2. Academic Validation
  3. Precision Oncology and Systemic Targeted Therapy in Pseudomyxoma Peritonei

Precision Oncology and Systemic Targeted Therapy in Pseudomyxoma Peritonei

  • Clin Cancer Res. 2024 Sep 13;30(18):4082-4099. doi: 10.1158/1078-0432.CCR-23-4072.
Jordi Martínez-Quintanilla # 1,  Débora Cabot # 1,  Doménico Sabia 2,  Oriol Arqués 1,  PMPnet Group,  Jordi Vergés 1,  Irene Chicote 1,  Lana Bijelic 2,  PMPnet Group,  Laia Cabellos 1,  Anna M Alcántara 1,  Isabel Ramos 3,  Pedro Barrios 4,  Oriol Crusellas 3 5,  Lina M Palacio 2,  PMPnet Group,  Juan A Cámara 6,  Jorge Barriuso 7 8,  PMPnet Group,  Juan J Jiménez 9,  Pau Muñoz-Torres 10,  Lara Nonell 10,  Raquel Flores 1,  Enzo Médico 11 12,  Marcello Guaglio 13,  PMPnet Group,  Javier Ros 14,  Elena Élez 14,  Josep Tabernero 14 15,  Omer Aziz 7 8,  Marcello Deraco 16,  Héctor G Palmer 1 15,  PMPnet Group,  PMPnet Group
Affiliations

Affiliations

  • 1 Translational Program, Stem Cells and Cancer Laboratory, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain.
  • 2 Peritoneal Surface Malignancies Surgery Unit, Hospital Sant Joan Despí, Moises Broggi, Sant Joan Despí, Spain.
  • 3 Department of General Surgery, Hospital Sant Joan Despí, Consorci Sanitari Integral, Sant Joan Despí, Spain.
  • 4 Former Peritoneal Surface Malignancies Surgery Unit, Hospital Sant Joan Despí, Moises Broggi, Sant Joan Despí, Spain.
  • 5 Department of General Surgery, Hospital de Barcelona, Assistència Sanitària Col·legial, Barcelona, Spain.
  • 6 Preclinical Therapeutics Core, University of California, San Francisco, California.
  • 7 Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, United Kingdom.
  • 8 Colorectal and Peritoneal Oncology Centre, The Christie NHSFT, Manchester, United Kingdom.
  • 9 Preclinical Imaging Platform, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.
  • 10 Bioinformatics Unit, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.
  • 11 Department of Oncology, University of Turin, Turin, Italy.
  • 12 Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy.
  • 13 Consultant Surgeon, Peritoneal Surface Malignancies Unit, Division of Colorectal Surgery, National Cancer Institute, Milan, Italy.
  • 14 Medical Oncology Service, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain.
  • 15 CIBERONC, Madrid, Spain.
  • 16 Peritoneal Surfaces Malignance Unit, Fondazione IRCCS Instituto Nazionale dei Tumori, Milan, Italy.
  • # Contributed equally.
PMID: 39018564 DOI: 10.1158/1078-0432.CCR-23-4072
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.

Figures
Products