Precision oncology and systemic targeted therapy in pseudomyxoma peritonei
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
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.
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.
Date Issued
2024-09-13
Date Acceptance
2024-07-10
Citation
Clinical Cancer Research, 2024, 30 (18), pp.4082-4099
ISSN
1078-0432
Publisher
American Association for Cancer Research (AACR)
Start Page
4082
End Page
4099
Journal / Book Title
Clinical Cancer Research
Volume
30
Issue
18
Copyright Statement
©2024 The Authors; Published by the American Association for Cancer Research This open access article is distributed under the Creative Commons Attribu tion 4.0 International (CC BY 4.0) license.
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/39018564
PII: 746393
Subjects
Pseudomyxoma Peritonei
Humans
Animals
Mice
Precision Medicine
Molecular Targeted Therapy
Xenograft Model Antitumor Assays
Peritoneal Neoplasms
Proto-Oncogene Proteins B-raf
Female
Male
Proto-Oncogene Proteins p21(ras)
Exome Sequencing
Mutation
Cell Line, Tumor
Organoids
Biomarkers, Tumor
Publication Status
Published
Coverage Spatial
United States
Date Publish Online
2024-09-13