Precision Oncology and Systemic Targeted Therapy in Pseudomyxoma Peritonei

Abstract

Systemic targeted therapy; Pseudomyxoma Peritonei

Teràpia sistèmica dirigida; Pseudomixoma peritonei

Terapia sistémica dirigida; Pseudomixoma peritoneal

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.

The Project was funded by the PMPNet Research Project, sustained by an Accelerator Award on a project entitled Pseudomyxoma peritonei: building a European multicentric cohort to accelerate new therapeutic perspectives funded by the AECC (GEACC19004PAL; J. Martínez-Quintanilla, D. Cabot and H.G. Palmer), CRUK (A29365; J. Barriuso and O. Aziz) and AIRC (24285; M. Guaglio and M. Deraco). We thank Javier Carmona for revising the cover letter, and Fundación CELLEX for its institutional support. The graphical abstract and schematic representations were created thanks to the BioRender platform. J. Martínez-Quintanilla was granted by an individual fellowship from EU Marie Sklodowska-Curie actions (704319). H.G. Palmer was granted with a Miguel Servet contract (MSII14/ 00037). VHIO would like to acknowledge the Cellex Foundation for providing research facilities and equipment, the CERCA Programme from the Generalitat de Catalunya, the FERO Foundation, the Centro de Investigación Biomédica en Red Cáncer (CIBERONC) and the Agencia Estatal de Investigación for their support on this research as a Center of Excellence Severo Ochoa (CEX2020- 001024-S/AEI/10.13039/501100011033).