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Ma, Fen

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Fen

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Ma, Fen

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2016 - 20172

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Author's Publications: search.filters.isAuthorOfPublication.f44d1144-6c3c-4bec-95bf-ad1f10aae339

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    Positive feedback loop mediated by protein phosphatase 1α mobilization of P-TEFb and basal CDK1 drives androgen receptor in prostate cancer
    (Oxford University Press, 2017) Liu, Xiaming; Gao, Yanfei; Ye, Huihui; Gerrin, Sean; Ma, Fen; Wu, Yiming; Zhang, Tengfei; Russo, Joshua; Cai, Changmeng; Yuan, Xin; Liu, Jihong; Chen, Shaoyong; Balk, Steven
    Abstract P-TEFb (CDK9/cyclin T) plays a central role in androgen receptor (AR)-mediated transactivation by phosphorylating both RNA polymerase 2 complex proteins and AR at S81. CDK9 dephosphorylation mobilizes P-TEFb from an inhibitory 7SK ribonucleoprotein complex, but mechanisms targeting phosphatases to P-TEFb are unclear. We show that AR recruits protein phosphatase 1α (PP1α), resulting in P-TEFb mobilization and CDK9-mediated AR S81 phosphorylation. This increased pS81 enhances p300 recruitment, histone acetylation, BRD4 binding and subsequent further recruitment of P-TEFb, generating a positive feedback loop that sustains transcription. AR S81 is also phosphorylated by CDK1, and blocking basal CDK1-mediated S81 phosphorylation markedly suppresses AR activity and initiation of this positive feedback loop. Finally, androgen-independent AR activity in castration-resistant prostate cancer (CRPC) cells is driven by increased CDK1-mediated S81 phosphorylation. Collectively these findings reveal a mechanism involving PP1α, CDK9 and CDK1 that is used by AR to initiate and sustain P-TEFb activity, which may be exploited to drive AR in CRPC.
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    The efficacy and safety of anti-PD-1/PD-L1 antibodies for treatment of advanced or refractory cancers: a meta-analysis
    (Impact Journals LLC, 2016) Zhang, Tengfei; Xie, Jing; Arai, Seiji; Wang, Liping; Shi, Xuezhong; Shi, Ni; Ma, Fen; Chen, Sen; Huang, Lan; Yang, Li; Ma, Wang; Zhang, Bin; Han, Weidong; Xia, Jianchuan; Chen, Hu; Zhang, Yi
    Purpose To systematically evaluate the overall efficacy and safety of current anti-PD-1/PD-L1 antibodies for treatment of patients with advanced or refractory cancer. Results: Fifty-one trials including 6,800 patients were included. The overall response rates for melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma (RCC) were 29% (95% CI: 1.53−2.41), 21% (95% CI: 17%−25%) and 21% (95% CI: 16%−27%) respectively. While the overall adverse effects rate for melanoma, NSCLC, RCC were 16% (95% CI: 6%−28%), 11% (95% CI: 8%−14%) and 20% (95% CI: 11%−32%) respectively. Tumor PD-L1 expression and patient smoking status might serve as biomarkers to predict response of anti-PD-1/PD-L1 antibody treatment. Compared to tumors with negative PD-L1 expression, tumors with positive PD-L1 expression had a significantly higher clinical response rate (41.4% versus 26.5%) with RR = 1.92 (95% CI: 1.53−2.41, P < 0.001). Smoker patients also showed a significantly higher response rate (33.7%) than patients who never smoked (4.2%) with RR = 6.02 (95% CI: 1.22−29.75, P = 0.028). Nivolumab and Pembrolizumab were associated with significantly increased response rate (RR = 2.89, 95% CI: 2.46−3.40, P < 0.001), reduced death risk (HR= 0.53; 95% CI: 0.48−0.57; P < 0.001), and decreased adverse effect rate (RR = 0.49, 95% CI: 0.30−0.80, P = 0.004) compared with other therapies. Experimental Design Clinical trials reporting response or safety of anti-PD-1/PD-L1 antibodies for advanced or refractory cancer patients published before January 31th 2016 were searched in PubMed and EMBASE database. Meta-analyses using random effects models were used to calculate the overall estimate. Conclusions: Anti-PD-1/PD-L1 antibodies have high response rates and low adverse effect rates for advanced or refractory cancers.