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Efficacy of Minnelide in a Next-Generation Dual-Recombinase Regulated Genetically Engineered Mouse Model of CIC::DUX4
MaKenna R Browne1,2,3, Axel V Silver4, Risha Banerjee4
1Cell and Molecular Biology Program, Duke University Medical Center, Durham, NC, USA.
Abstract:
CIC::DUX4 sarcoma (CDS) is a lethal cancer driven by a fusion between tumor suppressor Capicua (CIC) and pioneer transcription factor double homeobox 4 (DUX4). To develop an immunocompetent pre-clinical model of CDS, we previously generated three genetically engineered mouse models (GEMMs) of CDS with CIC::DUX4 regulated by loxP-STOP-loxP cassettes. However, all three models developed spontaneous tumors without Cre recombinase. Here, we established an innovative GEMM of CDS (dFLEx CDS) that employs a dual recombinase (Cre + FLPE) FLEx-switch design to activate CIC::DUX4 expression and initiate sarcomagenesis in a spatially and temporally-controlled manner. Because CIC::DUX4 drives sarcoma development by activating a distinct oncogenic transcriptional program, we performed a drug screen on human-derived CDS cell lines using a library of compounds that modulate transcriptional regulation. This screen identified Minnelide, an inhibitor of RNA polymerase II-mediated transcription, as a selective inhibitor of CDS. Mechanistically, Minnelide acted through xeroderma pigmentosum type B to alter phosphorylation of RPB1, the largest subunit of RNA polymerase II. Subsequently, RPB1 underwent degradation leading to apoptosis of CDS cells. Minnelide demonstrated in vivo efficacy in autochthonous dFLEx CDS GEMMs and in human CDS xenografts. As Minnelide has already been demonstrated to be safe in clinical trials with activity for adult cancers, these findings nominate Minnelide as a novel therapeutic option to test in CDS patients.
Insights
A new mouse model for CIC::DUX4 sarcoma (CDS) was created. Minnelide, an RNA polymerase II inhibitor, effectively targets CDS tumors, showing promise as a potential therapy for patients.
Area of Science:
- Oncology
- Genetics
- Pharmacology
Background:
- CIC::DUX4 sarcoma (CDS) is a fatal cancer driven by CIC-DUX4 fusion.
- Previous mouse models failed to control tumor initiation.
- A precise, inducible model is needed for preclinical studies.
Purpose of the Study:
- To develop a controllable, immunocompetent preclinical model for CDS.
- To identify targeted therapies for CDS by screening transcriptional regulators.
- To evaluate Minnelide as a potential CDS treatment.
Main Methods:
- Generation of a dual-recombinase (Cre/FLPE) FLEx-switch mouse model (dFLEx CDS) for inducible CIC::DUX4 expression.
- Drug screening of human CDS cell lines with transcriptional modulators.
- Mechanistic studies of Minnelide's effect on RNA polymerase II and CDS cells.
- In vivo efficacy testing in dFLEx CDS GEMMs and human xenografts.
Main Results:
- The dFLEx CDS model allows spatiotemporal control of sarcomagenesis.
- Minnelide selectively inhibited CDS cell growth by targeting RNA polymerase II.
- Mechanism involves RPB1 phosphorylation and degradation, leading to apoptosis.
- Minnelide showed efficacy in both mouse models and human xenografts.
Conclusions:
- The dFLEx CDS GEMM is a valuable tool for studying CDS.
- Minnelide is a promising, safe therapeutic candidate for CDS patients.
- Targeting RNA polymerase II offers a novel therapeutic strategy for CDS.
