Crazy 8 Initiative
Background:
The protein MYCN is the cause of many of the most aggressive pediatric cancers, including high-risk neuroblastoma and medulloblastoma. One of the holy grails of pediatric cancer drug development is finding a way to directly target MYCN in patient tumors, but this has been elusive. In this project we follow two goals:
1. We plan to “drug the undruggable” by developing hybrid molecules that can specifically induce the degradation of the Aurora-A/MYCN complex, which will lead to cancer cell death.
2. We are identifying and characterizing vulnerabilities in MYCN complexes.
3. We are analyzing the role of complexes of MYCN oncoprotein in the development and growth of neuroblastoma in vivo.
For more information about the Crazy 8 Initiative click here.
Principles of the research:
1. Targeted protein degradation via bifunctional molecules
2. Targeted protein degradation via AID Knock in systems for target validation
Lead: Prof. Dr. Martin Eilers
Daniel Fleischhauer (PhD Student)
Stefanie Anh Ha (PhD Student)
Lead: Prof. Dr. Elmar Wolf
Lorenz Eing (Postdoc)
Lead: Prof. Dr. Gabriele Büchel
Mareike Müller (PhD Student)
Katrin Trunk (PhD Student)
Project related literature:
Bozilovic J*, Eing L*, Berger BT, Adhikari B, Weckesser J, Berner NB, Wilhelm S, Kuster B, Wolf E*, Knapp S* (2022) Novel, highly potent PROTACs targeting AURORA-A kinase. Current Research in Chemical Biology doi: 10.1016/j.crchbi.2022.100032.
Roeschert I, Poon E, Henssen AG, Dorado Garcia H, Gatti M, Giansanti C, Jamin Y, Ade CP, 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 (2021) Combined inhibition of Aurora-A and ATR kinase resultsin regression of MYCN-amplifiedneuroblastoma, Nature Cancer, doi: /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 (2021) Drugging the 'undruggable' MYCN oncogenic transcription factor: Overcoming previous obstacles to impact childhood cancers, Cancer Research, doi: 10.1158/0008-5472.CAN-20-3108
Adhikari B, Bozilovic J, Diebold M,Schwarz JD, Hofstetter J, Schröder M, Wanior M, Narain A, Vogt M, DudvarskiStankovic N, Baluapuri A, Schönemann L, Eing L, Bhandare P, Kuster B, SchlosserA, Heinzlmeir S, Sotriffer C, Knapp S*, WolfE* (2020) PROTAC-mediated degradation reveals a non-catalytic function of AURORA-A kinase, Nature Chemical Biology, 2020, https://www.nature.com/articles/s41589-020-00652-y
Wolf E and Eilers M (2020) Targeting MYC Proteins for Tumor Therapy, Annual Review of Cancer Biology, 4. doi: 10.1146/annurev-cancerbio-030518-055826
Baluapuri A, Wolf E, Eilers M (2020) Target gene-independent functions of Myc oncoproteins. Nat Rev Mol Cell Biol. 2020 Feb 18. doi: 10.1038/s41580-020-0215-2. Review
Herold S, Kalb J, Büchel G, Ade CP, 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, 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
Baluapuri A*, Hofstetter J*, Dudvarski Stankovic N, Endres T, Bhandare P, Vos SM, Adhikari B, Schwarz JD, Narain A, Vogt M, Wang SY, Düster R, Jung LA, Vanselow JT, Wiegering A, Geyer M, Maric HM, Gallant P, Walz S, Schlosser A, Cramer P, Eilers M, Wolf E (2019) MYC recruits SPT5 to RNA polymerase II to promote processive transcription elongation. Mol Cell. 2019 May 16;74(4):674-687.e11.doi: 10.1016/j.molcel.2019.02.031.
Rickman DS, Schulte JH, Eilers M (2018) The expanding world of N-Myc driven tumors. Cancer Discovery, Feb;8(2):150-163. doi: 10.1158/2159-8290.CD-17-0273
Büchel G, Carstensen A, Mak KY, Roeschert I, Leen E, Sumara O, Hofstetter J, Herold S, Kalb J, Baluapuri A, Poon E, Kwok C, Chesler L, Maric HM, Rickman DS, 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.
