(P 196) THERAPEUTIC VULNERABILITY AND RESISTANCE DURING PROGRESSION OF AN AGGRESSIVE SOLITARY FIBROUS TUMOUR

Objective: Solitary fibrous tumours (SFTs) comprise a histologic spectrum of fibroblastic mesenchymal neoplasms characterised by pathognomonic NAB2-STAT6 gene fusions and STAT6 nuclear expression. SFTs of the central nervous system are rare entities; ventricular SFTs with metastatic potential are even more unusual, with only one other case reported previously. Surgical resection remains the primary treatment modality for most SFTs, however for patients who develop local recurrences and/or distant metastases, salvage systemic options are often limited and ineffective. We previously developed a high-throughput drug screening method – Quadratic Phenotypic Optimization Drug Screening Platform (QPOP) that was applied successfully in drug-resistant multiple myeloma. Here, we used QPOP for the discovery of therapeutic vulnerability and resistance to a drug panel in a locally recurrent ventricular SFT and its distant liver metastasis.

Methods: Early passage cell lines were derived from the patient’s liver metastasis and locally recurrent tumour. These were characterised by immunostaining of key SFT markers and detection of NAB2-STAT6 via transcriptomic analysis and RT-PCR. The QPOP analytic platform was used to rank all possible system-specific drug combinations from a 12-drug set. Pre-experimental selection of drug candidates included standard of care chemotherapy and agents which have shown signal in sarcomas, as well as other drugs such as epigenetic inhibitors and targeted therapies. Top QPOP-ranked drug combinations were evaluated by the combination index (CI) theorem of Chou-Talalay, while drug targeting was validated by immunofluorescence assay. RNAseq transcriptomic analysis was further performed to explore potential biomarkers associated with the differential treatment response.

Results: We applied the QPOP analytic platform to a rare case of ventricular SFT in a 33-year old lady with recurrence and development of distant metastasis. Transcriptomic sequencing and RT-PCR detected NAB2-STAT6 gene fusion accompanied by positive immunoreactivity to STAT6, Vimentin, BCL2, CD34, and ALDH1 confirm patient-derived SFT cells from both her liver metastasis and locally recurrent primary tumour. Dose-response drug sensitivity assays revealed Doxorubicin resistance in both samples, and Pazopanib sensitivity specific to the liver metastasis, consistent with clinicoradiological response. A QPOP-based combinatorial drug screen revealed distinct drug combination sensitivities between the paired samples, with enhanced BETi-pazopanib synergy in the metastatic liver lesion compared to the locally recurrent primary tumour, consistent with parabolic response surface mapping and further supported by the CI theorem. These results were corroborated by downregulated c-MYC and c-KIT expression and changes in early response genes associated with apoptosis following combinatorial treatment, compared with single drug treatment. In the locally recurrent primary lesion which showed clinicoradiological resistance to pazopanib, resistance was also recapitulated ex vivo. Transcriptomic analyses showed marked upregulation of UGT1A10 with pazopanib treatment.

Conclusion: We demonstrate the feasibility of an ex vivo patient-based drug sensitivity analytic approach in identifying therapeutic options in an ultra-rare soft tissue sarcoma. A novel BETi-pazopanib combination was more effective with enhanced synergy compared to standard of care treatment in the metastatic tumour. In SFT, UGT1A10 is a potential biomarker associated with pazopanib resistance.