Ex vivo drug testing in an ultra-rare sarcoma reveals therapeutic vulnerability and resistance

Solitary fibrous tumors (SFTs) are rare soft tissue sarcomas for which therapeutic options are limited and ineffective. We successfully demonstrated how functional personalized treatment was implemented in the clinic for an ultra-rare sarcoma with otherwise limited options, through a combined strategy of patient-derived model development and computational drug analytics. Molecular profiling of tumours and patient-derived models uncovered potential biomarkers to predict responses to specific drugs. We generated patient-derived SFT cells (PDSC) and used a computational combinatorial drug screening analytics platform, Quadratic Phenotypic Optimization Platform (QPOP), to determine therapeutic vulnerability and resistance in an ultra-rare locally recurrent brain SFT and its distant liver metastasis. QPOP derived and ranked the efficacy of 531,441 drug combinations, revealing BETi-pazopanib synergy in the liver lesion that outperforms standard-of-care combination doxorubicin-ifosfamide, which was antagonistic. In tumour and PDSC from the pazopanib-resistant brain lesion, transcriptomic analyses identified the UGT1A family as potential biomarkers of pazopanib resistance. Eribulin sensitivity was predicted to be shared across both lesions. Our patient was therefore treated with eribulin and successfully gained clinically meaningful disease control. ### Competing Interest Statement EKC is a shareholder of KYAN Therapeutics. ### Clinical Trial NCT04986748 ### Funding Statement This work was supported by the National Medical Research Council Transition Award (TA20nov-0020), SingHealth Duke-NUS Oncology Academic Clinical Programme (08/FY2020/EX/67-A143 and 08/FY2021/EX/17-A47), the Khoo Pilot Collaborative Award (Duke-NUS-KP(Coll)/2022/0020A), the National Medical Research Council Clinician Scientist-Individual Research Grant-New Investigator Grant (CNIGnov-0025), the National Research Foundation Cancer Science Institute of Singapore RCE Main Grant and the Ministry of Education Academic Research Fund (MOE AcRF Tier 2 [MOE2019-T2-1-115]). CJO is supported by the National Medical Research Council Clinician Scientist-Individual Research Grant (CIRG21jun-0038). VSY is supported by the National Medical Research Council Transition Award (TA20nov-0020). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committee of the SingHealth Centralized Institution Review Board (CIRB-2018/3182) and the National University of Singapore Institutional Review Board (NUS-IRB-2021-251) gave ethical approval for this work I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors * SFT: : Solitary fibrous tumour STS: : Soft tissue sarcoma PDSC: : Patient-derived SFT cells WHO: : World Health Organization QPOP: : Quadratic Phenotypic Optimization Drug Screening Platform OACD: : Orthogonal array composite design IC 50 : half maximal inhibitory concentration RSM: : Response surface mapping MRI: : Magnetic resonance imaging CT: : Computed tomography CTCF: : Corrected total cell fluorescence GDSC: : Genomics of Drug Sensitivity FPKM: : Fragments per kilobase of transcript per million mapped reads GSEA : Gene set enrichment analysis F a : Fraction affected CI: : Combination Index FDR: : False discovery rate CPM: : Counts per million BBB: : Blood brain barrier