AG Büchel

Gabriele Büchel: Protein-dynamic of MYC/MYCN complexes


Protein-dynamic of MYC/MYCN complexes

MYC proteins interact with a variety of other proteins. Those interaction partners play a role in diverse processes. Therefore, by changing interaction partners MYC can regulate different processes. The aim of our studies is to investigate the protein dynamic of MYC complexes, identify vulnerabilities and exploit it for therapy.

Targeting transcription-replication conflicts in MYCN-driven neuroblastoma

MYC proteins are transcription factors that bind to active promoters and promote transcriptional elongation. In neuroblastoma, a solid tumor in childhood, expression of MYCN is deregulated in high risk patients. Despite multimodal therapies the outcome of those patients is very poor showing the urgent need for new therapy options.
We could show already that MYC-driven tumors are dependent on Aurora-A and a sensitive to Aurora-A inhibitors. Those inhibitors entered already clinical trials but they have a lot of side effects and patients eventually relapse. We want to exploit combination therapies with Aurora-A inhibitors. Understanding the mechanisms how combination therapy is affecting the tumor will show new and specific vulnerabilities for improving therapy of neuroblastoma.

Selected Publications

Kalogirou C, Linxweiler J, Schmucker P, Snaebjornsson MT, Schmitz W, Wach S, Krebs M, Hartmann E, Puhr M, Müller A, Spahn M, Seitz AK, Frank T, Marouf H, Büchel G, Eckstein M, Kübler H, Eilers M, Saar M, Junker K, Röhrig F, Kneitz B, Rosenfeldt MT, Schulze A, MiR-205-driven downregulation of cholesterol biosynthesis through SQLE-inhibition identifies therapeutic vulnerability in aggressive prostate cancer. Nature Commun, 2021 Aug 20;12(1):5066. doi: 10.1038/s41467-021-25325-9.

Roeschert I., Poon E., Henssen A.G., Garica H.D., Gatti M., Giansanti C., Jamin Y., Ade C.P., Gallant P., Schülein-Völk C., Beli P., Richards M.,  Rosenfeldt M., Altmeyer M., Anderson J., Eggert A., Dobbelstein M.,  Chesler L.1), Büchel G.1) and Eilers M.1), Combined inhibition of Aurora-A and ATR kinase results in regression MYCN-amplified neuroblastoma. Nature Cancer, 11. Februar 2021, DOI: 10.1038/s43018-020-00171-8, 1) Corresponding authors

Wolpaw A.J.,  Bayliss R.,  Büchel G.,  Dang C.V., Eilers M., Gustafson W.C.,  Hansen G.H., Jura N.,  Knapp S., Lemmon M.A., Levens D., Maris J.M., Marmorstein R., Metallo S.J., Park J.R.,  Penn L.Z.,  Rape M., Roussel M.F., Shokat K.M., Tansey W.P., Verba K.A.,  Vos S.M., Weiss W.A., Wolf E. and Mossé Y.P., Drugging the “Undruggable” MYCN Oncogenic Transcription Factor: Overcoming Previous Obstacles to Impact Childhood Cancers. Cancer Res. 2021 Jan 28:canres.3108.2020. doi: 10.1158/0008-5472.CAN-20-3108. Review.

Herold, S. 1), Kalb, J. 1), Büchel, G. 1), Ade, C.P., Baluapuri, A., Xu, J., Koster, J., Solvie, D., Carstensen, A., Klotz, C., Rodewald, S., Schulein-Volk, C., Dobbelstein, M., Wolf, E., Molenaar, J., Versteeg, R., Walz, S., and Eilers, M. (2019). Recruitment of BRCA1 limits MYCN-driven accumulation of stalled RNA polymerase. Nature 567, 545-549. 1) Joint first authors

Batzke, K., Büchel, G., Hansen, W., and Schramm, A. (2018). TrkB-Target Galectin-1 Impairs Immune Activation and Radiation Responses in Neuroblastoma: Implications for Tumour Therapy. Int J Mol Sci 19.