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Generation of novel patient-derived CIC- DUX4 sarcoma xenografts and cell lines
Rieko Oyama1, Mami Takahashi2, Akihiko Yoshida3
1Department of Innovative Seeds Evaluation, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
Abstract:
CIC-DUX4 sarcoma (CDS) is a group of rare, mesenchymal, small round cell tumours that harbour the unique CIC-DUX4 translocation, which causes aberrant gene expression. CDS exhibits an aggressive course and poor clinical outcome, thus novel therapeutic approaches are needed for CDS treatment. Although patient-derived cancer models are an essential modality to develop novel therapies, none currently exist for CDS. Thus, the present study successfully established CDS patient-derived xenografts and subsequently generated two CDS cell lines from the grafted tumours. Notably, xenografts were histologically similar to the original patient tumour, and the expression of typical biomarkers was confirmed in the xenografts and cell lines. Moreover, the xenograft tumours and cell lines displayed high Src kinase activities, as assessed by peptide-based tyrosine kinase array. Upon screening 119 FDA-approved anti-cancer drugs, we found that only actinomycine D and doxorubicin were effectively suppress the proliferation among the drugs for standard therapy for Ewing sarcoma. However, we identified molecular targeting reagents, such as bortezomib and crizotinib that markedly suppressed the growth of CDS cells. Our models will be useful modalities to develop novel therapeutic strategies against CDS.
Insights
New patient-derived models for CIC-DUX4 sarcoma (CDS) were established, showing promise for developing targeted therapies. These models revealed bortezomib and crizotinib as effective treatments, unlike standard Ewing sarcoma drugs.
Area of Science:
- Oncology
- Cancer Biology
- Genetics
Background:
- CIC-DUX4 sarcoma (CDS) is a rare, aggressive small round cell tumor with a poor prognosis.
- Novel therapeutic strategies are urgently needed for CDS due to its aggressive nature.
- The absence of patient-derived cancer models hinders therapeutic development for CDS.
Purpose of the Study:
- To establish and characterize patient-derived xenografts (PDX) and cell lines for CIC-DUX4 sarcoma.
- To evaluate the efficacy of FDA-approved anti-cancer drugs against CDS models.
- To identify potential molecularly targeted therapies for CDS.
Main Methods:
- Generation of patient-derived xenografts (PDX) from CDS tumors.
- Establishment of CDS cell lines from PDX models.
- Histological and biomarker analysis of PDX and cell lines.
- Peptide-based tyrosine kinase activity profiling.
- Screening of 119 FDA-approved anti-cancer drugs.
Main Results:
- PDX models retained histological similarity and biomarker expression of original tumors.
- Established CDS cell lines exhibited high Src kinase activity.
- Actinomycin D and doxorubicin showed limited efficacy, unlike in Ewing sarcoma.
- Bortezomib and crizotinib demonstrated significant suppression of CDS cell growth.
Conclusions:
- Successfully established novel, reliable preclinical models for CIC-DUX4 sarcoma.
- Identified bortezomib and crizotinib as promising targeted therapies for CDS.
- These models will facilitate the development of new therapeutic strategies for CDS.
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