Abstract 523: Minnelide as a potential treatment strategy for CIC::DUX4 sarcoma
Bibliographic record
Abstract
Background: CIC::DUX4 Sarcoma (CDS) is driven by t(4;19) or t(10;19) chromosomal translocations and is associated with high rates of metastasis, chemoresistance, and poor outcomes. Previously classified as “Ewing-like sarcoma” due to overlapping morphological and immunobiological features, CDS differs from Ewing sarcoma in several key aspects: it rarely arises in bone, lacks the Ewing-defining ETS gene fusion, and has a more aggressive clinical course. Despite recent reclassification by the World Health Organization as its own entity, CDS patients are still treated with ineffective Ewing-based chemotherapies. This study evaluates the therapeutic potential of 160 compounds in human CDS cells, identifying Triptolide as a top candidate. Minnelide, the water-soluble prodrug of Triptolide, is currently undergoing Phase I/II trials for various cancers, including pancreatic and gastric cancer. Methods: We conducted a viability drug screen on human CDS cells using a Tocriscreen compound library. The top hit, Triptolide, was subsequently validated using its water-soluble prodrug, Minnelide, which replicated the screen results. To investigate the mechanism of action, cells were treated for 72 hours at the IC50 concentration and processed for RNA sequencing. Finally, we modeled CDS by generating subcutaneous xenograft tumors in immunodeficient NSG mice. Mice were transplanted with CDS tumor-derived cells and treated with Minnelide (or vehicle control) once daily for 21 days. The drug doses (0.21 mg/kg and 0.27 mg/kg) were selected based on bioavailability data and maximum tolerability observed in Phase I/II clinical trials. Results: Minnelide treatment decreased CDS cell viability and significantly reduced the growth of CIC::DUX4 sarcoma xenografts within 21 days. The Phase I clinical trial data indicates that the recommended starting dose for patients is 0.67 mg/m2, which corresponds to a dosage of 0.21 mg/kg in mice. The average tumor volume of the 0.21 mg/kg Minnelide treatment group was significantly (two-way ANOVA, P = 0.0001) lower than that of the control group at day 21 post-treatment initiation. Moreover, drug treatment was not associated with any adverse side effects. RNA sequencing and western blot analysis of CDS cells treated with Minnelide revealed downregulation of many CIC::DUX4 target genes, such as ETV1/4/5 and DUSP6. These results suggest that Minnelide alters the CDS transcriptional program and could represent an efficacious treatment alternative. Conclusion: Therapeutic advancements for CIC::DUX4 sarcoma have been limited to date, and there are currently no clinical trials available for CDS patients. Our findings demonstrate that Minnelide effectively reduces CDS cell viability and xenograft growth, while downregulating key CIC::DUX4 target genes. Given the role of CIC::DUX4 as a potent transcriptional activator, Minnelide's disruption of this activation may offer a promising therapeutic approach for CDS. Citation Format: MaKenna R. Browne, Peter G. Hendrickson, David G. Kirsch. Minnelide as a potential treatment strategy for CIC::DUX4 sarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 523.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.004 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".