High-Throughput Drug Screening of Primary Tumor Cells Identifies Therapeutic Strategies for Treating Children with High-Risk Cancer

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

Author(s): 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;
Details: Publication Year 2023-08-15,Volume 83,Issue #16,Page 2716-2732
Journal Title: Cancer Research
Publication Type: Research article
Abstract: 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. SIGNIFICANCE: 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.
Publisher: American Association for Cancer Research
Keywords: Humans; Child; Drug Evaluation, Preclinical; Early Detection of Cancer; *Neoplasms/drug therapy/genetics; *Antineoplastic Agents/pharmacology/therapeutic use; High-Throughput Screening Assays/methods
Department(s): Laboratory Research
PubMed ID: 37523146
Publisher's Version: https://doi.org/10.1158/0008-5472.CAN-22-3702
Open Access at Publisher's Site: https://doi.org/10.1158/0008-5472.Can-22-3702
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2023-11-08 07:27:50

Last Modified: 2023-11-08 07:28:27