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Home»News»The research may pave the way for systemic targeted therapy for patients with pseudomyxoma peritoneal
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The research may pave the way for systemic targeted therapy for patients with pseudomyxoma peritoneal

healthtostBy healthtostJuly 21, 2024No Comments5 Mins Read
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The Research May Pave The Way For Systemic Targeted Therapy
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Posted in Clinical Cancer Research, the results of a preclinical study led by the researchers of the Stem Cell and Cancer Group of the Vall d’Hebron Institute of Oncology (VHIO), led by Héctor G. Palmer, pave the way for systematic targeted therapy in patients with pseudomyxoma peritoneal, a rare form of cancer with very few treatment options available. This work was carried out in collaboration with colleagues at the Hospital San Joan Despí Moises Broggi, Barcelona.

Researchers have created the largest collection of in vitro and in vivo patient-derived pseudomyxoma peritoneal mouse models with ident KRAS and BRAF drug targets to guide the selection of molecularly targeted therapies. As a proof of concept, they studied the therapeutic efficacy of BRAF inhibitor encorafenib in these preclinical models. Patients who have these mutations – which account for approximately 4-8% of cases – have a poor prognosis. The researchers observed that treatment with encorafenib significantly reduced tumor growth and prolonged survival in mice.

“The results of this proof-of-concept study represent an important first step toward the development and implementation of systemic targeted therapy in the clinic for patients who for the first time could benefit from individualized, molecularly matched therapies. Currently, cytoreductive surgery is the mainstay of treatment, but many patients develop early relapse and eventually succumb to disease progression.There is an urgent medical need to provide new therapeutic strategies to more effectively combat this disease. says Héctor G. Palmer, senior author of this present study.

Pseudomyxoma peritonei is a poorly understood cancer that usually begins in the appendix with an incidence of 1 to 3 cases per million per year. Although rare, this disease is more likely to be diagnosed in people aged 40 and over.

“We have created the world’s largest collection of patient-derived organoids and xenografts from patients with pseudomyxoma peritoneal and have shown that they are powerful preclinical models for studying this disease. To do this, we processed a total of 120 samples from 50 patients.”observes Jordi Martínez-Quintanilla, Senior Researcher in the Palmer group and co-first author of this study with Débora Cabot, Laboratory Technician in the same group.

Uncovering druggable mutations: genomic characterization of preclinical models and intra-abdominal mucus biopsy

For the first time, researchers used intra-abdominal mucus biopsy to detect circulating tumor DNA (ctDNA) derived from cancer cells. They then identified those preclinical models that exhibited druggable mutations and observed that 80% of the preclinical models exhibited KRAS the BRAF mutations.

“While mutations in the KRAS gene were much more common, we decided to evaluate the effectiveness of the BRAF inhibitor encorafenib in our BRAFV600E models. BRAF inhibitors have revolutionized the treatment of BRAF-mutated metastatic colorectal cancer or melanoma, while KRAS inhibitors are currently in clinical development. Therefore, we believe that BRAF inhibition will be the fastest molecularly matched treatment option in this patient population, particularly considering that encorafenib monotherapy is already approved for the treatment of other tumor types.” explains Débora Cabot.

The organelle cultures were derived from high quality BRAFV600E-Patient samples with mutated pseudomyxoma peritoneal and tumors were generated in mice. The researchers observed that encorafenib treatment slowed tumor growth in all cases.

“For the first time, we have shown that systemic targeted therapy for pseudomyxoma peritoneal can effectively control tumor growth in animal models. BRAF inhibition could represent a new therapeutic opportunity for patients with BRAF-mutated disease who have a poor prognosis.” Our data show great promise in extending precision oncology to these patients, who could for the first time benefit from personalized targeted therapies.” Palmer concludes.

The next step will be to validate this data on his other models BRAF-mutated pseudomyxoma peritoneal to confirm whether KRAS inhibitors, currently being investigated in clinical trials, show the same systemic antitumor activity in animal models.

This work was supported by the PMPnet Accelerator Award on Appendiceal Mucinous Neoplasms and Pseudomyxoma Peritonei: creation of a European multicenter cohort to accelerate new therapeutic perspectives, funded by AECC, CRUK and AIRC and by CIBERONC/ISCIII.

PMPnet – Accelerator for PMP research

Coordinated by Marcello Deraco at la Fondazione IRCCS Istituto Nazionale dei Tumori, Milan (Italy), the Accelerator Award provides support to four major institutions with high expertise in peritoneal surface malignancies (PSM) across the UK, Spain and Italy to investigate and advance pseudomyxoma peritoneal translational research, develop prognostic tools, omics platforms and new chemotherapy resources to change the research landscape. Combining the expertise of researchers at the VHIO and San Joan Despí Moises Broggi Hospital in Barcelona, ​​Cancer Research UK (CRUK) Manchester Institute and the University of Manchester in the UK and the Istituto di Candiolo in Italy, this consortium aims to develop the largest group of patients with pseudomyxoma peritoneal in Europe in vitro and in vivo of this disease and identify new therapeutic targets to help develop new therapeutic strategies.

Source:

Institute of Oncology Vall d’Hebron

Journal Reference:

Martínez-Quintanilla, J., et al. (2024). Precision Oncology and Systemic Targeted Therapy in Pseudomyxoma Peritoneum. Clinical Cancer Research. doi.org/10.1158/1078-0432.ccr-23-4072.

Patients pave peritoneal pseudomyxoma research systemic Targeted Therapy
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