Dataset Information

Porous Paclitaxel Mesh Reduces Local Recurrence in Patient-Derived Xenograft Resection Model.

ABSTRACT:

Background

Drug-loaded meshes offer a promising delivery strategy for the prevention of local recurrence. Patient-derived xenograft (PDX) models are representative of individual patient tumors and predictive of clinical outcomes.

Methods

A PDX model was established in NSG (NOD-scid IL2Rgamma^null) mice using tumor tissue from a patient with aggressive lung adenocarcinoma. Polyglycolic acid (PGA) meshes loaded with paclitaxel (PGA+PTX) were electrospun. Tumor-bearing mice were randomized into 4 groups after macroscopic complete resection: (1) no treatment (n = 10); (2) intraperitoneal PTX at 20 mg/kg (n = 10); (3) PGA mesh without drug (n = 14); and (4) PGA+PTX mesh at 12 mg/kg (n = 14). A 1-cm² mesh was placed onto the tumor resection beds. Groups were observed for local recurrence for 120 postoperative days.

Results

PDX mice treated with PGA+PTX meshes after resection exhibited a >5-fold increase in recurrence-free survival (P < .0001) compared with systemically treated and untreated control groups. Median recurrence-free survival was 24 days for untreated and intraperitoneal PTX groups, 28 days for unloaded PGA mesh group, and undefined for the PGA+PTX mesh group.

Conclusions

Development of a PDX surgical resection model of non-small cell lung cancer permits robust assessment of postresection local recurrence for preclinical studies of patient-derived tumors. Intraoperative placement of drug-loaded meshes demonstrates superior local disease treatment, suggesting that this approach may improve recurrence-free survival in early-stage non-small cell lung cancer patients undergoing limited resection.

SUBMITTER: Tsai LL

PROVIDER: S-EPMC10172394 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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Publications

Porous Paclitaxel Mesh Reduces Local Recurrence in Patient-Derived Xenograft Resection Model.

Tsai Lillian L LL Fitzgerald Danielle M DM Liu Rong R Korunes-Miller Jenny T JT Neal Eliza E Hung Yin P YP Bilton Samantha S Hata Aaron A Grinstaff Mark W MW Colson Yolonda L YL

The Annals of thoracic surgery 20221112 1

<h4>Background</h4>Drug-loaded meshes offer a promising delivery strategy for the prevention of local recurrence. Patient-derived xenograft (PDX) models are representative of individual patient tumors and predictive of clinical outcomes.<h4>Methods</h4>A PDX model was established in NSG (NOD-scid IL2Rgamma<sup>null</sup>) mice using tumor tissue from a patient with aggressive lung adenocarcinoma. Polyglycolic acid (PGA) meshes loaded with paclitaxel (PGA+PTX) were electrospun. Tumor-bearing mice ...[more]

PMID: 36376135

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Project description:Abstract Rationale A high risk of post‐operative recurrence contributes to the poor prognosis and low survival rate of oesophageal squamous cell carcinoma (ESCC) patients. Increasing experimental evidence suggests that integrin adhesion receptors, in particular integrin αv (ITGAV), are important for cancer cell survival, proliferation and migration. Therefore, targeting ITGAV may be a rational approach for preventing ESCC recurrence. Materials and methods Protein levels of ITGAV were determined in human ESCC tumour tissues using immunohistochemistry. MTT, propidium iodide staining, and annexin V staining were utilized to investigate cell viability, cell cycle progression, and induction of apoptosis, respectively. Computational docking was performed with the Schrödinger Suite software to visualize the interaction between indomethacin and ITGAV. Cell‐derived xenograft mouse models, patient‐derived xenograft (PDX) mouse models, and a humanized mouse model were employed for in vivo studies. Results ITGAV was upregulated in human ESCC tumour tissues and increased ITGAV protein levels were associated with poor prognosis. ITGAV silencing or knockout suppressed ESCC cell growth and metastatic potential. Interestingly, we identified that indomethacin can bind to ITGAV and enhance synovial apoptosis inhibitor 1 (SYVN1)‐mediated degradation of ITGAV. Integrin β3, one of the β subunits of ITGAV, was also decreased at the protein level in the indomethacin treatment group. Importantly, indomethacin treatment suppressed ESCC tumour growth and prevented recurrence in a PDX mouse model. Moreover, indomethacin inhibited the activation of cytokine TGFβ, reduced SMAD2/3 phosphorylation, and increased anti‐tumour immune responses in a humanized mouse model. Conclusion ITGAV is a promising therapeutic target for ESCC. Indomethacin can attenuate ESCC growth through binding to ITGAV, promoting SYVN1‐mediated ubiquitination of ITGAV, and potentiating cytotoxic CD8+ T cell responses. Integrin αvβ3 was upregulated in ESCC tumour tissue compared to adjacent tissue. Indomethacin binds to ITGAV and promotes SYVN1‐mediated ubiquitination of ITGAV, thereby attenuating the αvβ3/PI3K/AKT/GS3Kβ signalling pathway. Inhibition of αvβ3 by indomethacin treatment blocks TGFβ/SMAD2/SMAD3 signalling and increases anti‐tumour immune responses in a humanized mouse model. Indomethacin suppresses ESCC tumour growth and recurrence in a PDX mouse model.

Dataset Information

Porous Paclitaxel Mesh Reduces Local Recurrence in Patient-Derived Xenograft Resection Model.

Background

Methods

Results

Conclusions

Publications

Porous Paclitaxel Mesh Reduces Local Recurrence in Patient-Derived Xenograft Resection Model.

Similar Datasets

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