In most cases, targeted monotherapies do not elicit durable responses, with resistance developing due to acquisition of new genetic alterations or by selection of primarily resistant subclones. It is therefore of crucial importance to develop rational combination therapies based on an understanding of these resistance mechanisms gained through preclinical testing in faithful patient-derived xenograft (PDX) models.
In TORPEDO, each group will focus on one tumor entity or subgroup, and aims to identify at least one rational combination therapy approach based on solid preclinical evidence (primary goal).Until now we have molecularly characterized >150 orthotopic PDX models of pediatric brain tumors representing 26 distinct molecular subtypes, including subtypes for which there were no preclinical models available yet. All molecular data of the PDX models and their associated primary tumors are available via the online tool called ‘PDX Explorer”, developed within this project.More specifically, in a MET-driven high-grade glioma model it could be shown that there is a synergistic effect when combining the MET inhibitor capmatinib (recently approved by the FDA for us in lung cancer) with radiotherapy.
Furthermore, drug screenings were performed in aggressive medulloblastoma tumors (high-risk MYC amplified) in order to identify if any of these single drugs would have synergistic effects with a the class I HDACi eninostat (which is already used as treatment agent): 17 drugs showed a potentially synergistic cytotoxic effect in MYC amplified cell lines and are under further investigation.
Data integration studies identified sources of intratumoral heterogeneity within Ewing sarcoma tumors and high throughput drug screening identified potential hits to target these heterogeneous populations. Treatment of PDX derived short term culture and PDX models with inhibitors of specific, identified pathways provided therapeutic efficacy in these models.In another WP, more than 90 PDX models have been established within the MAPPYACTS trial: here the goal was to assess the anti-proliferative potential of epigenetically modifying drugs: especially the EZH2 inhibitor EPZ011989-8 and the HDAC inhibitors vorinostat (inhibiting HDACs 1, 2, 3, 6, 8), mocetinostat (inhibiting HDACs 1, 2, 3, 11), panobinostat (inhibiting HDACs 1-11) were screened in vitro using live cell imaging (Incucyte) and/or MTS for their impact on cell proliferation.
Another WP worked on the establishment of organoid cultures of different tumor entities (amongst are Neuroblastom). Compound screening assays were used to identify potential compound interventions that overcome resistance.
Furthermore, a potential therapeutic value of DNMTi in the treatment of bone sarcomas could be identified. Thus, we were able to develop rational combination therapies for different childhood solid malignancies within this joint venture project TORPEDO