Inhibition of Chondrosarcoma Growth by mTOR Inhibitor in an In Vivo Syngeneic Rat Model
Open Access
- 27 June 2012
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 7 (6), e32458
- https://doi.org/10.1371/journal.pone.0032458
Abstract
Chondrosarcomas are the second most frequent primary malignant type of bone tumor. No effective systemic treatment has been identified in advanced or adjuvant phases for chondrosarcoma. The aim of the present study was to determine the antitumor effects of doxorubicin and everolimus, an mTOR inhibitor on chondrosarcoma progression. Doxorubin and/or everolimus were tested in vivo as single agent or in combination in the rat orthotopic Schwarm chondrosarcoma model, in macroscopic phase, as well as with microscopic residual disease. Response to everolimus and/or doxorubicin was evaluated using chondrosarcoma volume evolution (MRI). Histological response was evaluated with % of tumor necrosis, tumor proliferation index, metabolism quantification analysis between the treated and control groups. Statistical analyses were performed using chi square, Fishers exact test. Doxorubicin single agent has no effect of tumor growth as compared to no treatment; conversely, everolimus single agent significantly inhibited tumor progression in macroscopic tumors with no synergistic additive effect with doxorubicin. Everolimus inhibited chondrosarcoma proliferation as evaluated by Ki67 expression did not induce the apoptosis of tumor cells; everolimus reduced Glut1 and 4EBP1 expression. Importantly when given in rats with microscopic residual diseases, in a pseudo neoadjuvant setting, following R1 resection of the implanted tumor, everolimus significantly delayed or prevented tumor recurrence. MTOR inhibitor everolimus blocks cell proliferation, Glut1 expression and HIF1a expression, and prevents in vivo chondrosarcoma tumor progression in both macroscopic and in adjuvant phase post R1 resection. Taken together, our preclinical data indicate that mTOR inhibitor may be effective as a single agent in treating chondrosarcoma patients. A clinical trial evaluating mTOr inhibitor as neo-adjuvant and adjuvant therapy in chondrosarcoma patients is being constructed.Keywords
This publication has 37 references indexed in Scilit:
- Inhibition of mTOR in combination with doxorubicin in an experimental model of hepatocellular carcinomaJournal of Hepatology, 2008
- Targeting survival cascades induced by activation of Ras/Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways for effective leukemia therapyLeukemia, 2008
- Inhibition of mTOR pathway by everolimus cooperates with EGFR inhibitors in human tumours sensitive and resistant to anti-EGFR drugsBritish Journal of Cancer, 2008
- The Clinical Approach Towards ChondrosarcomaThe Oncologist, 2008
- The Biology Behind mTOR Inhibition in SarcomaThe Oncologist, 2007
- The AKT-mTOR pathway plays a critical role in the development of leiomyosarcomasNature Medicine, 2007
- RAD001 (Everolimus) Delays Tumor Onset and Progression in a Transgenic Mouse Model of Ovarian CancerCancer Research, 2007
- Rapamycin induces feedback activation of Akt signaling through an IGF-1R-dependent mechanismOncogene, 2006
- Current development of mTOR inhibitors as anticancer agentsNature Reviews Drug Discovery, 2006
- Zoledronic acid slows down rat primary chondrosarcoma development, recurrent tumor progression after intralesional curretage and increases overall survivalInternational Journal of Cancer, 2006