Reference Detail

Ref Type

Journal Article

PMID

(38985431)

Authors

Jeising S, Nickel AC, Trübel J, Felsberg J, Picard D, Leprivier G, Wolter M, Huynh MK, Olivera MB, Kaulich K, Häberle L, Esposito I, Klau GW, Steinmann J, Beez T, Rapp M, Sabel M, Dietrich S, Remke M, Cornelius JF, Reifenberger G, Qin N

Title

A clinically compatible in vitro drug-screening platform identifies therapeutic vulnerabilities in primary cultures of brain metastases.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Journal of neuro-oncology	169	3	2024 Sep	613-623	J Neurooncol

URL

Abstract Text

Brain metastases represent the most common intracranial tumors in adults and are associated with a poor prognosis. We used a personalized in vitro drug screening approach to characterize individual therapeutic vulnerabilities in brain metastases.Short-term cultures of cancer cells isolated from brain metastasis patients were molecularly characterized using next-generation sequencing and functionally evaluated using high-throughput in vitro drug screening to characterize pharmacological treatment sensitivities.Next-generation sequencing identified matched genetic alterations in brain metastasis tissue samples and corresponding short-term cultures, suggesting that short-term cultures of brain metastases are suitable models for recapitulating the genetic profile of brain metastases that may determine their sensitivity to anti-cancer drugs. Employing a high-throughput in vitro drug screening platform, we successfully screened the cultures of five brain metastases for response to 267 anticancer compounds and related drug response to genetic data. Among others, we found that targeted treatment with JAK3, HER2, or FGFR3 inhibitors showed anti-cancer effects in individual brain metastasis cultures.Our preclinical study provides a proof-of-concept for combining molecular profiling with in vitro drug screening for predictive evaluation of therapeutic vulnerabilities in brain metastasis patients. This approach could advance the use of patient-derived cancer cells in clinical practice and might eventually facilitate decision-making for personalized drug treatment.

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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
JAK3 V718L	esophagus adenocarcinoma	sensitive	Pacritinib	Preclinical - Patient cell culture	Actionable	In a preclinical study, Vonjo (pacritinib) inhibited viability of cells derived from the brain metastases of a patient with esophagus adenocarcinoma harboring JAK3 V718L in culture (PMID: 38985431).	38985431
JAK3 V718L	esophagus adenocarcinoma	sensitive	Fedratinib	Preclinical - Patient cell culture	Actionable	In a preclinical study, Inrebic (fedratinib) inhibited viability of cells derived from the brain metastases of a patient with esophagus adenocarcinoma harboring JAK3 V718L in culture (PMID: 38985431).	38985431
JAK3 V718L	esophagus adenocarcinoma	sensitive	Momelotinib	Preclinical - Patient cell culture	Actionable	In a preclinical study, Momelotinib (CYT387) inhibited viability of cells derived from the brain metastases of a patient with esophagus adenocarcinoma harboring JAK3 V718L in culture (PMID: 38985431).	38985431
JAK3 V718L	esophagus adenocarcinoma	sensitive	Quizartinib	Preclinical - Patient cell culture	Actionable	In a preclinical study, Vanflyta (quizartinib) inhibited viability of cells derived from the brain metastases of a patient with esophagus adenocarcinoma harboring JAK3 V718L in culture (PMID: 38985431).	38985431