<> "The repository administrator has not yet configured an RDF license."^^ . <> . . "Exploring molecular mechanisms involved in tumor rebound growth after MAPKi withdrawal in pLGG"^^ . "Pediatric low-grade gliomas (pLGGs) are the most common primary brain tumors in children and are almost exclusively driven by alterations in the mitogen-activated protein kinase (MAPK) pathway, most commonly BRAF fusions and BRAFV600E point mutations. This makes pLGGs a fitting candidate for targeted therapies using MAPK inhibitors (MAPKi), which have shown promising results in clinical trials. This led to the FDA-approval of dabrafenib and trametinib combination as front-line treatment for BRAFV600E driven pLGGs. However, despite the efficacy of MAPKi treatment, a subset of patients experiences a rapid tumor regrowth upon treatment stop, also referred to as rebound growth, which constitutes a significant clinical challenge.\r\n\r\nTo model rebound growth in vitro, based on viable cell counts in response to MAPKi treatment and withdrawal, four patient-derived pLGG models were tested. Following, a multi-omics dataset of the rebound model, encompassing different MAPKi withdrawal timepoints, was generated using RNA sequencing and LC-MS/MS-based phospho-/proteomics. Using this data set, I identified putative rebound growth driving mechanisms, which were further validated in vitro and in vivo. \r\n\r\nOf the tested models, BT-40 (BRAFV600E, CDKN2A/Bdel) showed rebound growth, characterized by faster cell regrowth after MAPKi withdrawal compared to standard-of-care chemotherapy, thereby mimicking what is observed in patients. Using this model, I observed MAPK pathway reactivation within hours after withdrawal, associated with a transient overactivation of key MAPK molecules on transcriptional (e.g. FOS) and phosphorylation (e.g. pMEK) levels. Furthermore, AKT activity and expression and secretion of cytokines (in particular CCL2, CX3CL1, CXCL10 and CCL7) were increased upon MAPKi treatment and maintained during early withdrawal (until 6-24 h). While neither increased AKT activity nor cytokine expression affected rebound growth in a tumor cell intrinsic manner, upregulated cytokines mediated increased attraction of microglia cells during MAPKi treatment and withdrawal. Importantly, MAPK pathway reactivation during rebound growth and increased expression of CX3CL1 and CXCL10 upon MAPKi treatment were also observed in vivo using the BT-40 orthotopic xenograft model.\r\n\r\nIn summary, this study suggests rapid MAPK reactivation as a tumor cell intrinsic rebound driving mechanism and modulation of MAPK activity during treatment withdrawal may be a possible strategy to target rebound growth, which should be further investigated. Furthermore, I could show increased microglia attraction, mediated by cytokines induced upon MAPKi treatment, suggesting a possible role of the immune microenvironment, in particular microglia cells, during MAPKi treatment and withdrawal, which warrants further investigation."^^ . "2024" . . . . . . . "Daniela"^^ . "Kocher"^^ . "Daniela Kocher"^^ . . . . . . "Exploring molecular mechanisms involved in tumor rebound growth after MAPKi withdrawal in pLGG (PDF)"^^ . . . "Thesis_Kocher_2024.pdf"^^ . . . "Exploring molecular mechanisms involved in tumor rebound growth after MAPKi withdrawal in pLGG (Other)"^^ . . . . . . "indexcodes.txt"^^ . . . "Exploring molecular mechanisms involved in tumor rebound growth after MAPKi withdrawal in pLGG (Other)"^^ . . . . . . "lightbox.jpg"^^ . . . "Exploring molecular mechanisms involved in tumor rebound growth after MAPKi withdrawal in pLGG (Other)"^^ . . . . . . "preview.jpg"^^ . . . "Exploring molecular mechanisms involved in tumor rebound growth after MAPKi withdrawal in pLGG (Other)"^^ . . . . . . "medium.jpg"^^ . . . "Exploring molecular mechanisms involved in tumor rebound growth after MAPKi withdrawal in pLGG (Other)"^^ . . . . . . "small.jpg"^^ . . "HTML Summary of #34857 \n\nExploring molecular mechanisms involved in tumor rebound growth after MAPKi withdrawal in pLGG\n\n" . "text/html" . .