Physiologically-based pharmacokinetic and pharmacodynamic models for gemcitabine and birinapant in pancreatic cancer xenografts

Zhu, Xu; Trueman, Sheryl; Straubinger, Robert M.; Jusko, William J.

doi:10.1007/s10928-018-9603-z

Cited by 8 publications

(3 citation statements)

References 33 publications

(53 reference statements)

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“…( B ) Graphs depicting cell viability of OV-054 DSRCT (blue) and the two Ewing sarcoma models (gray), upon a 5-day incubation with different drug concentrations (µM). Known plasma concentrations are shown with the vertical dashed line [ 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 ].…”

Section: Figurementioning

confidence: 99%

EWSR1-WT1 Target Genes and Therapeutic Options Identified in a Novel DSRCT In Vitro Model

Bleijs

Pleijte

Engels

et al. 2021

Cancers

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Desmoplastic small round cell tumor (DSRCT) is a rare and aggressive soft tissue sarcoma with a lack of effective treatment options and a poor prognosis. DSRCT is characterized by a chromosomal translocation, resulting in the EWSR1-WT1 gene fusion. The molecular mechanisms driving DSRCT are poorly understood, and a paucity of preclinical models hampers DSRCT research. Here, we establish a novel primary patient-derived DSRCT in vitro model, recapitulating the original tumor. We find that EWSR1-WT1 expression affects cell shape and cell survival, and we identify downstream target genes of the EWSR1-WT1 fusion. Additionally, this preclinical in vitro model allows for medium-throughput drug screening. We discover sensitivity to several drugs, including compounds targeting RTKs. MERTK, which has been described as a therapeutic target for several malignancies, correlates with EWSR1-WT1 expression. Inhibition of MERTK with the small-molecule inhibitor UNC2025 results in reduced proliferation of DSRCT cells in vitro, suggesting MERTK as a therapeutic target in DSRCT. This study underscores the usefulness of preclinical in vitro models for studying molecular mechanisms and potential therapeutic options.

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Section: Figurementioning

confidence: 99%

EWSR1-WT1 Target Genes and Therapeutic Options Identified in a Novel DSRCT In Vitro Model

Bleijs

Pleijte

Engels

et al. 2021

Cancers

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“…The chemotherapeutic agents were serially diluted in an RPMI 1640 culture medium and tested in 9 therapeutically relevant tissue concentrations [39]. Vehicle controls were included in each condition.…”

Section: Chemotherapeutics and Hyperthermia Schedulementioning

confidence: 99%

Hyperthermia Enhances Efficacy of Chemotherapeutic Agents in Pancreatic Cancer Cell Lines

et al. 2022

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Chemotherapy (CT) is the standard care for advanced pancreatic ductal adenocarcinoma (PDAC); however, with limited efficacy. Hyperthermia (HT) treatment has been suggested as a sensitizer to improve outcomes. However, the direct effect of the HT and CT combination is not fully understood. Therefore, we aim to assess the direct cytotoxic effect of HT in PDAC cells as monotherapy or in combination with chemotherapeutics. Different temperatures (37-, 40.5-, 41-, and 41.5 °C) and durations (6-, 12-, and 24 h) were tested in PDAC cell lines (BxPC-3, Capan-1, Capan-2, PANC-1, and MIA-PaCa-2). Different concentrations of gemcitabine, 5-fluorouracil, and cisplatin were also tested in these conditions. The impact on cell metabolic activity was determined by an MTS assay. Enhancement of chemosensitivity was assessed by a reduction in half-maximal inhibitory concentration (IC50). HT and chemotherapeutics interactions were classified as antagonistic, additive, or synergistic using the combination index. HT inhibited cell proliferation in a cell type, temperature, and duration-dependent manner. The induction of apoptosis was seen after 6 h of HT treatment, eventually followed by secondary necrosis. The HT and CT combination led to an IC50 reduction of the tested CT. At 12 h of HT, this effect was between 25 to 90% and reached a 95% reduction at 24 h. The additive or synergistic effect was demonstrated in all cell lines and chemotherapeutics, although, again, this depended on cell type, duration, and temperature. HT is cytotoxic and enhances the therapeutic effectiveness of gemcitabine, 5-fluorouracil, and cisplatin on PDAC cells. This result was further confirmed by the decrease in the expression of RRM2, TS, and ERCC1 in BxPC-3 and Capan-2 cells. These observations warrant further study in specific subsets of PDAC patients to improve their clinical outcomes.

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“…13,14 In addition, some clinical studies in patients with pancreatic cancer treated with dFdC associated different expressions of the transporters or the target enzymes activity with a high or low survival probabilities. 13,15 The dFdC effects on pancreatic cancer have been described previously by using pharmacokinetic/pharmacodynamic (PK/PD), mechanistic, and semimechanistic models in in vitro, [16][17][18][19] preclinical in vivo, 20,21 and clinical stages. 22,23 However, to the best of our knowledge, the models developed in clinical stages do not consider the intersubject variability in dFdC metabolism (e.g., individual concentrations of enzymes involved in dFdC metabolism).…”

Section: What Does This Study Add To Our Knowledge?mentioning

confidence: 99%

Mechanistic Multiscale Pharmacokinetic Model for the Anticancer Drug 2’,2’‐difluorodeoxycytidine (Gemcitabine) in Pancreatic Cancer

Garcia‐Cremades

Melillo

Trocóniz

et al. 2020

Clinical Translational Sci

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The aim of this work is to build a mechanistic multiscale pharmacokinetic model for the anticancer drug 2', 2'-difluorodeoxycytidine (gemcitabine, dFdC), able to describe the concentrations of dFdC metabolites in the pancreatic tumor tissue in dependence of physiological and genetic patient characteristics, and, more in general, to explore the capabilities and limitations of this kind of modeling strategy. A mechanistic model characterizing dFdC metabolic pathway (metabolic network) was developed using in vitro literature data from two pancreatic cancer cell lines. The network was able to describe the time course of extracellular and intracellular dFdC metabolites concentrations. Moreover, a physiologically-based pharmacokinetic model was developed to describe clinical dFdC profiles by using enzymatic and physiological information available in the literature. This model was then coupled with the metabolic network to describe the dFdC active metabolite profile in the pancreatic tumor tissue. Finally, global sensitivity analysis was performed to identify the parameters that mainly drive the interindividual variability for the area under the curve (AUC) of dFdC in plasma and of its active metabolite (dFdCTP) in tumor tissue. From this analysis, cytidine deaminase (CDA) concentration was identified as the main driver of plasma dFdC AUC interindividual variability, whereas CDA and deoxycytidine kinase concentration mainly explained the tumor dFdCTP AUC variability. However, the lack of in vitro and in vivo information needed to characterize key model parameters hampers the development of this kind of mechanistic approach. Further studies to better characterize pancreatic cell lines and patient enzymes polymorphisms are encouraged to refine and validate the current model. 2′,2′-difluorodeoxycytidine (gemcitabine, dFdC) is a nucleoside antimetabolite prodrug effective against several solid tumors. 1-4 Treatment with dFdC represents the firstline therapy of pancreatic cancer, that constitutes one of the most aggressive and lethal oncology diseases, with an overall 5-year survival rate of < 5%. 5 As a prodrug, dFdC has to be intracellularly metabolized to its active metabolite, dFdC triphosphate (dFdCTP), to Multiscale PK Model for dFdC in Pancreatic Cancer Garcia-Cremades et al. www.cts-journal.comMultiscale PK Model for dFdC in Pancreatic Cancer Garcia-Cremades et al. www.cts-journal.comMultiscale PK Model for dFdC in Pancreatic Cancer Garcia-Cremades et al.

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Physiologically-based pharmacokinetic and pharmacodynamic models for gemcitabine and birinapant in pancreatic cancer xenografts

Cited by 8 publications

References 33 publications

EWSR1-WT1 Target Genes and Therapeutic Options Identified in a Novel DSRCT In Vitro Model

EWSR1-WT1 Target Genes and Therapeutic Options Identified in a Novel DSRCT In Vitro Model

Hyperthermia Enhances Efficacy of Chemotherapeutic Agents in Pancreatic Cancer Cell Lines

Mechanistic Multiscale Pharmacokinetic Model for the Anticancer Drug 2’,2’‐difluorodeoxycytidine (Gemcitabine) in Pancreatic Cancer

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