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Ref Type Journal Article
PMID (37523146)
Authors Mayoh C, Mao J, Xie J, Tax G, Chow SO, Cadiz R, Pazaky K, Barahona P, Ajuyah P, Trebilcock P, Malquori A, Gunther K, Avila A, Yun DY, Alfred S, Gopalakrishnan A, Kamili A, Wong M, Cowley MJ, Jessop S, Lau LMS, Trahair TN, Ziegler DS, Fletcher JI, Gifford AJ, Tsoli M, Marshall GM, Haber M, Tyrrell V, Failes TW, Arndt GM, Lock RB, Ekert PG, Dolman MEM
Title High-Throughput Drug Screening of Primary Tumor Cells Identifies Therapeutic Strategies for Treating Children with High-Risk Cancer.
URL
Abstract Text For one-third of patients with pediatric cancer enrolled in precision medicine programs, molecular profiling does not result in a therapeutic recommendation. To identify potential strategies for treating these high-risk pediatric patients, we performed in vitro screening of 125 patient-derived samples against a library of 126 anticancer drugs. Tumor cell expansion did not influence drug responses, and 82% of the screens on expanded tumor cells were completed while the patients were still under clinical care. High-throughput drug screening (HTS) confirmed known associations between activating genomic alterations in NTRK, BRAF, and ALK and responses to matching targeted drugs. The in vitro results were further validated in patient-derived xenograft models in vivo and were consistent with clinical responses in treated patients. In addition, effective combinations could be predicted by correlating sensitivity profiles between drugs. Furthermore, molecular integration with HTS identified biomarkers of sensitivity to WEE1 and MEK inhibition. Incorporating HTS into precision medicine programs is a powerful tool to accelerate the improved identification of effective biomarker-driven therapeutic strategies for treating high-risk pediatric cancers.Integrating HTS with molecular profiling is a powerful tool for expanding precision medicine to support drug treatment recommendations and broaden the therapeutic options available to high-risk pediatric cancers.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ALK F1245I neuroblastoma sensitive Ceritinib Preclinical - Pdx & cell culture Actionable In a preclinical study, Zykadia (ceritinib) inhibited viability of patient-derived neuroblastoma cells harboring ALK F1245I in culture and inhibited tumor growth in a patient-derived xenograft model (PMID: 37523146). 37523146
ALK F1245I neuroblastoma sensitive Crizotinib Preclinical - Pdx & cell culture Actionable In a preclinical study, Xalkori (crizotinib) inhibited viability of patient-derived neuroblastoma cells harboring ALK F1245I in culture, inhibited tumor growth, and prolonged event-free survival in a patient-derived xenograft model (PMID: 37523146). 37523146
PIK3CA mutant Ewing sarcoma predicted - sensitive Temsirolimus Preclinical - Pdx Actionable In a preclinical study, Torisel (temsirolimus) treatment increased event-free survival in a Ewing sarcoma patient-derived xenograft (PDX) model harboring a PIK3CA mutation (PMID: 37523146). 37523146
ALK F1245I neuroblastoma sensitive Lorlatinib Case Reports/Case Series Actionable In a clinical study, Lorbrena (lorlatinib) treatment resulted in a partial response in a pediatric patient with neuroblastoma harboring ALK F1245I, inhibited viability of patient-derived cells in culture, decreased tumor growth and prolonged event-free survival in a patient-derived xenograft model (PMID: 37523146; NCT03336931). 37523146
PIK3CA mutant Ewing sarcoma predicted - sensitive Irinotecan + Temozolomide + Temsirolimus Case Reports/Case Series Actionable In a clinical study, Torisel (temsirolimus), Temodar (temozolomide), and Camptosar (irinotecan) combination treatment resulted in a partial response in a pediatric patient with Ewing sarcoma harboring a PIK3CA mutation (PMID: 37523146; NCT03336931). 37523146
ALK F1245I neuroblastoma sensitive Alectinib Preclinical - Pdx & cell culture Actionable In a preclinical study, Alecensa (alectinib) inhibited viability of patient-derived neuroblastoma cells harboring ALK F1245I in culture, inhibited tumor growth, and prolonged event-free survival in a patient-derived xenograft model (PMID: 37523146). 37523146