2026-04-17T11:53:50Zhttps://recercat.cat/oai/request

oai:recercat.cat:11351/94782025-02-05T03:43:47Zcom_2072_378070com_2072_378040col_2072_378092

00925njm 22002777a 4500 dc belli, valentina author Napolitano, Stefania author Ciaramella, Vincenza author ciardiello, davide author Belli, Andrea author Puig Borreil, Isabel author Ramírez Corpas, Lorena author Chicote Ramos, Irene author Mancuso, Francesco Mattia author Caratù, Ginevra author Serres-Créixams, Xavier author fasani, roberta author Jiménez Flores, José Antonio author Ros, Javier author Baraibar, Iosune author Vivancos, Ana author Elez, Elena author Palmer, Hector author Argilés Martinez, Guillem author Tabernero, Josep author Dienstmann, Rodrigo author MARTINI, Giulia author 2023-05-08T12:52:57Z 2023-05-08T12:52:57Z 2023-06 Colorectal cancer; Personalized medicine; Resistance Cáncer colorrectal; Medicina personalizada; Resistencia Càncer colorectal; Medicina personalitzada; Resistència Background Metastatic colorectal cancer (mCRC) patients tend to have modest benefits from molecularly driven therapeutics. Patient-derived tumor organoids (PDTOs) represent an unmatched model to elucidate tumor resistance to therapy, due to their high capacity to resemble tumor characteristics. Materials and methods We used viable tumor tissue from two cohorts of patients with mCRC, naïve or refractory to treatment, respectively, for generating PDTOs. The derived models were subjected to a 6-day drug screening assay (DSA) with a comprehensive pipeline of chemotherapy and targeted drugs against almost all the actionable mCRC molecular drivers. For the second cohort DSA data were matched with those from PDTO genotyping. Results A total of 40 PDTOs included in the two cohorts were derived from mCRC primary tumors or metastases. The first cohort included 31 PDTOs derived from patients treated in front line. For this cohort, DSA results were matched with patient responses. Moreover, RAS/BRAF mutational status was matched with DSA cetuximab response. Ten out of 12 (83.3%) RAS wild-type PDTOs responded to cetuximab, while all the mutant PDTOs, 8 out of 8 (100%), were resistant. For the second cohort (chemorefractory patients), we used part of tumor tissue for genotyping. Four out of nine DSA/genotyping data resulted applicable in the clinic. Two RAS-mutant mCRC patients have been treated with FOLFOX–bevacizumab and mitomycin–capecitabine in third line, respectively, based on DSA results, obtaining disease control. One patient was treated with nivolumab–second mitochondrial-derived activator of caspases mimetic (phase I trial) due to high tumor mutational burden at genotyping, experiencing stable disease. In one case, the presence of BRCA2 mutation correlated with DSA sensitivity to olaparib; however, the patient could not receive the therapy. Conclusions Using CRC as a model, we have designed and validated a clinically applicable methodology to potentially inform clinical decisions with functional data. Undoubtedly, further larger analyses are needed to improve methodology success rates and propose suitable treatment strategies for mCRC patients. This Translational Research Fellowship Project was supported by the ESMO with the aid of a grant from Amgen, by the Accelerator (ACRCelerator) [grant number A26825] and Ayuda a médicos jóvenes investigadores from Fundacion Científica—Asociacion Española Contra el Cancer (FC-AECC)/Associazione Italiana per la Ricerca sul Cancro (AIRC)/Cancer Research United Kingdom (CRUK) and by Familia Armangué. Any views, opinions, findings, conclusions or recommendations expressed in this material are those solely of the author(s) and do not necessarily reflect those of ESMO or Amgen. We thank Regione Campania (I-Cure Research Project) [grant number: Cup 21C17000030007], ESMO Translational Research Fellowship Program. Recte - Càncer - Tractament Còlon - Càncer - Tractament Medicina personalitzada DISEASES::Neoplasms::Neoplasms by Site::Digestive System Neoplasms::Gastrointestinal Neoplasms::Intestinal Neoplasms::Colorectal Neoplasms Other subheadings::Other subheadings::Other subheadings::/drug therapy ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT::Therapeutics::Precision Medicine ENFERMEDADES::neoplasias::neoplasias por localización::neoplasias del sistema digestivo::neoplasias gastrointestinales::neoplasias intestinales::neoplasias colorrectales Otros calificadores::Otros calificadores::Otros calificadores::/farmacoterapia TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS::terapéutica::medicina de precisión Establishment of patient-derived tumor organoids to functionally inform treatment decisions in metastatic colorectal cancer