Research Objectives: to understand how high-grade soft tissue sarcomas, such as Malignant Peripheral Nerve Sheath Tumors (MPNSTs), grow and how to treat them more efficiently.
The Torres Laboratory's research has provided a molecular epigenetic understanding and rationale for epigenetic therapeutic strategies for patients who suffer from high-grade sarcomas, such as MPNSTs. We have developed multiple cell line models and patient-derived xenograft models of rare sarcomas for deeper study into the molecular mechanisms driving progression in these diseases.
- Epigenetic regulation of sarcomas: Up to 70–90% of MPNSTs carry mutations in the genes of the polycomb repressive complex 2 (PRC2) components SUZ12 and EED, and demonstrate loss of histone 3 lysine 27 trimethylation (H3K27me3). These genes, along with EZH2 (the catalytic subunit of PRC2), are part of the polycomb repressive complex 2 (PRC2) that modifies histone 3 and silences genes necessary for tumor growth. Building on this finding, the Torres Lab is systematically examining chromatin (DNA and histones) structure modifications in human MPNSTs.
- Model development for sarcomas: The limited number of available sarcoma cell lines makes studying sarcomas in a laboratory setting challenging. One of the long-standing goals of the Torres Lab is to generate additional cell lines and patient-derived xenografts to further the study of these rare cancers. Cell line models that can form tumors in mice are valuable tools to advance the understanding of soft tissue sarcomas like MPNST that lack known genetic drivers.
- Early detection and monitoring of tumor progression: Identifying malignant transformation with current methods is challenging because malignant transformation may not be apparent from standard imaging and monitoring approaches for NF1-affected individuals with plexiform or atypical neurofibromas. Further, biopsies around a nerve are very painful and may be inconclusive, given the heterogeneous nature of MPNSTs. To address this issue, the Torres Lab is investigating blood-based biomarkers that can serve as a non-invasive diagnostic tool for MPNSTs. Non-invasive cfDNA-based biomarkers could potentially transform MPNST treatment by facilitating early and accurate minimally invasive diagnosis, evaluation of response to therapy, and surveillance, and by consequently expediting appropriate treatment, thereby improving patient survival.
- Comparative oncology studies: Although some of the epigenetic drivers in MPNSTs are defined, the rarity of MPNSTs presents challenges to performing informative clinical trials. Further, the inability of laboratory animal models, such as mice, to fully recapitulate the complex genetic, biological, and environmental factors driving complex diseases such as MPNST has impeded the identification of effective therapies for these patients. To address this problem, the Torres Lab applies comparative oncology approaches to identify evolutionarily conserved genomic and epigenomic defects across species.