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A novel CDK4/6 inhibitor combined with irradiation demonstrates potent anti-tumor efficacy in diffuse midline glioma

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Abstract

Objective

Diffuse midline glioma, H3 K27-altered (DMG) is a lethal pediatric brainstem tumor. Despite numerous efforts to improve survival benefits, its prognosis remains poor. This study aimed to design and synthesize a novel CDK4/6 inhibitor YF-PRJ8-1011, which exhibited more potent antitumor activity against a panel of patient-derived DMG tumor cells in vitro and in vivo compared with palbociclib.

Methods

Patient-derived DMG cells were used to assess the antitumor efficacy of YF-PRJ8-1011 in vitro. The liquid chromatography tandem-mass spectrometry method was used to measure the activity of YF-PRJ8-1011 passing through the blood–brain barrier. DMG patient-derived xenograft models were established to detect the antitumor efficacy of YF-PRJ8-1011.

Results

The results showed that YF-PRJ8-1011 could inhibit the growth of DMG cells both in vitro and in vivo. YF-PRJ8-1011 could well penetrate the blood–brain barrier. It also significantly inhibited the growth of DMG tumors and prolonged the overall survival of mice compared with vehicle or palbociclib. Most notably, it exerted potent antitumor efficacy in DMG in vitro and in vivo compared with palbociclib. In addition, we also found that YF-PRJ8-1011 combined with radiotherapy also showed more significant inhibition of DMG xenograft tumor growth than radiotherapy alone.

Conclusion

Collectively, YF-PRJ8-1011 is a novel, safe, and selective CDK4/6 inhibitor for DMG treatment.

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Data availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

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Funding

This study was funded by Multicenter clinical big data study and multi-path tumorigenesis mechanisms and precision treatment research on brainstem glioma (JINGYIYAN2018-7).

Author information

Author notes

  1. Pengcheng Zuo and Yaopeng Li contributed equally.

Authors and Affiliations

  1. Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China

    Pengcheng Zuo, Zhen Wu, Junting Zhang & Liwei Zhang

  2. China National Clinical Research Center for Neurological Diseases (NCRC-ND), Beijing, China

    Liwei Zhang

  3. School of Pharmaceutical Sciences, Peking-Tsinghua Center for Life Sciences, Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Tsinghua University, Beijing, China

    Yaopeng Li, Tantan Wang & Xuebin Liao

  4. Advanced Innovation Center for Human Brain Protection, Beijing Tiantan Hospital, Capital Medical University, Beijing, China

    Xuebin Liao

  5. Zhuhai Yufan Biotechnologies Co., Ltd, Zhuhai, 519000, Guangdong, China

    Xingyu Lin

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  1. Pengcheng Zuo
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Contributions

PZ: writing—original draft and conceptualization; YL: formal analysis and investigation; TW: Bioinformatics analysis; XL: Drug design; ZW, JZ: methodology and resources; XL and LZ: review and editing, and supervision. All authors contributed to the article and approved the submitted version.

Corresponding authors

Correspondence to Xuebin Liao or Liwei Zhang.

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The authors have no relevant financial or non-financial interests to disclose.

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This study was approved by the human research ethics committee of Beijing Tiantan Hospital. The written informed consent was obtained from the subjects.

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Written informed consent was obtained from the parents.

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Written informed consent for publication was obtained from all participants.

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Zuo, P., Li, Y., Wang, T. et al. A novel CDK4/6 inhibitor combined with irradiation demonstrates potent anti-tumor efficacy in diffuse midline glioma. J Neurooncol 163, 159–171 (2023). https://doi.org/10.1007/s11060-023-04323-5

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  • DOI: https://doi.org/10.1007/s11060-023-04323-5

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