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Identification of Novel Therapeutic Targets for Fibrolamellar Carcinoma Using Patient-Derived Xenografts and
Gadi Lalazar1,2, David Requena1, Lavoisier Ramos-Espiritu3
1Laboratory of Cellular Biophysics, The Rockefeller University, New York, New York.
Abstract:
To repurpose therapeutics for fibrolamellar carcinoma (FLC), we developed and validated patient-derived xenografts (PDX) from surgical resections. Most agents used clinically and inhibitors of oncogenes overexpressed in FLC showed little efficacy on PDX. A high-throughput functional drug screen found primary and metastatic FLC were vulnerable to clinically available inhibitors of TOPO1 and HDAC and to napabucasin. Napabucasin's efficacy was mediated through reactive oxygen species and inhibition of translation initiation, and specific inhibition of eIF4A was effective. The sensitivity of each PDX line inversely correlated with expression of the antiapoptotic protein Bcl-xL, and inhibition of Bcl-xL synergized with other drugs. Screening directly on cells dissociated from patient resections validated these results. This demonstrates that a direct functional screen on patient tumors provides therapeutically informative data within a clinically useful time frame. Identifying these novel therapeutic targets and combination therapies is an urgent need, as effective therapeutics for FLC are currently unavailable. SIGNIFICANCE: Therapeutics informed by genomics have not yielded effective therapies for FLC. A functional screen identified TOPO1, HDAC inhibitors, and napabucasin as efficacious and synergistic with inhibition of Bcl-xL. Validation on cells dissociated directly from patient tumors demonstrates the ability for functional precision medicine in a solid tumor.This article is highlighted in the In This Issue feature, p. 2355.
Insights
This study developed patient-derived xenografts for fibrolamellar carcinoma (FLC) drug discovery. Functional screening identified novel therapies, including TOPO1, HDAC inhibitors, and napabucasin, offering new hope for FLC treatment.
Area of Science:
- Oncology
- Drug Discovery
- Precision Medicine
Background:
- Fibrolamellar carcinoma (FLC) lacks effective therapeutics, with genomic approaches showing limited success.
- Patient-derived xenografts (PDX) were developed to model FLC for drug repurposing and discovery.
- Existing clinical agents and oncogene inhibitors demonstrated minimal efficacy in preclinical FLC models.
Purpose of the Study:
- To identify effective therapeutic agents and combination strategies for FLC through functional drug screening.
- To validate the utility of patient-derived models and direct patient cell screening for precision medicine in FLC.
- To uncover novel drug targets and therapeutic vulnerabilities in FLC.
Main Methods:
- Development and validation of patient-derived xenografts (PDX) from surgical FLC resections.
- High-throughput functional drug screening on PDX models and patient-derived cells.
- Assessment of drug efficacy, mechanisms of action (reactive oxygen species, translation initiation), and synergistic effects.
Main Results:
- FLC PDX models were largely unresponsive to standard clinical agents and oncogene inhibitors.
- Functional screening identified efficacy of topoisomerase 1 (TOPO1) and histone deacetylase (HDAC) inhibitors, and napabucasin.
- Napabucasin's efficacy involved reactive oxygen species and translation initiation inhibition, with specific eukaryotic initiation factor 4A (eIF4A) inhibition also effective.
- Tumor sensitivity inversely correlated with antiapoptotic BCL-2 like 1 (Bcl-xL) expression; Bcl-xL inhibition showed synergistic effects.
- Direct screening on patient-derived cells validated the identified therapeutic strategies.
Conclusions:
- Functional drug screening on patient-derived models provides therapeutically relevant data for FLC within a clinically actionable timeframe.
- Novel therapeutic targets including TOPO1, HDAC, napabucasin, and Bcl-xL, along with combination strategies, show promise for FLC treatment.
- This approach demonstrates the potential for functional precision medicine in solid tumors like FLC, addressing an unmet clinical need.
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