AG Büchel

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.

2021

Roeschert, I., Poon, E., Henssen, A.G., Dorado Garcia, H., 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., Bayliss, R., Chesler, L.*, Büchel, G.*, and Eilers, M.*, Combined inhibition of Aurora-A and ATR kinases results in regression of MYCN-amplified neuroblastoma. Nat Cancer (2021). https://doi.org/10.1038/s43018-020-00171-8

Wolpaw AJ, Bayliss R, Büchel G, Dang CV, Eilers M, Gustafson WC, Hansen GM, Jura N, Knapp S, Lemmon MA, Levens D, Maris JM, Marmorstein R, Metallo SJ, Park JR, Penn LZ, Rape M, Roussel MF, Shokat KM, Tansey WP, Verba KA, Vos SM, Weiss WA, Wolf E, Mossé YP, 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.

2019

Herold, S.*, Kalb, J.*, Büchel, G.*, Ade, C. P., Baluapuri, A., Xu, J., Koster, J., Solvie, D., Carstensen, A., Klotz, C., Rodewald, S., Schülein-Volk, C., Dobbelstein, M., Wolf, E., Molenaar, J., Versteeg, R., Walz, S., Eilers, M. (2019). Recruitment of BRCA1 limits MYCN-driven accumulation of stalled RNA Polymerase. Nature. 2019 Mar;567(7749):545-549. doi: 10.1038/s41586-019-1030-9, * joint first author

2018

Batzke K, Büchel G, Hansen W, Schramm A, TrkB-Target Galectin-1 Impairs Immune Activation and Radiation Responses in Neuroblastoma: Implications for Tumour Therapy. .Int J Mol Sci. 2018 Mar 2;19(3):718. doi: 10.3390/ijms19030718.PMID: 29498681

2017

Büchel, G., Carstensen, A., Mak, K.Y., Roeschert, I., Leen, E., Sumara, O., Hofstetter, J., Herold, S., Kalb, J., Baluapuri, A., Poon, E., Kwok, C., Chesler, L., Maric H. M., Rickman, D. S., Wolf, E., Bayliss, R., Walz, S., Eilers, M. (2017) Association with Aurora-A controls N-MYC-dependent promoter escape and pause release of RNA polymerase II during cell cycle. Cell Reports Dec 19;21(12):3483-3497. doi:10.1016/j.celrep.2017.11.090.

2016

Büchel G, Schulte JH, Harrison L, Batzke K, Schüller U, Hansen W, Schramm A , Immune response modulation by Galectin-1 in a transgenic model of neuroblastoma. Oncoimmunology. 2016 Feb 18;5(5):e1131378. doi: 10.1080/2162402X.2015.1131378. eCollection 2016 May.PMID: 27467948

2013

Schramm A, Köster J, Marschall T, Martin M, Schwermer M, Fielitz K, Büchel G, Barann M, Esser D, Rosenstiel P, Rahmann S, Eggert A, Schulte JH. Next-generation RNA sequencing reveals differential expression of MYCN target genes and suggests the mTOR pathway as a promising therapy target in MYCN-amplified neuroblastoma. Int J Cancer. 2013 Feb 1;132(3):E106-15. doi: 10.1002/ijc.27787.