Combining Unbiased Network Analysis And Cancer Genomics To Guide Precision Medicine-Oriented Early Phase Clinical Trials

Background: Precision medicine aims to tailor cancer therapies to target specific tumor-promoting aberrations. For tumors that lack actionable drivers, extensive molecular characterization and preclinical drug efficacy studies will be required to match a patient with the appropriate targeted therapy. Patients and Methods: Next-generation sequencing, high-throughput signaling network analysis, and drug efficacy trials were used in a tumor-derived cell line and a patient-derived xenograft (PDX) model to identify actionable targets for therapeutic intervention. Results: A patient-derived xenograft (PDX) model for preclinical research was successfully established and no actionable mutations were identified after whole exome sequencing of the patient’s DNA. Whole genome sequencing revealed amplification of the 3q and 5p chromosomal arms, which include the PIK3CA and RICTOR genes, respectively. Consistent with amplification of these genes, pathway analysis revealed activation of the AKT pathway. Based on this analysis, efficacy of PIK3CA and AKT inhibitors were evaluated, and response to the AKT inhibitor AZD5363 was observed in in vitro and in vivo models established from the patient’s biopsy, indicating the patient would benefit from targeted therapies directed against the serine/threonine kinase AKT. Conclusion: High-throughput signaling pathway analysis complements next-generation sequencing approaches for detection of actionable alterations and will aid in patient stratification into early-phase clinical trials. Citation Format: Pedro Torres-Ayuso, Sudhakar Sahoo, Christopher Chester, Cassandra Hodgkinson, Melanie Galvin, Hui Sun Leong, Kristopher Frese, Richard Marais, Caroline Dive, Matthew Krebs, John Brognard. Combining unbiased network analysis and cancer genomics to guide precision medicine-oriented early-phase clinical trials [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A185.