pruritus were the most common adverse events in both arms. Overall, 4 of 64 patients (6%) discontinued treatment owing to treatment-related adverse events. Objective response rate was 3.1% (95% CI, 0.08-16.22) for patients receiving combination therapy and 0% (95% CI, 0.00-10.58) for patients receiving monotherapy. Low patient numbers limited observation of the associations between treatment response and PD-L1 expression or microsatellite instability status. CONCLUSION AND RELEVANCE Treatment was well tolerated, and the efficacy of durvalumab plus tremelimumab therapy and durvalumab monotherapy reflected a population of patients with mPDAC who had poor prognoses and rapidly progressing disease. Patients were not enrolled in part B because the threshold for efficacy was not met in part A.

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Section: Discussionmentioning

confidence: 99%

“…One of those studies showed that treatment with a granulocyte-macrophage colony-stimulating factor–secreting PDAC vaccine upregulated PD-L1 membrane expression and, in combination with PD-1 blockade, led to improved survival in tumor-bearing mice . Other novel strategies are also aimed at potentiating immune checkpoint blockade in PDAC …”

Section: Discussionmentioning

confidence: 99%

Durvalumab With or Without Tremelimumab for Patients With Metastatic Pancreatic Ductal Adenocarcinoma

et al. 2019

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“…Heterogeneity has been observed in lung cancer at gene (genetic aberrations) and cellular level through high throughput techniques 61,62 . Careful inspection of PEEPs across LT survivors highlighted specific biological signatures associated with focal adhesion 63 , and extracellular matrix receptors 64 , which helps understand why these patients with PDAC survived longer. Furthermore, it is notable that multiple PDAC responsive pathways 65 were enriched across several LT survivors and, based on the perturbed gene sets, led to further subgrouping of LT survivors.…”

Section: Discussionmentioning

confidence: 99%

Deeper insights into long-term survival heterogeneity of pancreatic ductal adenocarcinoma (PDAC) patients using integrative individual- and group-level transcriptome network analyses

Bhardwaj

Josse

Daele

et al. 2022

Sci Rep

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Pancreatic ductal adenocarcinoma (PDAC) is categorized as the leading cause of cancer mortality worldwide. However, its predictive markers for long-term survival are not well known. It is interesting to delineate individual-specific perturbed genes when comparing long-term (LT) and short-term (ST) PDAC survivors and integrate individual- and group-based transcriptome profiling. Using a discovery cohort of 19 PDAC patients from CHU-Liège (Belgium), we first performed differential gene expression analysis comparing LT to ST survivor. Second, we adopted systems biology approaches to obtain clinically relevant gene modules. Third, we created individual-specific perturbation profiles. Furthermore, we used Degree-Aware disease gene prioritizing (DADA) method to develop PDAC disease modules; Network-based Integration of Multi-omics Data (NetICS) to integrate group-based and individual-specific perturbed genes in relation to PDAC LT survival. We identified 173 differentially expressed genes (DEGs) in ST and LT survivors and five modules (including 38 DEGs) showing associations to clinical traits. Validation of DEGs in the molecular lab suggested a role of REG4 and TSPAN8 in PDAC survival. Via NetICS and DADA, we identified various known oncogenes such as CUL1 and TGFB1. Our proposed analytic workflow shows the advantages of combining clinical and omics data as well as individual- and group-level transcriptome profiling.

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“…Notably, several genes were uniquely perturbed in an LT survivor, which strengthens our belief that LTS patients exhibit more abundant levels of heterogeneity. Careful inspection of PEEPs across LT survivors highlighted biological signatures: focal adhesion 49 , and ECM receptors 50 . Interestingly multiple PDAC responsive pathways 51 were enriched across several LT survivors and led to further subgrouping of LT survivors.…”

Section: Discussionmentioning

confidence: 99%

Deeper insights into long-term survival heterogeneity of Pancreatic Ductal Adenocarcinoma (PDAC) patients using integrative individual- and group-level transcriptome network analyses

Bhardwaj

Josse

Daele

et al. 2020

Preprint

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Background: Pancreatic ductal adenocarcinoma (PDAC) is categorized as the seventh leading cause of cancer mortality worldwide. Its predictive markers for long-term survival are not well known. Therefore, it is interesting to delineate individual-specific perturbed genes when comparing long-term (LT) and short-term (ST) PDAC survivors, and to exploit the integrative individual-and group-based transcriptome profiling.Method: Using a discovery cohort of 19 PDAC patients from CHU-Liège (Belgium), we first performed differential gene expression (DGE) analysis comparing LT to ST survivor. Second, we adopted unsupervised systems biology approaches to obtain gene modules linked to clinical features. Third, we created individual-specific perturbation profiles and identified key regulators across the LT patients. Furthermore, we applied two gene prioritization approaches: random walk-based Degree-Aware disease gene prioritizing (DADA) method to develop PDAC disease modules; Network-based Integration of Multi-omics Data (NetICS) to integrate group-based and individual-specific perturbed genes in relation to PDAC LT survival. Findings: We identified 173 differentially expressed genes (DEGs) in ST and LT survivors and five modules (including 38 DEGs) showing associations to clinical traits such as tumor size and chemotherapy. DGE analysis identified differences in genes involved in metabolic and cell cycle activity. Validation of DEGs in the molecular lab suggested a role of REG4 and TSPAN8 in PDAC survival. Individual-specific omics changes across LT survivors revealed biological signatures such as focal adhesion and extracellular matrix receptors, implying a potential role in molecular-level heterogeneity of LT PDAC survivors. Via NetICS and DADA we not only identified various known oncogenes such as CUL1, SCF62, EGF, FOSL1, MMP9, and TGFB1, but also highlighted novel genes (TAC1, KCNH7, IRS4, DKK4). Interpretation: Our proposed analytic workflow shows the advantages of combining clinical and omics data as well as individual-and group-level transcriptome profiling. It suggested novel potential transcriptome marks of LT survival heterogeneity in PDAC. Funding: Télévie-FRS-FNRS

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Focal Adhesion Kinase: A promising therapeutic target in pancreatic adenocarcinoma

Cited by 4 publications

References 7 publications

Durvalumab With or Without Tremelimumab for Patients With Metastatic Pancreatic Ductal Adenocarcinoma

Durvalumab With or Without Tremelimumab for Patients With Metastatic Pancreatic Ductal Adenocarcinoma

Deeper insights into long-term survival heterogeneity of pancreatic ductal adenocarcinoma (PDAC) patients using integrative individual- and group-level transcriptome network analyses

Deeper insights into long-term survival heterogeneity of Pancreatic Ductal Adenocarcinoma (PDAC) patients using integrative individual- and group-level transcriptome network analyses

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