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Selecting Chemotherapy With High-throughput Drug Screen Assay Using Patient Derived Organoids in Patients With Refractory Solid Tumours (SCORE)

ABSTRACT: This is a single-centre study based on the Simon 2-stage optimax design: 12 patients will be enrolled initially (Stage I), which will then be expanded to a further 13 patients (Stage II) if 3 or more patients enrolled in stage I of the study achieve an objective response with the chemotherapeutic agent selected by the drug screen assay. A total of 25 patients will be included in both stages of study. Patients enrolled on study will undergo a fresh biopsy of tumour lesion to obtain cells that will be used to generate patient-derived tumour organoids based on the Invitrocue technology. Organoids will then be subjected to a 10-drug panel screening including: 5-fluorouracil, carboplatin, cyclophosphamide, docetaxel, doxorubicin, gemcitabine, irinotecan, oxaliplatin, paclitaxel and vinorelbine. A further 5 drugs (etoposide, ifosfamide, methotrexate, pemetrexed and topotecan) will be screened if sufficient organoids are grown from the biopsy samples within the screening period. Physicians will be informed of the results, and choice of chemotherapy will be based on an IRS score of 70% or above. If more than 1 candidate drug with IRS of 70% or above is identified, the physician will exercise his/her discretion to select the most suitable drug based on patient’s comorbidities and organ function.

DISEASE(S): Organoids,Hnscc,Carcinoma, Ovarian Epithelial,Colorectal Cancer,Epithelial Ovarian Cancer

PROVIDER: 2330871 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Project description:Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of histological findings, from simple steatosis to steatohepatitis (NASH), the latter presenting a higher risk of cardiovascular and kidney diseases, type 2 diabetes and end-stage liver disease. NAFLD is seen as the hepatic manifestation of the metabolic syndrome and affects up to 70-80% of obese patients. There are currently no approved pharmacological therapies for NASH, thus the only option is lifestyle intervention or bariatric surgery in order to lose weight and to improve insulin resistance. Although surgical intervention has allowed collections of liver biopsies, transcriptomic data from livers are still scarce and especially follow-up data to evaluate the impact of weight loss intervention on the liver. Therefore we studied hepatic transcriptomic data in a large cohort of obese patients assessed for presence of NASH at baseline and 1 year follow-up. Patients visiting the obesity clinic of the Antwerp University Hospital for a problem of being overweight (BMI above 25 to 29.9 kg/m²) or obese (BMI above 30 kg/m²) were prospectively recruited and underwent a hepatic work-up. Patients were excluded from further analysis in case of significant alcohol consumption (>20 g/day), history of bariatric surgery, diagnosis of another liver disease, pre-existing diabetes. Patients who were, however, diagnosed with de novo diabetes at baseline or at follow-up were not excluded. If NAFLD was suspected, liver biopsy was proposed. For patients undergoing bariatric surgery (BS), a liver biopsy was proposed regardless of the criteria. Patients were reassessed after 1 year. Liver biopsy was performed percutaneously (16G Menghini) or peri-operatively (14G Tru-Cut). The different histological features of NAFLD were assessed using the NASH Clinical Research Network (NASH CRN) Scoring System. The presence of NASH was defined according to Chalasani et al. necessitating the combined presence of steatosis, ballooning and lobular inflammation.

Project description:AIM Vitamin D deficiency is associated with risk of several common cancers, including colorectal cancer (CRC). We investigated the effects of vitamin D on in vitro and ex vivo epithelial cell gene expression and assessed dysregulation of pathways involved in anti-tumour effects. METHODS We performed in vitro and ex vivo intervention studies using established CRC cell lines and patient-derived epithelial organoids developed from normal human colonic (resectional colorectal surgery) and rectal mucosa (rectal biopsy). RNA and protein were harvested after 16-24 hours’ calcitriol treatment. Gene expression was assessed by qRT-PCR, microarray and RNA-sequencing, and protein expression by immunoblotting and mass-spectrometry. Gene Ontology enrichment analysis was performed using GOrilla and Gene Set Enrichment Analysis. RESULTS Calcitriol increased the expression of the tumour suppressor gene CDH1 in CRC cell lines (SW480; FC=3.60, 95%CI 2.17-5.03) and patient-derived epithelial cell organoids (n=6, FC=1.64, 95%CI 1.49-1.80), with associated in vitro E-cadherin protein induction. Significant differential expression of a further 6 common genes was observed on microarray analysis of in vitro and ex vivo experiments, including genes with established links to carcinogenesis GADD45, EFTUD1 and KIAA1199. Numerous ontologies relevant to carcinogenesis were enriched (e.g. ‘regulation of Wnt signaling pathway’, ‘regulation of cell death’), with common enriched processes across in vitro and ex vivo cultures including ‘negative regulation of cell proliferation’, ‘regulation of cell migration’ and ‘regulation of cell differentiation’. CONCLUSIONS We report for the first time, common genes and pathways modulated by calcitriol treatment in both in vitro and ex vivo models, with several differentially expressed genes strongly linked to CRC tumourigenesis. Enrichment of biological pathways after calcitriol treatment provides further evidence of anti-tumour effects. These findings support epidemiological data and provide strong rationale for well-designed trials of vitamin D supplementation as a novel CRC chemopreventive and chemotherapeutic agent. see above

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Selecting Chemotherapy With High-throughput Drug Screen Assay Using Patient Derived Organoids in Patients With Refractory Solid Tumours (SCORE)

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