A Functional Precision Oncology Approach to Identify Treatment Strategies for Myxofibrosarcoma Patients.

Autor:	Pauli C; Department of Pathology and Molecular Pathology, University Hospital Zurich, Zurich, Switzerland. chantal.pauli@usz.ch., De Boni L; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York., Pauwels JE; Englander Institute for Precision Medicine, Weill Cornell Medicine-New York Presbyterian Hospital. New York, New York., Chen Y; Department of Pathology and Molecular Pathology, University Hospital Zurich, Zurich, Switzerland., Planas-Paz L; Department of Pathology and Molecular Pathology, University Hospital Zurich, Zurich, Switzerland., Shaw R; SEngine Precision Medicine, Seattle, Washington., Emerling BM; Cancer Metabolism and Signaling Networks, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California., Grandori C; SEngine Precision Medicine, Seattle, Washington., Hopkins BD; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York., Rubin MA; Englander Institute for Precision Medicine, Weill Cornell Medicine-New York Presbyterian Hospital. New York, New York.; Department for BioMedical Research, Bern, Switzerland.
Jazyk:	angličtina
Zdroj:	Molecular cancer research : MCR [Mol Cancer Res] 2022 Feb; Vol. 20 (2), pp. 244-252. Date of Electronic Publication: 2021 Nov 02.
DOI:	10.1158/1541-7786.MCR-21-0255
Abstrakt:	In this era of precision medicine, numerous workflows for the targeting of high-recurrent mutations in common tumor types have been developed, leaving patients with rare diseases with few options. Here, we implement a functional precision oncology approach utilizing comprehensive genomic profiling in combination with high-throughput drug screening, to identify tumor-specific drug sensitivities for patients with rare tumor types such as myxofibrosarcoma. From a patient with a high-grade myxofibrosarcoma, who was enrolled in the Englander Institute for Precision Medicine (EIPM) program, we established patient-derived 3D sarco - spheres and xenograft models for functional testing. In the absence of a large cohort of clinically similar cases, high-throughput drug screening was performed on the patient-derived cells, and compared with two other myxofibrosarcoma lines and a benign fibroblast line to functionally identify tumor-specific drug sensitivities. The addition of functional drug sensitivity testing to complement genomic profiling identified multiple therapeutic options that were further validated in patient derived xenograft models. Genomic analyses detected the frequently known codeletion of the tumor suppressors CDKN2A/B together with the methylthioadenosine phosphorylase ( MTAP ) and a TP53 E286fs*50 mutation. High-throughput drug screening demonstrated tumor-specific sensitivity to compounds targeting the cell cycle. Based on genomic analysis and high-throughput drug screening, we show that targeting the cell cycle in these tumors is a powerful approach. IMPLICATIONS: This study demonstrates the potential of functional testing to aid clinical decision making for patients with rare or molecularly complex malignancies when combined with comprehensive genomic profiling. (©2021 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
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