Funktionelle Validierung der DNA Methyltransferase 1 (DNMT1) als epigenetische Ziestruktur zur Behandlung von Sonic hedgehog Medulloblastomen

01/01/2023 to 31/12/2024

Sonic hedgehog-associated medulloblastoma (SHH MB) are a well-defined group of embryonal brain tumors that might respond to inhibition of the hedgehog component Smoothened (SMO), but tumors ultimately recur due to downstream resistance mechanisms, indicating a need for novel therapeutic options. Using genome-wide functional screening, we previously identified DNA methyltransferase 1 (DNMT1) as one of the top context-specific essential genes in SHH MB, whose loss-of-function synergizes with SMO inhibition. We hypothesize that DNMT1 is an ideal candidate for combination therapies in the context of SHH MB. We will here use a combination of distinct SHH MB cell lines and mouse models to investigate the role of DNMT1 on normal development of granule neuron precursors, the cell of origin for SHH MB, and the incidence and growth of SHH MB tumors. In parallel, we will conduct both loss-of-function and gain-of-function CRISPR/Cas9 drug screens in order to provide a comprehensive overview of modulators of response to DNMT1 inhibition in SHH MB cells. Last, we will use both epigenetic and transcriptomic analyses to define the mechanism by which DNMT1 inhibition impairs growth of SHH MB.