PD Dr. med. Till Milde
Group leader "Brain tumor models"
German Cancer Research Center
CCU Pediatric Oncology / G817
Im Neuenheimer Feld 280
The focus of our group “Translational brain tumor modeling” headed by PD Dr. med. Till Milde, which is also part of the DKFZ Clinical Cooperation Unit “Pediatric Oncology” (headed by Prof. Dr. Olaf Witt), lies on the development of novel pediatric brain tumor models and the development of novel therapeutic strategies. We aim to understand the molecular basis of the origin, maintenance, progression and therapy resistance of pediatric brain tumors as well as the development of novel targeted treatment concepts.
Medulloblastoma (MB) comprises at least four different subgroups (WNT, SHH, Group 3 and Group 4) with highly differing clinical and molecular characteristics. Despite aggressive multimodal treatment, patients with medulloblastoma of high-risk subgroups show poor overall survival rates. More efficient therapies with less side-effects are urgently needed.
MYC-driven Group 3 MB tumors have a particularly poor outcome. MYC-amplified Group 3 MB models are highly susceptible to class I histone deacetylase (HDAC) inhibitor treatment. Our studies on the molecular interaction of MYC and the class I HDAC HDAC2 showed that HDAC2 is a direct co-factor of MYC in MYC amplified medulloblastoma. In addition, inhibition of class I HDACs directly targets MYC´s trans-activating and -repressing function, suggesting HDAC2 as an important target for new treatments of MYC amplified medulloblastoma. Based on these findings we are currently developing novel treatment approaches including novel combination therapies.
Pilocytic astrocytoma (PA) is a well circumscribed, slow growing, low-grade (WHO I) brain tumor. It is considered a single-pathway disease with an activated MAPK-signaling in nearly 100% of the cases. Despite an excellent survival prognosis (overall survival > 90%), incompletely resected PAs can recur or progress, and patients often suffer from disease- and therapy-related morbidity.
The development of much needed novel therapies has been hampered by a considerable lack of suitable preclinical PA models. Recent results suggest oncogene-induced senescence (OIS), a tumor suppressive mechanism present in PA cells, to be responsible for the observed slow growth of PA cells both in patients as well as in vitro, preventing successful establishment of primary cultures.
We established a novel long-term expandable in vitro PA model DKFZ-BT66 by genetic modulation of OIS in primary PA cells. We have shown that the senescence-associated secretory phenotype (SASP) is regulating OIS in pediatric pilocytic astrocytoma, and identified senolytic drugs as potential novel treatments for PA. Using a MAPK-specific reporter we have identified combinations of MEK-, ERK-, and RAF-inhibitors as potential therapies for PA. The model is currently being used for medium-scaled drug screening for preclinical drug development including different novel inhibitors of the MAPK-signaling cascade and senolytic drugs as well as analysis of inflammatory signaling in PA and the tumor microenvironment.
We aim at the establishment of novel patient-derived xenograft (PDX) models of and the discovery of novel drug-based approaches to the treatment for DADDR (Diseases with abnormal DNA damage repair) using medium- to large-scale drug screens. Optimal treatments should be both effective (i.e. have anti-tumoral effects) as well as non-toxic. A particular focus is on Li-Fraumeni syndrome diseases, including SHH-TP53 medulloblastoma.
The Pediatric Targeted Therapy (PTT) program aims to identify targetable alterations in tumor tissue from pediatric patients suffering from relapse or progression of their disease under standard of care treatment.
As we have previously shown, personalized diagnostics using immunohistochemistry on FFPE material is clinically feasible, yields actionable targets (e.g. HDACs, EGFR , PDGFR, MAPK/ERK and PI3K/mTOR) in many cases and leads to informed clinical decision-making. Using next generation diagnostic tools (gene panel sequencing, whole genome methylation array) in addition to a limited set of immunohistochemical stainings, the current program PTT2.0 now aims to improve the accuracy of target identification in order to yield measurable benefit for the patients.
1. Ecker J, Thatikonda V, Sigismondo G, Selt F, Valinciute G, Oehme I, Müller C, Buhl JL, Ridinger J, Usta D, et al., and Jäger N, Pfister SM, Witt O, Milde T. Reduced chromatin binding of MYC is a key effect of HDAC inhibition in MYC amplified medulloblastoma. Neuro Oncol. 2020 Aug 21:noaa191. doi: 10.1093/neuonc/noaa191. Online ahead of print. PMID: 32822486
2.Usta D, Sigaud R, Buhl JL, Selt F, Marquardt V, Pauck D, Jansen J, Pusch S, Ecker J, et al., and Pfister SM, Jones DTW, Remke M, Brummer T, Witt O, Milde T. A Cell-Based MAPK Reporter Assay Reveals Synergistic MAPK Pathway Activity Suppression by MAPK Inhibitor Combination in BRAF-Driven Pediatric Low-Grade Glioma Cells. Mol Cancer Ther. 2020 Aug;19(8):1736-1750. doi: 10.1158/1535-7163.MCT-19-1021. Epub 2020 May 25. PMID: 32451331
3. Buhl JL, Selt F, Hielscher T, Guiho R, Ecker J, Sahm F, Ridinger J, Riehl D, Usta D, Ismer B, et al., and Brummer T, Pfister SM, Jones DTW, Witt O, Milde T. The Senescence-associated Secretory Phenotype Mediates Oncogene-induced Senescence in Pediatric Pilocytic Astrocytoma. Clin Cancer Res. 2019 Mar 15;25(6):1851-1866. doi: 10.1158/1078-0432.CCR-18-1965. Epub 2018 Dec 7. PMID: 30530705
4. Selt F, Hohloch J, Hielscher T, Sahm F, Capper D, Korshunov A, Usta D, Brabetz S, Ridinger J, Ecker J, et al., and Pfister SM, Brummer T, Jones DT, Witt O, Milde T. Establishment and application of a novel patient-derived KIAA1549:BRAF-driven pediatric pilocytic astrocytoma model for preclinical drug testing. Oncotarget. 2017 Feb 14;8(7):11460-11479. doi: 10.18632/oncotarget.14004.
5. Selt F, Deiß A, Korshunov A, Capper D, Witt H, van Tilburg CM, Jones DT, Witt R, Sahm F, Reuss D, Kölsche C, Ecker J, Oehme I, Hielscher T, von Deimling A, Kulozik AE, Pfister SM, Witt O, Milde T. Pediatric targeted therapy: Clinical feasibility of personalized diagnostics in children with relapsed and progressive tumors. Brain Pathol. 2015 Oct 7. doi: 10.1111/bpa.12326.
6. Ecker J, Oehme I, Mazitschek R, Korshunov A, Kool M, Hielscher T, Kiss J, Selt F, Konrad C, Lodrini M, Deubzer HE, von Deimling A, Kulozik AE, Pfister SM, Witt O, Milde T. Targeting class I histone deacetylase 2 in MYC amplified group 3 medulloblastoma. Acta Neuropathol Commun. 2015 Apr 3;3:22. doi: 10.1186/s40478-015-0201-7.
7. Ecker J, Witt O, Milde T. Targeting of histone deacetylases in brain tumors. CNS Oncol. 2013 Jul;2(4):359-76. doi: 10.2217/cns.13.24.
8. Milde T, Lodrini M, Savelyeva L, Korshunov A, Kool M, Brueckner LM, Antunes AS, Oehme I, Pekrun A, Pfister SM, Kulozik AE, Witt O, Deubzer HE. HD-MB03 is a novel Group 3 medulloblastoma model demonstrating sensitivity to histone deacetylase inhibitor treatment. J Neurooncol. 2012 Dec;110(3):335-48. doi: 10.1007/s11060-012-0978-1. Epub 2012 Oct 6.