Title: Targeting Of Resistance in PEDiatric Oncology
Michael PFISTER (Germany) German Cancer Research Center, Division of Pediatric Neurooncology, Heidelberg
Olaf WITT (Germany) German Cancer Research Center, CCU Pediatric Oncology, Heidelberg
Gudrun SCHLEIERMACHER (France) Institut Curie, U830 Inserm and Department of Pediatric Oncology, Paris
Georger BIRGIT (France) Gustave Roussy, UMR 8203 CNRS and Department of Pediatric and Adolescent Oncology, Villejuif
Jan MOLENAAR (Netherlands) Department of Onco-genomics AMC-UVA, Amsterdam
Katia SCOTLANDI (Italy) Rizzoli Institute, CRS Development of Biomolecular Therapies, Bologna
a. Background and rationale: As a consortium, we have established a harmonized next-generation diagnostic infrastructure for relapsed childhood malignancies across several European countries to match patients to targeted drugs and recruit them into early phase clinical trials.
b. Hypothesis: In most cases, targeted monotherapies do not elicit durable responses, with resistance developing due to acquisition of new genetic alterations or by selection of a resistant subclone from a heterogeneous tumor mass. It is therefore of crucial importance to develop rational combination therapies based on an understanding of these resistance mechanisms gained through longitudinal sampling of patients and preclinical testing in faithful patient-derived xenograft (PDX) models.
c. Aims (primary and secondary): 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). A secondary goal is the generation of a shared resource of molecularly well characterized PDX models across all subgroups and genotypes for further preclinical experiments.
d. Methods: Collectively, we have already generated a repertoire of 65 PDX models (Table 1), which will be shared within the consortium as necessary for this project and beyond (e.g., for common targets across entities). All sites will additionally establish new models to extend this repertoire throughout the course of this project. Tumor-bearing orthotopic PDX mice will be treated with an (initially) effective monotherapy until the tumor progresses, at which point the tumor will be subjected to molecular profiling. Based on the resistance mechanism (also considering information from longitudinal patient samples with a similar genotype), a combination therapy will be designed and efficacy compared against the monotherapy. Furthermore, it will be molecularly determined, whether the resistance mechanism was rather a de novo event (acquired resistance) or selection of a pre-existing subclone. These clonality analyses will be performed in the in vivo model systems as well as in longitudinal patient samples.
e. Expected results and potential impact: Expected results include (i) the development of rational combination therapies for different childhood solid malignancies to be tested as a next wave of clinical trials within the ITCC early phase clinical trial consortium (http://www.itcc-consortium.org), with which the applicants are closely associated; (ii) the identification of common resistance mechanisms to targeted drugs; (iii) the establishment of a joint European repertoire of molecularly well-characterized PDX models and (iv) an increased understanding about the role of tumor subclone heterogeneity in determining the response to targeted drugs. All of these results will significantly enhance the repertoire of treatment options for relapsed childhood malignancies.
(Project funded under JTC 2014)