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

Hsu, Cheng Lung; Lui, Kar Wai; Liu, Ming; Kuo, Yung Chia; Chao, Yin‐Kai; Yeh, Chun‐Nan; Lee, Li Yu; Huang, Yen‐Lin; Lin, Tsan-Shiun; Huang, Mei Yuan; Lai, Yi Ru; Yeh, Yuan Ming; Fan, Hsien Chi; Lin, An Chi; Lu, Yen Jung; Hsieh, Chia Hsun; Chang, Kai Ping; Tsang, Ngan Ming; Wang, Hung Ming; Chang, Alex Y.; Chang, Yu Sun; Li, Hsin Pai

doi:10.1186/s13046-018-0873-5

Cited by 26 publications

(29 citation statements)

References 49 publications

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“…Previous attempts to establish NPC-PDX in vivo have been successful in nude mice and NOD scid mice. In the present study, fresh NPC biopsies obtained from stage IV metastatic and/or recurrent patients were transplanted in NSG mice and the tumor take rate for PDX engraftment was 18.9%, which is comparable to those aforementioned studies [18][19][20]34]. Yet, the lack of comprehensive…”

Section: Discussionsupporting

confidence: 74%

“…Firstly, the take rate can be improved. Hsu et al reported that PDX engraftment-positive patients had shorter survival than PDX engraftment-negative patients, regardless of their EBV DNA load and previous treatments that the patients received [34]. Hence, it would be of interest to unravel the underlying factors that govern the tumor take rate, which can plausibly increase the bioavailability of NPC-PDX for EBV and NPC research.…”

Section: Discussionmentioning

confidence: 99%

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Establishment and Characterization of Humanized Mouse NPC-PDX Model for Testing Immunotherapy

Liu

Fong

Tan

et al. 2020

Cancers

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Immune checkpoint blockade (ICB) monotherapy shows early promise for the treatment of nasopharyngeal carcinoma (NPC) in patients. Nevertheless, limited representative NPC models hamper preclinical studies to evaluate the efficacy of novel ICB and combination regimens. In the present study, we engrafted NPC biopsies in non-obese diabetic-severe combined immunodeficiency interleukin-2 receptor gamma chain-null (NSG) mice and established humanized mouse NPC-patient-derived xenograft (NPC-PDX) model successfully. Epstein–Barr virus was detected in the NPC in both NSG and humanized mice as revealed by Epstein–Barr virus-encoded small RNA (EBER) in situ hybridization (ISH) and immunohistochemical (IHC) staining. In the NPC-bearing humanized mice, the percentage of tumor-infiltrating CD8+ cytotoxic T cells was lowered, and the T cells expressed higher levels of various inhibitory receptors, such as programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) than those in blood. The mice were then treated with nivolumab and ipilimumab, and the anti-tumor efficacy of combination immunotherapy was examined. In line with paired clinical data, the NPC-PDX did not respond to the treatment in terms of tumor burden, whilst an immunomodulatory response was elicited in the humanized mice. From our results, human proinflammatory cytokines, such as interferon-gamma (IFN-γ) and interleukin-6 (IL-6) were significantly upregulated in plasma. After treatment, there was a decrease in CD4/CD8 ratio in the NPC-PDX, which also simulated the modulation of intratumoral CD4/CD8 profile from the corresponding donor. In addition, tumor-infiltrating T cells were re-activated and secreted more IFN-γ towards ex vivo stimulation, suggesting that other factors, including soluble mediators and metabolic milieu in tumor microenvironment may counteract the effect of ICB treatment and contribute to the tumor progression in the mice. Taken together, we have established and characterized a novel humanized mouse NPC-PDX model, which plausibly serves as a robust platform to test for the efficacy of immunotherapy and may predict clinical outcomes in NPC patients.

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Section: Discussionsupporting

confidence: 74%

Section: Discussionmentioning

confidence: 99%

Establishment and Characterization of Humanized Mouse NPC-PDX Model for Testing Immunotherapy

Liu

Fong

Tan

et al. 2020

Cancers

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“…High throughput sequencing in nasopharyngeal carcinoma reveals an increase in CCND1 copy number combined with CDKN2A gene deletion. Palbociclib significantly inhibits CDK4 signaling pathway activation in patient derived xenograft (PDX) model [13]. Palbociclib has antitumor activity for NRAS-mutant melanomas in a preclinical mouse model, indicating the CDK4 pathway as a potential therapeutic target [14].…”

Section: Introductionmentioning

confidence: 99%

Frequent genetic aberrations in the cell cycle related genes in mucosal melanoma indicate the potential for targeted therapy

Cheng

Cui

et al. 2019

J Transl Med

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Background Melanoma is one of the most aggressive cancers with extremely poor prognosis, and the median survival time for stage IV patients is approximately 6 to 8 months. Unlike cutaneous melanoma, mucosal melanoma is a rare melanoma subtype among Caucasian patients but its incidence remains as high as 22.6% among Chinese patients. Screening specific genetic variations is the guideline to select targeted drugs for the treatment of advanced melanoma, whereas the genetic variation spectrum and potential therapeutic targets for mucosal melanoma are largely unclear. It is urgent to identify promising genetic variants for mucosal melanoma so as to develop effective targeted therapies for this disease. Methods Tumor samples from 213 Chinese mucosal melanoma patients were involved in this study. P16 INK4a /Cyclin D1/CDK4 copy number was examined using the QuantiGene Plex DNA assay and the correlation between abnormal copy number and clinicopathological parameters was analyzed. Patient-derived xenograft models (PDX) were performed to detect the effects of CDK4/6 inhibitors on the proliferation of mucosal melanoma cells with altered copy number of CDK4 pathway ( CDK4, Cyclin D1 and P16 INK4 a ). The molecular mechanisms of CDK4/6 inhibitors on the proliferation of mucosal melanoma were analyzed by RNAseq. Results Among the 213 samples, the amplification rate of CDK4 and CCND1 was 47.0% and 27.7%, respectively, and the deletion rate of P16 INK4a was 57.7%. Patients with more than one genetic abnormality were up to 81.7%. CDK4 pathway gene copy number variation was not associated with the prognosis of patients with mucosal melanoma (P > 0.05). Drug sensitivity tests showed that AT7519, a broad-spectrum CDK inhibitor, and PD0332991, a specific CDK4/6 inhibitor, exhibited higher inhibitory effect on CDK4 signaling pathway abnormal mucosal melanoma cells-derived PDX tumors growth than CDK4 signaling pathway normal ones. RNA-seq analysis showed that CDK4 inhibitors may affect tumor proliferation through multiple signaling pathways. Conclusions Abnormal copy number of cell cycle related genes is frequently found in mucosal melanoma. CDK4/6 inhibitors significantly suppress the PDX tumor growth with abnormal CDK4 pathway. CDK4 signaling variations predict the effectiveness of CDK4 inhibitors in mucosal melanoma. Electronic supplementary material The online version of this article (10.1186/s12967-019-1987-z) contains supplementary material, which is available to authorized users.

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“…(copy number ≥ 4) among oncogenes that promote cell proliferation and cell signaling, including MYC, CCND1, and JAK2 (Table S5). Given that EBV infection can induce genomic instability, 29,30 we examined the possible correlation between CNV events and the plasma EBV DNA concentration. We noted that plasma samples whose EBV DNA concentrations were greater than 1000 copies/mL had at least one gene (P = .018) in 409 cancer panel that had either gain or loss in CNV ( Figure 3A), indicating possible link between plasma EBV copy number and CNV in NPC tumor.…”

Section: Recurrence Metastasismentioning

confidence: 99%

Targeted sequencing of cancer‐related genes in nasopharyngeal carcinoma identifies mutations in the TGF‐β pathway

et al. 2019

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Approximately, 25% of nasopharyngeal carcinoma (NPC) patients develop recurrent disease. NPC may involve relatively few genomic alterations compared to other cancers due to its association with Epstein‐Barr virus (EBV). We envisioned that in‐depth sequencing of tumor tissues might provide new insights into the genetic alterations of this cancer. Thirty‐three NPC paired tumor/adjacent normal or peripheral blood mononuclear cell samples were deep‐sequenced (>1000×) with respect to a panel of 409 cancer‐related genes. Newly identified mutations and its correlation with clinical outcomes were evaluated. Profiling of somatic mutations and copy number variations (CNV) in NPC tumors identified alterations in RTK/RAS/PI3K, NOTCH, DNA repair, chromatin remodeling, cell cycle, NF‐κB, and TGF‐β pathways. In addition, patients harbored CNV among 409 cancer‐related genes and missense mutations in TGF‐β/SMAD signaling were associated with poor overall survival and poor recurrence‐free survival, respectively. The CNV events were correlated with plasma EBV copies, while mutations in TGFBR2 and SMAD4 abrogate SMAD‐dependent TGF‐β signaling. Functional analysis revealed that the new TGFBR2 kinase domain mutants were incapable of transducing the signal, leading to failure of phosphorylation of SMAD2/3 and activation of downstream TGF‐β‐mediated cell growth arrest. This study provides evidence supporting CNV and dysregulated TGF‐β signaling contributes to exacerbating the NPC pathogenesis.

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

Cited by 26 publications

References 49 publications

Establishment and Characterization of Humanized Mouse NPC-PDX Model for Testing Immunotherapy

Establishment and Characterization of Humanized Mouse NPC-PDX Model for Testing Immunotherapy

Frequent genetic aberrations in the cell cycle related genes in mucosal melanoma indicate the potential for targeted therapy

Targeted sequencing of cancer‐related genes in nasopharyngeal carcinoma identifies mutations in the TGF‐β pathway

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