Unknown

Dataset Information

0

Integrated genomic analyses in PDX model reveal a cyclin-dependent kinase inhibitor Palbociclib as a novel candidate drug for nasopharyngeal carcinoma.


ABSTRACT: BACKGROUND:Patient-derived xenograft (PDX) tumor model has become a new approach in identifying druggable tumor mutations, screening and evaluating personalized cancer drugs based on the mutated targets. METHODS:We established five nasopharyngeal carcinoma (NPC) PDXs in mouse model. Subsequently, whole-exome sequencing (WES) and genomic mutation analyses were performed to search for genetic alterations for new drug targets. Potential drugs were applied in two NPC PDX mice model to assess their anti-cancer activities. RNA sequencing and transcriptomic analysis were performed in one NPC PDX mice to correlate with the efficacy of the anti-cancer drugs. RESULTS:A relative high incident rate of copy number variations (CNVs) of cell cycle-associated genes. Among the five NPC-PDXs, three had cyclin D1 (CCND1) amplification while four had cyclin-dependent kinase inhibitor CDKN2A deletion. Furthermore, CCND1 overexpression was observed in >?90% FFPE clinical metastatic NPC tumors (87/91) and was associated with poor outcomes. CNV analysis disclosed that plasma CCND1/CDKN2A ratio is correlated with EBV DNA load in NPC patients' plasma and could serve as a screening test to select potential CDK4/6 inhibitor treatment candidates. Based on our NPC PDX model and RNA sequencing, Palbociclib, a cyclin-dependent kinase inhibitor, proved to have anti-tumor effects by inducing G1 arrest. One NPC patient with liver metastatic was treated with Palbociclib, had stable disease response and a drop in Epstein Barr virus (EBV) EBV titer. CONCLUSIONS:Our integrated information of sequencing-based genomic studies and tumor transcriptomes with drug treatment in NPC-PDX models provided guidelines for personalized precision treatments and revealed a cyclin-dependent kinase inhibitor Palbociclib as a novel candidate drug for NPC.

SUBMITTER: Hsu CL 

PROVIDER: S-EPMC6149192 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

altmetric image

Publications

Integrated genomic analyses in PDX model reveal a cyclin-dependent kinase inhibitor Palbociclib as a novel candidate drug for nasopharyngeal carcinoma.

Hsu Cheng-Lung CL   Lui Kar-Wai KW   Chi Lang-Ming LM   Kuo Yung-Chia YC   Chao Yin-Kai YK   Yeh Chun-Nan CN   Lee Li-Yu LY   Huang Yenlin Y   Lin Tung-Liang TL   Huang Mei-Yuan MY   Lai Yi-Ru YR   Yeh Yuan-Ming YM   Fan Hsien-Chi HC   Lin An-Chi AC   Lu Yen-Jung YJ   Hsieh Chia-Hsun CH   Chang Kai-Ping KP   Tsang Ngan-Ming NM   Wang Hung-Ming HM   Chang Alex Y AY   Chang Yu-Sun YS   Li Hsin-Pai HP  

Journal of experimental & clinical cancer research : CR 20180920 1


<h4>Background</h4>Patient-derived xenograft (PDX) tumor model has become a new approach in identifying druggable tumor mutations, screening and evaluating personalized cancer drugs based on the mutated targets.<h4>Methods</h4>We established five nasopharyngeal carcinoma (NPC) PDXs in mouse model. Subsequently, whole-exome sequencing (WES) and genomic mutation analyses were performed to search for genetic alterations for new drug targets. Potential drugs were applied in two NPC PDX mice model to  ...[more]

Similar Datasets

| S-EPMC4526396 | biostudies-literature
| S-EPMC5378171 | biostudies-literature
| S-EPMC7331461 | biostudies-literature
| S-EPMC8499046 | biostudies-literature
| S-EPMC10985888 | biostudies-literature
| S-EPMC4344889 | biostudies-literature
| S-EPMC3163504 | biostudies-literature
2019-09-13 | E-MTAB-7866 | biostudies-arrayexpress
| S-EPMC6398210 | biostudies-literature
| S-EPMC9868605 | biostudies-literature