ICK expression cancels the prognostic relevance of CTLs in highly immunogenic colon tumors and predicts a poor outcome in MSI CRC patients.
Background: Pediatric high-grade gliomas (pHGGs) are facing a very dismal prognosis and representative pre-clinical models are needed for new treatment strategies. Here, we examined the relevance of collecting functional, genomic, and metabolomics data to validate patient-derived models in a hypoxic microenvironment. Methods: From our biobank of pediatric brain tumor-derived models, we selected 11 pHGGs driven by the histone H3.3K28M mutation. We compared the features of four patient tumors to their paired cell lines and mouse xenografts using NGS (next generation sequencing), aCGH (array comparative genomic hybridization), RNA sequencing, WES (whole exome sequencing), immunocytochemistry, and HRMAS (high resolution magic angle spinning) spectroscopy. We developed a multicellular in vitro model of cell migration to mimic the brain hypoxic microenvironment. The live cell technology Incucyte© was used to assess drug responsiveness in variable oxygen conditions. Results: The concurrent 2D and 3D cultures generated from the same tumor sample exhibited divergent but complementary features, recreating the patient intra-tumor complexity. Genomic and metabolomic data described the metabolic changes during pHGG progression and supported hypoxia as an important key to preserve the tumor metabolism in vitro and cell dissemination present in patients. The neurosphere features preserved tumor development and sensitivity to treatment. Conclusion: We proposed a novel multistep work for the development and validation of patient-derived models, considering the immature and differentiated content and the tumor microenvironment of pHGGs.
3509 Background: The molecular subtyping of colon cancers (CC) has been the subject of several recent publications, leading to an international consensus. The clinical relevance of these molecular classifications remains to be evaluated on large prospective patient cohorts using a tool that can be widely used on formalin-fixed paraffin-embedded (FFPE) samples. Methods: We aimed to evaluate the clinical relevance of two molecular subtyping systems, CMS (Guinney et al. 2015) and CCMST (Marisa et al. 2013), on the PETACC-8 cohort, a randomized phase III trial comparing adjuvant FOLFOX with or without cetuximab in patients with stage III CC. For each of these two classification systems, a predictor tool was developed and adapted to FFPE samples. The NanoString nCounter platform was used to screen 196 genes. Predictors were built from 249 frozen tumor samples previously used to build our classification system and 61 new paired FFPE/frozen samples. Both predictors were then applied to 1781 PETACC-8 FFPE samples. Subtypes associations to clinical and molecular features were analyzed. Results: The CMS predictor assigned 297 samples to CMS1 (17%), 585 to CMS2 (34%), 68 to CMS3 (4%) and 770 to CMS4 (45%). CMS were significantly associated with several molecular and clinical features, including MSI status (49% in CMS1, p < 0.001), CIMP status (47% in CMS1, p < 0.001), KRAS mutation (75% in CMS3, p < 0.001), BRAF mutation (34% in CMS1, p < 0.001), tumor location (less proximal tumors in CMS2, p < 0.001), validating the predictor tool developed. The classification was significantly associated to prognosis in multivariate analysis, CMS4 subtype having a shorter overall survival (hazard ratio = 1.7, p= 0.021). A deleterious effect of cetuximab was observed in CMS1 (p < 0.05). Similar results were obtained with the CCMST classification. Conclusions: We validated molecular CC subtyping predictors for both CMS and CCMST classifications on PETACC-8 FFPE samples. The prognostic value of CMS and CCMST classifications was confirmed, stem-like tumors being associated with a poor prognosis. These results pave the avenue for widely use of the CC molecular classification in clinical routine.
Advanced colorectal cancer has a poor prognosis because of metastasis formation and resistance to combined therapies. Downstream of PI3K/Akt and Ras/MAPK pathways, the mTOR kinase plays a decisive role in treatment failure. We previously established that irinotecan has antiangiogenic properties and it is known that new mammalian target of rapamycin (mTOR) catalytic AZD inhibitors, unlike rapamycin, target both mTORC1 and mTORC2. Thus, we hypothesized that the complete inhibition of the PI3K/AKT/mTOR/HIF-1α axis with mTOR catalytic inhibitors and low doses of irinotecan may have antitumor effects. We showed that the AZD8055 and AZD2014 inhibitors were much more potent than rapamycin to reduce cell viability of four colon cell lines. On the other hand, whereas AZD2014 alone inhibits migration by 40%, the drug combination led to 70% inhibition. Similarly, neither irinotecan nor AZD2014 significantly reduced cell invasion, whereas a combination of the two inhibits invasion by 70%. In vivo, irinotecan and AZD2014 combination drastically reduced ectopic patient-derived colon tumor growth and this combination was more potent than Folfox or Folfiri. Finally, the combination totally inhibited liver and lung metastases developed from orthotopic implantation of SW480 cells. Thus, the use of mTOR catalytic inhibitors, in association with other chemotherapeutic agents like irinotecan at low doses, is potentially a hope for colon cancer treatment.
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