Evaluating anti-tumor activity of palbociclib plus radiation in anaplastic and radiation-induced meningiomas: pre-clinic
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RESEARCH ARTICLE
Evaluating anti‑tumor activity of palbociclib plus radiation in anaplastic and radiation‑induced meningiomas: pre‑clinical investigations A. Das1 · M. Alshareef1 · J. L. Martinez Santos1 · G. B. F. Porto1 · D. G. McDonald2 · L. K. Infinger1 · W. A. Vandergrift III1 · S. M. Lindhorst1 · A. K. Varma1 · S. J. Patel1 · D. Cachia1 Received: 24 January 2020 / Accepted: 16 March 2020 © Federación de Sociedades Españolas de Oncología (FESEO) 2020
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. Keywords Palbociclib · Ex vivo · Radiation · Mouse models · Preclinical studies
Introduction Meningiomas are the second most common primary brain tumor and arise from the arachnoid layers. They account for approximately 30% of primary neoplasms in the United States annually (Central Brain Tumor Registry of the United M. Alshareef and J. L. M. Santos contributed equally. * A. Das [email protected] 1
Department of Neurosurgery (Neuro‑oncology Division), Medical University of South Carolina, Charleston, SC, USA
Department of Radiation Oncology, Medical University of South Carolina, Charleston, SC, USA
2
States, 2014) [1]. The World’s health organization (WHO) classifies meningiomas in grade I, grade II (atypical), and grade III (anaplastic) [2]. Grade III meningiomas have a malignant behavior with higher recurrence a
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