Targeting transcription-coupled DNA damage responses in CLL
Final Report Abstract
Cancer is strongly associated with age. This is particularly the case for chronic lymphocytic leukemia (CLL), which is the most common age-associated leukemia. Many cancer types are highly proliferative and therefore sensitive to chemotherapies that inflict DNA damage that blocks replication. Such therapies, however, are less effective in CLL. Instead, cells that are not undergoing rapid cell divisions might be more sensitive to DNA lesions that instead of replication interfere with transcription, as cell constantly rely on mRNA synthesis regardless of cell cycle stage. Indeed, we observed that CLL cells responded highly sensitively to DNA damage types that block transcription. Transcription-blocking DNA lesions are removed by a specific repair mechanism called transcription-coupled nucleotide excision repair (TC-NER) that is induced when the RNA polymerase stalls at such a lesion. We systematically assessed treatments that inflict such damage types. Interestingly, we showed that cells are eliminated when experiencing high levels of transcription-blocking lesions but without using tumor suppressor mechanisms that are frequently defective in cancer cells. Therefore, our treatment indeed was highly effective in hard-to-manage CLL subsets. We have expanded our repertoire of chemotherapeutic options that in contrast to conventional therapy could effectively eliminate therapy resistant CLL cells. Moreover, we showed synergistic effectiveness with conventional CLL therapies. Therefore, our project opened new therapeutic avenues for CLL and particularly refractile CLL cases. We have successfully validated our approach in distinct pre-clinical CLL models and have provided new options for clinical development. Clinical trials around these principles and drugs (i.e. trabectedin) will follow. There were no major unanticipated aspects or roadblocks that could not be overcome. Admittedly, we had hoped to implement trabectedin in an early-phase clinical trial in r/r CLL patients, but the therapeutic landscape in this disease is currently biased by a strong propagation of CD20 antibodies, BTK inhibitors, and BCL2 antagonists. Real world data, however, clearly show that these strategies do not confer longterm remissions in a substantial fraction of patients. We are optimistic that the “community” and the “industry” will be resensitized towards repurposed mechanism-driven drugs like trabectedin, for which convincing pre-clinical data exist.
Publications
- AKT- pathway inhibition in chronic lymphocytic leukemia reveals response relationships defined by TCL1. Current cancer drug targets. 2014 14(8), 700-712
Schrader A, Popal W, Lilienthal N, Crispatzu G, Mayer P, Jones D, Hallek M, Herling M
(See online at https://doi.org/10.2174/1568009614666141028101711) - DNA repair mechanisms in cancer development and therapy. Front Genet. 2015 Apr 23;6:157
Torgovnick A, Schumacher B
(See online at https://doi.org/10.3389/fgene.2015.00157) - Genome Instability in Development and Aging: Insights from Nucleotide Excision Repair in Humans, Mice, and Worms. Biomolecules 2015, 5, 1855-1869
Edifizi D, Schumacher B
(See online at https://doi.org/10.3390/biom5031855) - Organometallic nucleosides induce non-classical leukemic cell death that is mitochondrial-ROS dependent and facilitated by TCL1-oncogene burden. Molecular Cancer. 2015 14(1), 1-18
Prinz C, Vasyutina E, Lohmann G, Schrader A, Romanski S, Hirschhäuser C, Mayer P, Frias C, Herling CD, Hallek M, Schmalz HG, Prokop A, Mougiakakos D, Herling M
(See online at https://doi.org/10.1186/s12943-015-0378-1) - The regulatory interaction of EVI1 with the TCL1A oncogene impacts cell survival and clinical outcome in CLL. Leukemia. 2015 29(10), 2003-2014
Vasyutina, E., Boucas, J. M., Bloehdorn, J., Aszyk, C., Crispatzu, G., Stiefelhagen M, Breuer A, Mayer P, Lengerke C, Döhner H, Beutner D, Rosenwald A, Stilgenbauer S, Hallek M, Benner A, Herling M
(See online at https://doi.org/10.1038/leu.2015.114) - A C. elegans homolog for the UV-hypersensitivity syndrome disease gene UVSSA. DNA Repair (Amst). 2016 Mar 25;41:8-15
Babu V, Schumacher B
(See online at https://doi.org/10.1016/j.dnarep.2016.03.008) - A novel recombinant anti-CD22 immunokinase delivers proapoptotic activity of death-associated protein kinase (DAPK) and mediates cytotoxicity in neoplastic B cells. Molecular cancer therapeutics. 2016 15(5), 971-984
Lilienthal N, Lohmann G, Crispatzu G, Vasyutina E, Zittrich S, Mayer, P, Herling CD, Tur MK, Hallek M, Pfitzer G, Barth S, Herling, M
(See online at https://doi.org/10.1158/1535-7163.mct-15-0685) - Ercc1 Deficiency Promotes Tumorigenesis and Increases Cisplatin Sensitivity in a Tp53 Context-Specific Manner. Mol Cancer Res. 2016 Nov;14(11):1110-1123
Jokić M, Vlašić I, Rinneburger M, Klümper N, Spiro J, Vogel W, Offermann A, Kümpers C, Fritz C, Schmitt A, Riabinska A, Wittersheim M, Michels S, Ozretić L, Florin A, Welcker D, Akyuz MD, Nowak M, Erkel M, Wolf J, Büttner R, Schumacher B, Thomale J, Persigehl T, Maintz D, Perner S, Reinhardt HC
(See online at https://doi.org/10.1158/1541-7786.mcr-16-0094) - Multilayered reprogramming in response to persistent DNA damage in C. elegans. Cell Rep. 2017 Aug 29;20(9):2026-2043
Edifizi D, Nolte H, Babu V, Castells-Roca L, Mueller MM, Brodesser S, Krüger M, Schumacher B
(See online at https://doi.org/10.1016/j.celrep.2017.08.028) - Systematic analysis of DNA crosslink repair pathways during development and aging in C. elegans. Nucleic Acids Res. 2017 Sep 19;45(16):9467-9480
Wilson DM 3rd, Rieckher M, Williams AB, Schumacher B
(See online at https://doi.org/10.1093/nar/gkx660) - Targeting transcription-coupled nucleotide excision repair overcomes resistance in chronic lymphocytic leukemia. Leukemia. 2017 May;31(5):1177-1186
Lohmann G, Vasyutina E, Bloehdorn J, Reinart N, Schneider JI, Babu V, Knittel G, Crispatzu G, Mayer P, Prinz C, Biersack B, Efremov DG, Chessa L, Herling CD, Stilgenbauer S, Hallek M, Schobert R, Reinhardt HC, Schumacher B, Herling M
(See online at https://doi.org/10.1038/leu.2016.294) - Two mouse models reveal an actionable PARP1 dependence in aggressive chronic lymphocytic leukemia. Nat Commun. 2017 Jul 28;8(1):153
Knittel G, Rehkämper T, Korovkina D, Liedgens P, Fritz C, Torgovnick A, Al-Baldawi Y, Al- Maarri M, Cun Y, Fedorchenko O, Riabinska A, Beleggia F, Nguyen PH, Wunderlich FT, Ortmann M, Montesinos-Rongen M, Tausch E, Stilgenbauer S, P Frenzel L, Herling M, Herling C, Bahlo J, Hallek M, Peifer M, Buettner R, Persigehl T, Reinhardt HC
(See online at https://doi.org/10.1038/s41467-017-00210-6) - Actionable perturbations of damage responses by TCL1/ATM and epigenetic lesions form the basis of T-PLL. Nat Commun. 2018 9(1), 1-22
Schrader A, Crispatzu G, Oberbeck S, Mayer P, Pützer S, von Jan J, Vasyutina E, Warner K, Weit N, Pflug N, Braun T, Andersson EI, Yadav B, Riabinska A, Maurer B, Ventura Ferreira MS, Beier F, Altmüller J, Lanasa M, Herling CD, Haferlach T, Stilgenbauer S, Hopfinger G, Peifer M, Brümmendorf TH, Nürnberg P, Elenitoba-Johnson KSJ, Zha S, Hallek M, Moriggl R, Reinhardt HC, Stern MH, Mustjoki S, Newrzela S, Frommolt P, Herling M
(See online at https://doi.org/10.1038/s41467-017-02688-6) - MPK-1/ERK pathway regulates DNA damage response during development through DAF-16/FOXO. Nucleic Acids Res. 2018 Jul 6;46(12):6129-6139
Bianco J, Schumacher B
(See online at https://doi.org/10.1093/nar/gky404) - The Cdkn1aSUPER mouse as a novel tool to study p53-mediated tumor suppression. Cell Rep. 2018 Oct 23;25(4), 1027–1039.e6
Torgovnick A, Heger JM, Liaki V, Isensee J, Schmitt A, Knittel G, Riabinska A, Beleggia F, Laurien L, Leeser U, Jüngst C, Siedek F, Vogel W, Klümper N, Nolte H, Wittersheim M, Tharun L, Castiglione R, Krüger M, Schauss A, Perner S, Pasparakis M, Büttner R, Persigehl T, Hucho T, Herter-Sprie GS, Schumacher B, Reinhardt HC
(See online at https://doi.org/10.1016/j.celrep.2018.09.079) - UBQLN4 represses homologous recombination and is overexpressed in aggressive tumors. Cell. 2019 Jan 24;176(3):505-519.e22
Jachimowicz RD, Beleggia F, Isensee J, Bhavana VB, Goergens J, Bustos MA, Doll MA, Shenoy A, Checa-Rodriguez C, Wiederstein JL, Baranes-Bachar K, Bartenhagen C, Hertwig F, Teper N, Nishi T, Schmitt A, Distelmaier F, Lüdecke HJ, Albrecht B, Krüger M, Schumacher B, Geiger T, Hoon DSB, Huertas P, Fischer M, Hucho T, Peifer M, Ziv Y, Reinhardt HC, Wieczorek D, Shiloh Y
(See online at https://doi.org/10.1016/j.cell.2018.11.024) - Reinstated p53 response and high anti-T-cell leukemia activity by the novel alkylating deacetylase inhibitor tinostamustine. Leukemia. 2020 34(9), 2513-2518
Pützer S, Varghese L, von Jan J, Braun T, Giri AK, Mayer P, Riet N, Timonen S, Oberbeck S, Kuusanmäki H, Mustjoki S, Stern MH, Aittokallio T, Newrzela S, Schrader A, Herling M
(See online at https://doi.org/10.1038/s41375-020-0772-6)
