PAX3-FOXO1 fusion

Here, We report a case of paratesticular alveolar rhabdomyosarcoma in an adult patient who initially complained of increased scrotal volume for two years and presented with a PAX3-FOXO1 fusion. This emphasizes the dire prognosis of the disease, reinforcing the need for thorough and directed diagnostic efforts.

We additionally show that, in some FP-RMS, KDM3A also increases PAX3-FOXO1 levels. Together, our studies illuminate mechanisms of action of the KDM3A/ETS1 regulatory module, and reveal novel targetable mechanisms of PAX3-FOXO1 chromatin complex regulation, in FP-RMS.

However, oncogenic fusions involving transcription factors such as PAX3-FOXO1 in alveolar fusion gene-positive rhabdomyosarcoma (FP-RMS) have been difficult to inhibit due to the apparent lack of tractable drug-like binding sites comparable to that recognized by Gleevec (imatinib mesylate) on the BCR-ABL1 tyrosine kinase fusion protein...To facilitate single-cell clonal isolation of knock-ins, the homology-directed repair template encoding HiBiT was followed by a P2A self-cleaving peptide for coexpression of an mCherry fluorescent protein as a fluorescence-activated cell sorter (FACS)-selectable marker. HiBiT tagging thus allows highly sensitive luminescence detection of endogenous PAX3-FOXO1 levels permitting quantitative high-throughput screening of large compound libraries for the discovery of PAX3-FOXO1 inhibitors and degraders.

These tumours have significant local recurrence rates but lack metastatic potential. Here, we report a case of BSNS with PAX3/FOXO1 fusion and discuss its clinicopathological features and differential diagnosis.

Thus, we report KDM inhibitors P3FI-63 and P3FI-90 with the highest specificity for KDM3B. Their potent suppression of PAX3-FOXO1 activity indicates a possible therapeutic approach for FP-RMS and other transcriptionally addicted cancers.

In the absence of CBP/p300, Pol2 long range enhancer loops collapse, Pol2 accumulates in CpG islands and fails to exit the gene body. These results reveal a potential novel axis for therapeutic interference with P3F in aRMS and clarify the molecular relationship of P3F and CBP/p300 in sustaining active Pol2 clusters essential for oncogenic transcription.

We show that NF-Y occupies CCAAT motifs present upstream of PAX3 to function as a transcriptional activator of PAX3-FOXO1 expression in RMS. These findings reveal a critical upstream role of NF-Y in the oncogenic PAX3-FOXO1 pathway, highlighting how a broadly essential transcription factor can perform tumor-specific roles in governing cellular state.

MRI was performed at every stage of diagnosis and treatment as well as during follow-up. It allowed for staging, monitoring of chemotherapy, and guided surgery.

Moreover, we provide evidence that the combination of futibatinib with currently used chemotherapies such as irinotecan and vincristine has a synergistic effect against RMS in vitro. Moreover, limited efficacy is only observed in a PAX3-FOXO1 fusion-negative (FN) RMS cell line with mutationally activated FGFR4, whereas little or no efficacy is observed in PAX3-FOXO1 fusion-positive (FP) RMS cell lines with FGFR4 overexpression. Alternative treatment modalities such as combining futibatinib with other kinase inhibitors or targeting FGFR4 with CAR T cells or antibody-drug conjugate may be more effective than the approaches tested in this study.

Moreover, it is a great tool to identify novel fusion genes. Overall, it provides useful information for molecular pathological diagnosis and improves the diagnosis rate of STSs.

Objective: LX-101, a next-generation, targeted therapy directed to the insulin-like growth factor 1 receptor (IGF-1R), consists of a proprietary IGF-1 variant coupled to a cytotoxic methotrexate (MTX) payload. These results demonstrate that LX-101 has potent preclinical anti-tumor activity against pediatric sarcoma cell lines with well-established ties to the IGF-1R pathway, including with different oncogenic gene fusions. These data further support the clinical development of LX-101 in IGF-1R-related pediatric cancers. A clinical trial is planned.

She initiated chemotherapy with vincristine, actinomycin and cyclophosphamide with 4500 cGY radiation therapy per COG ARST0531 and was disease-free at therapy completion. This case suggests RMS may be a rare manifestation of Lynch syndrome and highlights the importance of long-term follow-up and germline assessment for predisposition syndromes in children with RMS. This abstract was supported by the Sohn Conference Foundation.