Systemic therapy for metastatic clear cell sarcoma (CCS) bearing EWSR1-CREB1/ATF1 fusions remains an unmet clinical need in children, adolescents, and young adults.
To identify key signaling pathway vulnerabilities in CCS, a multi-pronged approach was taken: (i) genomic and transcriptomic landscape analysis, (ii) integrated chemical biology interrogations, (iii) development of CREB1/ATF1 inhibitors, and (iv) antibody-drug conjugate testing (ADC). The first approach encompassed DNA exome and RNA deep sequencing of the largest human CCS cohort yet reported consisting of 47 patient tumor samples and 8 cell lines.
Sequencing revealed recurrent mutations in cell cycle checkpoint, DNA double-strand break repair or DNA mismatch repair genes, with a correspondingly low to intermediate tumor mutational burden. DNA multi-copy gains with corresponding high RNA expression were observed in CCS tumor subsets. CCS cell lines responded to the HER3 ADC patritumab deruxtecan in a dose-dependent manner in vitro, with impaired long term cell viability.
These studies of the genomic, transcriptomic and chemical biology landscape represent a resource ‘atlas’ for the field of CCS investigation and drug development. CHK inhibitors are identified as having potential relevance, CREB1 inhibitors non-dependence of CCS on CREB1 activity was established, and the potential utility of HER3 ADC being used in CCS is found.
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DNA and RNA sequencing data performed for this manuscript is available for access through the EGA repository as Dataset: EGAD00001008611, Study: EGAS00001006072.
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We thank Drs. William Tap, Robert Maki, Lia Gore, Carrye Cost, Margaret Macy, and Robin Jones for assistance with therapeutic agent selection for the chemical screen. We are grateful for technical assistance of Kenneth Crawford. We are grateful to Daiichi Sankyo who provided materials for ADC studies. We thank Drs. Miguel Rivera, Emely Möller and Nicolò Riggi for histone track data related to their publication.
This work was supported by The Sara’s Cure Foundation, Rocker Collier Foundation and Golf Fights Cancer. We thank the Sam Day Foundation for funding for patient sample processing & sequencing through the CuReFast program at cc-TDI.org. DEF gratefully acknowledges support from the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, and NIH Grants 5R01AR043369–25, 5R01CA222871–04, 5P01CA163222–08, and 5R01AR072304–05.
CK has sponsored research agreements with Eli Lily, Roche-Genentech and Cardiff Oncology as well as recent collaborations with Novartis, and is co-founder of Tio Companies. Artisan Biopharma is a wholly-owned subsidiary of cc-TDI. PS has received honoraria from Blueprint Medicines, consults with Deciphera, Ellipses Pharma, Blueprint Medicines,Transgene, Exelixis, Boehringer Ingelheim, Ysios Capital, Studiecentrum voor Kernenergie, Modus Outcomes, Curio Science, SQZ Biotechnology, CRT Pioneer Fund LP, Adcendo, PharmaMar, Merck Healthcare KGaA, Advance Medical/Teladoc Health, and receives research funding from CoBioRes NV, Eisai, G1 Therapeutics, PharmaMar, Genmab, Merck, Sartar Therapeutics, and ONA Therapeutics. DEF has a financial interest in Soltego, a company developing salt inducible kinase inhibitors for topical skin-darkening treatments that might be used for a broad set of human applications. The interests of DEF were reviewed and are managed by Massachusetts General Hospital and Partners HealthCare in accordance with their conflict of interest policies. NEB is founder of First Ascent Biomedical.
Under institutional review board/human studies ethics committee approvals, de-identified CCS tissue samples were collected from the CuReFast Biobank (Advarra, protocol # cc-TDI-IRB-1), The Royal Marsden Hospital, Universitaire Ziekenhuizen Leuven (University Hospitals Leuven) and the European Organization for Research and Treatment of Cancer (EORTC) 90101 CREATE study . All patients gave written informed consent under approved institutional ethics board protocols (REB# 01–0138-U) and studies were conducted according to the Declaration of Helsinki.
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Rasmussen, S.V., Wozniak, A., Lathara, M. et al. Functional genomics of human clear cell sarcoma: genomic, transcriptomic and chemical biology landscape for clear cell sarcoma. Br J Cancer 128, 1941–1954 (2023). https://doi.org/10.1038/s41416-023-02222-0