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

Autor: Das A; Department of Neurosurgery (Neuro-oncology Division), Medical University of South Carolina, Charleston, SC, USA. dasa@musc.edu., Alshareef M; Department of Neurosurgery (Neuro-oncology Division), Medical University of South Carolina, Charleston, SC, USA., Martinez Santos JL; Department of Neurosurgery (Neuro-oncology Division), Medical University of South Carolina, Charleston, SC, USA., Porto GBF; Department of Neurosurgery (Neuro-oncology Division), Medical University of South Carolina, Charleston, SC, USA., McDonald DG; Department of Radiation Oncology, Medical University of South Carolina, Charleston, SC, USA., Infinger LK; Department of Neurosurgery (Neuro-oncology Division), Medical University of South Carolina, Charleston, SC, USA., Vandergrift WA 3rd; Department of Neurosurgery (Neuro-oncology Division), Medical University of South Carolina, Charleston, SC, USA., Lindhorst SM; Department of Neurosurgery (Neuro-oncology Division), Medical University of South Carolina, Charleston, SC, USA., Varma AK; Department of Neurosurgery (Neuro-oncology Division), Medical University of South Carolina, Charleston, SC, USA., Patel SJ; Department of Neurosurgery (Neuro-oncology Division), Medical University of South Carolina, Charleston, SC, USA., Cachia D; Department of Neurosurgery (Neuro-oncology Division), Medical University of South Carolina, Charleston, SC, USA.
Jazyk: angličtina
Zdroj: Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico [Clin Transl Oncol] 2020 Nov; Vol. 22 (11), pp. 2017-2025. Date of Electronic Publication: 2020 Apr 06.
DOI: 10.1007/s12094-020-02341-7
Abstrakt: 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.
Databáze: MEDLINE
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