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

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

  • J Exp Clin Cancer Res. 2018 Sep 20;37(1):233. doi: 10.1186/s13046-018-0873-5.
Cheng-Lung Hsu 1,  Kar-Wai Lui 2,  Lang-Ming Chi 3,  Yung-Chia Kuo 1,  Yin-Kai Chao 4,  Chun-Nan Yeh 5,  Li-Yu Lee 6,  Yenlin Huang 6,  Tung-Liang Lin 1,  Mei-Yuan Huang 7,  Yi-Ru Lai 7,  Yuan-Ming Yeh 8,  Hsien-Chi Fan 1,  An-Chi Lin 1,  Yen-Jung Lu 9,  Chia-Hsun Hsieh 1,  Kai-Ping Chang 10,  Ngan-Ming Tsang 11,  Hung-Ming Wang 1,  Alex Y Chang 12,  Yu-Sun Chang 7 8 10,  Hsin-Pai Li 13 14 15
Affiliations

Affiliations

  • 1 Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University, No.5, Fuxing St., Guishan Dist, Taoyuan City, 333, Lin-Kou, Taiwan, Republic of China.
  • 2 Department of Medical Imaging and Intervention, Chang Gung Memorial Hospital, Chang Gung University, No.5, Fuxing St., Guishan Dist, Taoyuan City, 333, Lin-Kou, Taiwan, Republic of China.
  • 3 Clinical Proteomics Core Laboratory, Chang Gung Memorial Hospital, No.5, Fuxing St., Guishan Dist, Taoyuan City, 333, Lin-Kou, Taiwan, Republic of China.
  • 4 Division of Thoracic and Cardiovascular Surgery, Department of Surgery, Chang Gung Memorial Hospital, No.5, Fuxing St., Guishan Dist, Taoyuan City, 333, Lin-Kou, Taiwan, Republic of China.
  • 5 Department of General Surgery, Liver Research Center, Chang Gung Memorial Hospital, Chang Gung University, No.5, Fuxing St., Guishan Dist, Taoyuan City, 333, Lin-Kou, Taiwan, Republic of China.
  • 6 Department of Pathology, Chang Gung Memorial Hospital, Chang Gung University, No.5, Fuxing St., Guishan Dist, Taoyuan City, 333, Lin-Kou, Taiwan, Republic of China.
  • 7 Department of Microbiology and Immunology, Molecular Medicine Research Center, Chang Gung University, No.259, Wenhua 1st Rd., Guishan Dist., Lin-Kou, Taoyuan, 333, Taiwan, Republic of China.
  • 8 Molecular Medicine Research Center, Chang Gung University, No.259, Wenhua 1st Rd., Guishan Dist, Taoyuan City, 333, Taiwan, Republic of China.
  • 9 ACT Genomics, Co. Ltd., 1F., No.280, Xinhu 2nd Rd., Neihu Dist, Taipei City, 114, Taiwan, Republic of China.
  • 10 Department of Otolaryngology-Head and Neck Surgery, Chang Gung Memorial Hospital, Chang Gung University, No.5, Fuxing St., Guishan Dist, Taoyuan City, 333, Lin-Kou, Taiwan, Republic of China.
  • 11 Department of Radiation, Chang Gung Memorial Hospital, Chang Gung University, No.5, Fuxing St., Guishan Dist, Taoyuan City, 333, Lin-Kou, Taiwan, Republic of China.
  • 12 Johns Hopkins Singapore International Medical Centre, 11 Jalan Tan Tock Seng, Singapore City, 308433, Singapore.
  • 13 Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University, No.5, Fuxing St., Guishan Dist, Taoyuan City, 333, Lin-Kou, Taiwan, Republic of China. [email protected].
  • 14 Department of Microbiology and Immunology, Molecular Medicine Research Center, Chang Gung University, No.259, Wenhua 1st Rd., Guishan Dist., Lin-Kou, Taoyuan, 333, Taiwan, Republic of China. [email protected].
  • 15 Molecular Medicine Research Center, Chang Gung University, No.259, Wenhua 1st Rd., Guishan Dist, Taoyuan City, 333, Taiwan, Republic of China. [email protected].
PMID: 30236142 DOI: 10.1186/s13046-018-0873-5
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.

Keywords

CDK4/6 inhibitor; EBV; Nasopharyngeal carcinoma; Patient derived xenograft; RNA sequencing; Whole-exome sequencing.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-50767
    99.94%, CDK4/6 Inhibitor
    CDK