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Evaluating anti-tumor activity of palbociclib plus radiation in anaplastic and radiation-induced meningiomas: pre-clinical investigations

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Abstract

Purpose

Meningiomas are common brain tumors, the majority of which are considered benign. Despite surgery and/or radiation therapy, recurrence rates are approximately 8–10%. One likely cause is the dysregulation of cyclin d-cyclin-dependent kinases 4 and 6 (CDK4/6)-retinoblastoma (Rb) pathway, which controls the cell cycle restriction point. This pathway is commonly dysregulated in anaplastic meningioma cell lines (AM) and radiation-induced meningioma cells (RIM), making it a rational target for anti-meningioma therapy. In this study, we investigate the effect of a CDK4/6 inhibitor, palbociclib, with radiation in relevant pre-clinical models.

Methods

In vitro cell culture, ex vivo slice culture and in vivo cell line-derived orthotopic xenograft animal models of AM/RIM were utilized to assess treatment efficacy with palbociclib plus radiation. Treatment effects were examined by immunoblot, cell viability, apoptosis, and cell cycle progression.

Results

The in vitro and ex vivo studies demonstrate that palbociclib plus radiation treatment reduced proliferation and has additional effects on cell cycling, including induction of an RB-associated G (1) arrest in Rb+ AM and RIM cells, but not in Rb− cells. Our results also demonstrated reduced CDK4 and CDK6 expression as well as reduced E2F target gene expression (CCNA2 and CCNE2) with the combination therapy. MRI results in vivo demonstrated reduced tumor size at 5 weeks when treated with 14 days palbociclib (10 mg/kg) plus 6 Gy radiation compared to saline-treated tumors. Finally, no hepatic toxicity was found after treatments.

Conclusion

A pre-clinical murine model provides preclinical evidence for use of palbociclib plus radiation as a therapeutic agent for Rb+ meningiomas.

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Funding

This study was supported in part by pilot research funding from an American Cancer Society Institutional Research Grant awarded to the Hollings Cancer Center, Medical University of South Carolina to David Cachia, Supported in part by the Flow Cytometry Shared Resource, Hollings Cancer Center, Medical University of South Carolina (P30 CA138313) and the Department of Neurosurgery (MUSC). The authors confirm that the funder had no influence over the study design, content of the article, or selection of this journal.

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Author notes

  1. M. Alshareef and J. L. M. Santos contributed equally.

Authors and Affiliations

  1. Department of Neurosurgery (Neuro-oncology Division), Medical University of South Carolina, Charleston, SC, USA

    A. Das, M. Alshareef, J. L. Martinez Santos, G. B. F. Porto, L. K. Infinger, W. A. Vandergrift III, S. M. Lindhorst, A. K. Varma, S. J. Patel & D. Cachia

  2. Department of Radiation Oncology, Medical University of South Carolina, Charleston, SC, USA

    D. G. McDonald

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  1. A. Das
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  2. M. Alshareef
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  3. J. L. Martinez Santos
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  4. G. B. F. Porto
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  5. D. G. McDonald
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  6. L. K. Infinger
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  7. W. A. Vandergrift III
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  8. S. M. Lindhorst
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  9. A. K. Varma
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  10. S. J. Patel
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Contributions

Conceived and designed the experiments: AD, DGM, and DC. Analyzed the data: AD, MA, GBFP, JLMS and DC. Wrote the first draft of the manuscript: AD, MA, GBFP, JLMS and DC. Contributed to the writing of the manuscript: AD, MA, GBFP, JLMS, DGM, LKI, WAV, SML, AKV, SJP, and DC (all authors). Agree with manuscript results and conclusions: All authors. Jointly developed the structure and arguments for the paper: All authors. Made critical revisions and approved final version: AD and DC. All authors reviewed and approved of the final manuscript.

Corresponding author

Correspondence to A. Das.

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Conflict of interest

Pfizer Inc. supplied palbociclib for this study. The results of this research and any intellectual property arising from this research are subject to existing rights and obligations to a third party, Pfizer Inc.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Subjects gave their written, informed consent to participate.

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Das, A., Alshareef, M., Martinez Santos, J.L. et al. Evaluating anti-tumor activity of palbociclib plus radiation in anaplastic and radiation-induced meningiomas: pre-clinical investigations. Clin Transl Oncol 22, 2017–2025 (2020). https://doi.org/10.1007/s12094-020-02341-7

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