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. Furthermore, long-term survivors suffer from severe treatment-associated morbidity. Hence, new therapies with better efficacy and less side-effects are urgently needed. In tumors of Group 3 MB patients high levels of the transcription factor and oncogene MYC, for example, predict a particularly poor outcome. At the same time, MYC-amplified Group 3 MB cell lines are highly susceptible to class I histone deacetylase (HDAC) inhibitor treatment. Considering special features of MB subgroups, we are currently developing novel treatment approaches.
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-signalling 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, however, 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. OIS therefore prevents successful establishment of primary cultures. Furthermore, OIS influences the tumor microenvironment by inducing the secretion of inflammatory factors.
We established a novel long-term expandable in vitro PA model by genetic modulation of OIS in primary PA cells. This model is currently being used for medium-scaled drug screening for preclinical drug development, as well as analysis of inflammatory signaling in PA and the tumor microenvironment.
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 the majority of cases (93%) and leads to informed clinical decision-making (41% of cases). 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. Selt F, Hohloch J, Hielscher T, Sahm F, Capper D, Korshunov A, Usta D, Brabetz S, Ridinger J, Ecker J, Oehme I, Gronych J, Marquardt V, Pauck D, Bächli H, Stiles CD, von Deimling A, Remke M, Schuhmann MU, 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.
2. 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.
3. 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.
4. 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.
5. 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.