Reference Detail

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.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer research	83	16	2023 Aug 15	2716-2732	Cancer Res

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
ALK	F1245I	missense	unknown	ALK F1245I lies within the protein kinase domain of the Alk protein (UniProt.org). F1245I has been identified in the scientific literature (PMID: 30778092, PMID: 34282791, PMID: 37523146), but has not been biochemically characterized and therefore, its effect on Alk protein function is unknown (PubMed, Aug 2024).

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
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
TSC2 mutant	osteosarcoma	no benefit	Irinotecan + Temozolomide + Temsirolimus	Case Reports/Case Series	Actionable	In a clinical case study, Torisel (temsirolimus), Temodar (temozolomide), and Camptosar (irinotecan) combination treatment resulted in progressive disease in a pediatric patient with osteosarcoma harboring a TSC2 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
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	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
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
TSC2 mutant	osteosarcoma	no benefit	Temsirolimus	Preclinical - Pdx	Actionable	In a preclinical study, Torisel (temsirolimus) treatment did not improve event-free survival in an osteosarcoma patient-derived xenograft (PDX) model harboring a TSC2 mutation (PMID: 37523146).	37523146
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