Phase II Study of 5-Fluorouracil, Oxaliplatin plus Dasatinib (FOLFOX-D) in First-Line Metastatic Pancreatic Adenocarcinoma

George, Thomas J.; Ali, Azka; Wang, Yu; Lee, Ji-Hyun; Ivey, Alison Marguerite; DeRemer, David L.; Daily, Karen; Allegra, Carmen J.; Hughes, Steven J.; Fan, Z. Hugh; Cameron, Miles E.; Judge, Andrew R.; Treviño, José G.

doi:10.1002/onco.13853

Cited by 12 publications

(8 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The preceding results suggest that dasatinib could be useful in the treatment of PDAC through inhibition of the SFK/YAP axis. However, clinical trials in patients with PDAC using dasatinib in combination with gemcitabine ( 12 ) or 5-fluorouracil and oxaliplatin ( 14 ) were unsuccessful. We considered that SFK inhibitors not only hinder YAP activation but concomitantly trigger activation of a compensatory pathway(s) that mediates resistance to these drugs ( 46 ).…”

Section: Discussionmentioning

confidence: 99%

“…An early study demonstrated that administration of the SFK inhibitor dasatinib (10) prevented metastatic dissemination in preclinical models of PDAC but did not interfere with the growth of the primary tumor (11). Subsequent clinical trials in PDAC patients using dasatinib in combination with gemcitabine (12,13) or 5-fluorouracil and oxaliplatin (14) failed to demonstrate significant clinical benefit in PDAC patients. The mechanism(s) leading to dasatinib resistance in PDAC are poorly understood.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Opposite Effects of Src Family Kinases on YAP and ERK Activation in Pancreatic Cancer Cells: Implications for Targeted Therapy

Sinnett‐Smith

Anwar

Reed

et al. 2022

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

Pancreatic ductal adenocarcinoma (PDAC) remains an aggressive disease that is expected to become the second cause of cancer fatalities during the next decade. As therapeutic options are limited, novel targets and agents for therapeutic intervention are urgently needed. Previously, we identified potent positive crosstalk between insulin/IGF-1 receptors and G protein-coupled (GPCR) signaling systems leading to mitogenic signaling in PDAC cells. Here, we show that a combination of insulin and the GPCR agonist neurotensin induced rapid activation of Src family of tyrosine kinases (SFKs) within PANC-1 cells, as shown by FAK phosphorylation at Tyr576/577 and Tyr861, sensitive biomarkers of SFK activity within intact cells and Src419 autophosphorylation. Crucially, SFKs promoted YAP nuclear localization and phosphorylation at Tyr357, as shown by using the SFK inhibitors dasatinib, saracatinib, the preferential YES1 inhibitor CH6953755, short interfering RNA (siRNA)-mediated knockdown of YES1 and transfection of epitogue-tagged YAP mutants in PANC-1 and MiaPaCa-2 cancer cells, models of the aggressive squamous subtype of PDAC. Surprisingly, our results also demonstrate that exposure to SFK inhibitors, including dasatinib or knockdown of YES and Src induces ERK over-activation in PDAC cells. Dasatinib-induced ERK activation was completely abolished by exposure to the FDA-approved MEK inhibitor trametinib. A combination of dasatinib and trametinib potently and synergistically inhibited colony formation by PDAC cells and suppessed the growth of MiaPaCa-2 cells xenografted into the flank of nude mice. The results provide rationale for considering a combination(s) of FDA-approved SFK (dasatinib) and MEK (e.g. trametinib) inhibitors in prospective clinical trials for the treatment of PDAC.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Opposite Effects of Src Family Kinases on YAP and ERK Activation in Pancreatic Cancer Cells: Implications for Targeted Therapy

Sinnett‐Smith

Anwar

Reed

et al. 2022

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

show abstract

“…improving from 2016 to 2020, and with a signi cant difference between adjacent years. Icotinib 10 [30] 1.06 0.73 0.22 0.16 Lapatinib 6.8 [31] 0.84 0.57 0.18 0.13 Ge tinib 10 [32] 1.25 0.61 0.27 0.13 Axitinib 12 [33] 2.64 1.89 0.56 0.41…”

Section: Affordabilitymentioning

confidence: 99%

Access to Essential and Innovative Anti-cancer Medicines: A Longitudinal Study in Nanjing, China

Cao,

Wang,

et al. 2023

Preprint

View full text Add to dashboard Cite

Purpose To evaluate the availability, cost, affordability, and drug utilization of anti-cancer medicines in Nanjing, Jiangsu.Methods Based on the standard survey methods of World Health Organization/Health Action International(WHO/HAI), a longitudinal tracking investigation study was performed to collect information about 24 essential anti-cancer medicines (EAMs) and 17 innovative anti-cancer medicines (IAMs) in 26 healthcare institutions in Nanjing from 2016 to 2020. The availability, defined daily dose cost (DDDc), defined daily doses (DDDs) and affordability of EAMs and IAMs were investigated. Wilcoxon’s rank-sum test was used to analyze the available data of adjacent years to check whether there was a statistical difference.Results The availability of EAMs during the study period showed no significant changes in Nanjing, but the availability of IAMs showed a significant increase in 2018 and 2019 and tended to stabilize in 2020. For EAMs, the DDDc of lowest-priced generics (LPGs) showed no significant changes during the study period, and the DDDc of originator brands (OBs) and IAMs significantly decreased. The DDDs of EAMs (LPGs) showed a decreasing trend since 2016 and rose again in 2019. Overall, the DDDs of EAMs(LPGs) decreased by 25.18% between 2016 and 2020, but the proportion selected for clinical treatment remained at 67.35% in 2020. The DDDs of EAMs (OBs) and IAMs both showed an increasing trend year by year, with a proportional increase of 207.72% and 652.68%, respectively; but the proportion selected for clinical treatment was only 16.09% and 16.56% respectively in 2020. Under the standard set in this study, EAMs (LPGs) had good affordability for urban residents but poor affordability for rural residents; all IAMs were affordable to urban residents, but most IAMs(11/17) were not affordable to rural residents by 2020. However, the affordability of these drugs was constantly improving.Conclusions There were no significant changes in the availability and cost of EAMs (LPGs), whose lower prices showed better affordability, especially for urban residents. Although their relative change in drug utilization showed a decreasing trend, they still dominated clinical treatment. Driven by the national drug price negotiation (NDPN) policy, the availability of IAMs was on the rise. The prices of IAMs and EAMs (OBs) decreased year by year with significantly improving affordability, but the high prices of these drugs remained unaffordable for rural residents. It is necessary to further develop and strengthen policies for essential medicines procurement assessment to improve the accessibility of EAMs. Meanwhile, a comprehensive strategy is needed in the future to improve the affordability of IAMs.

show abstract

“…Cabozantinib was successfully combined with gemcitabine in a Phase I trial (28) and is currently being studied at more advanced clinical settings (Phase II study in combination with pembrolizumab: NCT05052723). On the other hand, dasatinib has failed in Phase II trials in combination with established protocols (FOLFOX (29) or gemcitabine (30) treatment) to induce remarkable improvements in patient survival. Finally, MAP2K1 is a dual-speci city kinase in the MAP signal transduction pathway, which is involved in growth, adhesion, differentiation among other processes (31), and is targeted by cobimetinib and trametinib (shown here), and solumetinib (see Supplementary Fig.…”

Section: Genes In Driver Pathways Represent Promising Targets For Pha...mentioning

confidence: 99%

Identification of early diagnosis markers of pancreatic ductal adenocarcinoma (PDAC) using publicly available transcriptomic tumour and blood sample data

Sionakidis

Lalagkas²,

Malousi

et al. 2022

Preprint

View full text Add to dashboard Cite

Background Pancreatic ductal adenocarcinoma (PDAC) is the most frequently diagnosed form of pancreatic cancer worldwide. It is associated with poor survival rates (~ 5%) mainly due to the disease being usually diagnosed at late stages. Few gene expression studies have been conducted on samples from PDAC patients, however their sample size was limited and their final outcome inconclusive. We aimed to identify general PDAC disease biomarkers that may improve earlier diagnosis and patient stratification for improved mortality outcomes. Methods Publicly available gene expression data from 10 studies with tumour tissue (448 samples) blood samples (128 samples) from PDAC patients prior to treatment were analysed. Validation of markers was performed using Cancer Genome Atlas (TCGA) PDAC expression data. Tissue samples had AJCC (American Joint Committee for Cancer) staging information available. Differential gene expression analysis was carried out to compare tumour and normal samples (stage-specific tissue samples vs. normal tissue samples and PDAC blood samples vs. normal blood samples). Active subnetwork search and miRNA enrichment analysis were used to identify enriched gene networks and miRNA interactions. Results We identified 820 consistently deregulated (either up- or down-regulated) genes between tissue samples of all stages and blood samples. The prognostic potential of these markers was validated in TCGA data in predicting PDAC outcome (dead/alive status), in the form of custom risk scores (up-regulated genes score: p = 0.004 and down-regulated genes score: p = 0.03). Active subnetwork analysis revealed enriched ribosome, proteasome, adherens junction and cell cycle pathways in tumors across all stages and blood samples. Stage-specific enriched miRNAs were also identified (miR-21, miR-29, miR-124, miR-30, for stages 1–4 respectively). Conclusions We identified PDAC markers deregulated across all stages and different sample sets. Extensive gene expression deregulation was found in all clinical stages with significant overlap. Additionally, miRNA contribution to PDAC pathology may be important and probably mediated by distinct miRNAs in each stage of PDAC. We therefore present a list of markers and miRNAs that could potentially act as a diagnostic tool for early detection of PDAC onset to be evaluated in other clinical and epidemiologic studies.

show abstract

Phase II Study of 5-Fluorouracil, Oxaliplatin plus Dasatinib (FOLFOX-D) in First-Line Metastatic Pancreatic Adenocarcinoma

Cited by 12 publications

References 24 publications

Opposite Effects of Src Family Kinases on YAP and ERK Activation in Pancreatic Cancer Cells: Implications for Targeted Therapy

Opposite Effects of Src Family Kinases on YAP and ERK Activation in Pancreatic Cancer Cells: Implications for Targeted Therapy

Access to Essential and Innovative Anti-cancer Medicines: A Longitudinal Study in Nanjing, China

Identification of early diagnosis markers of pancreatic ductal adenocarcinoma (PDAC) using publicly available transcriptomic tumour and blood sample data

Contact Info

Product

Resources

About