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Organoid technologies represent a major breakthrough in biomedical research since they offer increasingly sophisticated models for studying biological mechanisms supporting human development and disease. Organoids are three-dimensional (3D) physiological in vitro systems that recapitulate the genetic, histological and functional features of the in vivo tissues of origin more accurately than classical cell culture methods. In the last decade, organoids have been derived from various healthy and diseased tissues and used for a wide range of applications in basic and translational research, including (cancer) tissue biology, development, regeneration, disease modeling, precision medicine, gene editing, biobanking and drug screening. Here, we report the current applications of organoid models to study (stem) cell metabolism in several pathophysiological contexts such as cancer and metabolic diseases. More precisely, we discuss the relevance and limitations of these 3D cultures to model and study metabolic (dys)functions associated with hepatic, renal or pancreatic disorders, as well as tumor development and progression. We also describe the use of organoids to understand the dynamic interaction between diet, microbiota and the intestinal epithelium. Finally, this review explores recent methodological improvements in organoid culture that may help to better integrate the influence of microenvironmental conditions in the study of tumor cell metabolic phenotypes.

Background: Neratinib is an oral small-molecule irreversible pan-HER tyrosine kinase inhibitor in late stage clinical development for advanced HER-2 positive breast cancer. Prophylactic loperamide (4mg qds Day 1, tds days 2-14, bd days 15-28 then prn) and budesonide (9mg od for 28 days) are required to reduce the incidence and severity of diarrhoea. Methods: Patients enrolled within the Puma Biotechnology Neratinib Managed Access Program between 01/01/2016 and 01/06/2018 with advanced HER2 positive breast cancer were identified for this retrospective analysis. Data were collected from electronic patient records. The primary endpoint was progression free survival (PFS). Secondary objectives were overall survival (OS), response rate (RR, RECIST v1.1), clinical benefit rate (CBR) and toxicity graded by CTCAE v4.0. Results: We identified 29 patients, median age 54 years (IQR: 50-61) who received a median of 4 (range 1-6) prior lines of therapy for advanced breast cancer. 15 patients (51.7%) received neratinib 240mg/day as monotherapy (one with sc trastuzumab), 14 (48.2%) in combination with capecitabine 1500mg/m 2 /day for 2 weeks of a 3 week cycle. Median follow-up was 8.5 months (IQR: 5.1 -11.6). Median PFS was 7.4 months (95%CI 3.5 -17.9) and was significantly longer with combination therapy than monotherapy (17.9 (3.5-NR) vs 5.8 months (2.0-10.2), P ¼ 0.043). Median OS was not reached but was not significantly different in the two treatment cohorts. The RR in monotherapy patients was 33% compared to 57% in combination patients. Two combination patients had complete responses which remain ongoing at 17 and 25 months. The CBR was 47% and 79% respectively. Grade 3-4 toxicities were reported in 4 patients (13.8%). Dose delays were required in 19 patients (65.5%), dose reductions in 4 (13.8%) and discontinuation in 4 due to pneumonitis (n ¼ 1); nausea and vomiting (n ¼ 2) and diarrhoea (n ¼ 1). Any grade diarrhoea was reported by 15 patients (51.7%) despite prophylaxis, as above. There was no grade 3-4 diarrhoea. Conclusions: In this cohort of heavily pre-treated HER2 positive advanced breast cancer patients, neratinib demonstrated durable anti-cancer activity with a manageable toxicity profile both as monotherapy and in combination with capecitabine.