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Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/212624
Expansion of a Malignant Peripheral Nerve Sheath Tumor preclinical platform and its application in a high-throughput screening strategy to identify novel drug treatments
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[eng] Malignant Peripheral Nerve Sheath Tumors (MPNSTs) are aggressive soft-tissue sarcomas. They usually appear in the clinical context of Neurofibromatosis type 1 (NF1), however, they also occur at a low frequency in the general population. There is a medical need to develop new therapies to treat MPNSTs as they are the leading cause of death in NF1 patients, and the five-year survival rate is low. Additionally, the intrinsic heterogeneity of MPNSTs complicates their histological classification, particularly in sporadic cases.
For several years, our group has been collecting patient MPNSTs to develop a preclinical platform of cell lines and patient-derived orthotopic xenograft (PDOX) mouse models to study MPNST biology, as well as to use them to conduct preclinical trials and personalized medicine strategies. Through using this platform, this PhD thesis centers on two main objectives: the identification of new synergistic drug combinations to treat MPNSTs from a high-throughput screening (HTS) of a large library of almost 2,000 drugs and the expansion of the platform by comprehensively characterizing six primary tumors diagnosed as MPNSTs and their derived PDOX and cell line models.
HTS identified a total of 113 synergistic pairwise drug combinations, from which we selected 21 according to two synergy models (Bliss Independence and Highest Single Agent) and their targeted pathways. We tested these combinations to replicate the observed synergy in vitro using several tumor-derived cell lines, some of them derived by our group. The combination of MK-1775 (a WEE1 inhibitor) with Doxorubicin (a DNA Topoisomerase II inhibitor) is the only one presenting synergy in most cell lines, especially in those with gene TP53 mutated, significantly reducing the tumor growth rate in PDOX models.
Regarding the second objective, the three cell models and six PDOXs generated from the six primary tumors clinically diagnosed as MPNSTs faithfully recapitulate the patients’ main genomic and histological features. Notably, we have generated three pairs of in vitro-in vivo models derived from the same primary tumors for the preclinical platform. The study of the six primary tumors was performed at different levels: 1) genetically, by analyzing the mutational status of the most recurrently mutated tumor suppressor genes in MPNSTs (NF1, CDKN2A, and SUZ12/EED from PRC2), and the mutational burden and signatures; 2) epigenetically, by analyzing the methylome profile of the three cell lines for molecular tumor classification; and
3) histologically, by analyzing the expression of markers clinically relevant for MPNST (SOX10, S100B, H3K27me3). The results illuminated the clinical reality of MPNSTs, finding that three of
the tumors (all sporadic cases) presented features incompatible with their initial clinical classification as MPNSTs and were thus reclassified as distinct tumor entities.
In conclusion, our preclinical platform is a bona fide tool for the study of MPNSTs since it is representative of the clinical diversity of tumors diagnosed as MPNSTs, as well as being an excellent tool to test and identify novel therapeutic approaches.
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CREUS BACHILLER, Edgar. Expansion of a Malignant Peripheral Nerve Sheath Tumor preclinical platform and its application in a high-throughput screening strategy to identify novel drug treatments. [consulta: 10 de desembre de 2025]. [Disponible a: https://hdl.handle.net/2445/212624]