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Updated: Jun 20, 2025
Culture and Imaging of Ex Vivo Organotypic Pseudomyxoma Peritonei Tumor Slices from Resected Human Tumor Specimens
Published on: December 9, 2022
Precision Oncology and Systemic Targeted Therapy in Pseudomyxoma Peritonei
Jordi Martínez-Quintanilla1, Débora Cabot1, Doménico Sabia2
1Translational Program, Stem Cells and Cancer Laboratory, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain.
Purpose:
Pseudomyxoma peritonei (PMP) is a rare and poorly understood malignant condition characterized by the accumulation of intra-abdominal mucin produced from peritoneal metastases. Currently, cytoreductive surgery remains the mainstay of treatment but disease recurrence and death after relapse frequently occur in patients with PMP. New therapeutic strategies are therefore urgently needed for these patients.
Experimental Design:
A total of 120 PMP samples from 50 patients were processed to generate a collection of 50 patient-derived organoid (PDO) and xenograft (PDX) models. Whole exome sequencing, immunohistochemistry analyses, and in vitro and in vivo drug efficacy studies were performed.
Results:
In this study, we have generated a collection of PMP preclinical models and identified druggable targets, including BRAFV600E, KRASG12C, and KRASG12D, that could also be detected in intra-abdominal mucin biopsies of patients with PMP using droplet digital PCR. Preclinical models preserved the histopathological markers from the original patient sample. The BRAFV600E inhibitor encorafenib reduced cell viability of BRAFV600E PMP-PDO models. Proof-of-concept in vivo experiments showed that a systemic treatment with encorafenib significantly reduced tumor growth and prolonged survival in subcutaneous and orthotopic BRAFV600E-PMP-PDX mouse models.
Conclusions:
Our study demonstrates for the first time that systemic targeted therapies can effectively control PMP tumors. BRAF signaling pathway inhibition represents a new therapeutic opportunity for patients with BRAFV600E PMP who have a poor prognosis. Importantly, our present data and collection of preclinical models pave the way for evaluating the efficacy of other systemic targeted therapies toward extending the promise of precision oncology to patients with PMP.
Insights
New preclinical models of pseudomyxoma peritonei (PMP) identified BRAFV600E as a druggable target. Systemic BRAF inhibition with encorafenib effectively controlled PMP tumors in preclinical models, offering a new therapeutic strategy.
Area of Science:
- Oncology
- Gastroenterology
- Translational Research
Background:
- Pseudomyxoma peritonei (PMP) is a rare malignancy characterized by mucin accumulation.
- Current treatments like cytoreductive surgery have high recurrence rates, necessitating novel therapeutic strategies.
Purpose of the Study:
- To develop preclinical models for Pseudomyxoma peritonei (PMP).
- To identify druggable targets and evaluate targeted therapies for PMP.
Main Methods:
- Generated 50 patient-derived organoid (PDO) and xenograft (PDX) models from 120 PMP samples.
- Performed whole exome sequencing, immunohistochemistry, and in vitro/in vivo drug efficacy studies.
- Utilized droplet digital PCR to detect mutations in patient biopsies.
Main Results:
- Identified BRAFV600E, KRASG12C, and KRASG12D as druggable targets in PMP models and patient biopsies.
- BRAFV600E PMP-PDO models showed reduced viability with BRAFV600E inhibitor encorafenib.
- Encorafenib treatment significantly reduced tumor growth and prolonged survival in BRAFV600E-PMP-PDX mouse models.
Conclusions:
- Systemic targeted therapies can effectively control PMP tumors.
- BRAF signaling pathway inhibition offers a new therapeutic avenue for BRAFV600E PMP patients.
- Developed preclinical models provide a platform for evaluating other targeted therapies in PMP, advancing precision oncology.
