Reference Detail

Ref Type

Journal Article

PMID

(34911818)

Authors

Jo H, Yagishita S, Hayashi Y, Ryu S, Suzuki M, Kohsaka S, Ueno T, Matsumoto Y, Horinouchi H, Ohe Y, Watanabe SI, Motoi N, Yatabe Y, Mano H, Takahashi K, Hamada A

Title

Comparative Study on the Efficacy and Exposure of Molecular Target Agents in Non-small Cell Lung Cancer PDX Models with Driver Genetic Alterations.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer therapeutics	21	2	2022 Feb	359-370	Mol Cancer Ther

URL

Abstract Text

Patient-derived xenografts (PDX) can adequately reflect clinical drug efficacy. However, the methods for evaluating drug efficacy are not fully established. We selected five non-small cell lung cancer (NSCLC) PDXs with genetic alterations from established PDXs and the corresponding molecular targeted therapy was administered orally for 21 consecutive days. Genetic analysis, measurement of drug concentrations in blood and tumors using LC/MS-MS, and analysis of drug distribution in tumors using matrix-assisted laser desorption/ionization mass spectrometry were performed. Fifteen (20%) PDXs were established using samples collected from 76 patients with NSCLC with genetic alterations. The genetic alterations observed in original patients were largely maintained in PDXs. We compared the drug efficacy in original patients and PDX models; the efficacies against certain PDXs correlated with the clinical effects, while those against the others did not. We determined blood and intratumor concentrations in the PDX model, but both concentrations were low, and no evident correlation with the drug efficacy could be observed. The intratumoral spatial distribution of the drugs was both homogeneous and heterogeneous for each drug, and the distribution was independent of the expression of the target protein. The evaluation of drug efficacy in PDXs enabled partial reproduction of the therapeutic effect in original patients. A more detailed analysis of systemic and intratumoral pharmacokinetics may help clarify the mode of action of drugs. Further development of evaluation methods and indices to improve the prediction accuracy of clinical efficacy is warranted.

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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
EML4 - ALK	lung adenocarcinoma	sensitive	Brigatinib	Preclinical - Pdx	Actionable	In a preclinical study, Alunbrig (brigatinib) treatment decreased tumor growth in a patient-derived xenograft (PDX) model of lung adenocarcinoma harboring EML4-ALK (PMID: 34911818).	34911818
EML4 - ALK	lung adenocarcinoma	predicted - sensitive	Alectinib	Case Reports/Case Series	Actionable	In a clinical case study, Alecensa (alectinib) treatment resulted in a partial response lasting 17.5 months in a patient with lung adenocarcinoma harboring EML4-ALK (PMID: 34911818).	34911818
EML4 - ALK	lung adenocarcinoma	predicted - sensitive	Ceritinib	Case Reports/Case Series	Actionable	In a clinical case study, Zykadia (ceritinib) treatment resulted in a partial response lasting 8.7 months in a patient with lung adenocarcinoma harboring EML4-ALK, who progressed on prior Alecensa (alectinib) treatment (PMID: 34911818).	34911818
EML4 - ALK	lung adenocarcinoma	sensitive	Lorlatinib	Preclinical - Pdx	Actionable	In a preclinical study, Lorbrena (lorlatinib) treatment decreased tumor growth in a patient-derived xenograft (PDX) model of lung adenocarcinoma harboring EML4-ALK (PMID: 34911818).	34911818