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Cancers (Basel). 2019 Oct 21;11(10). pii: E1604. doi: 10.3390/cancers11101604.

The Brain Penetrating and Dual TORC1/TORC2 Inhibitor, RES529, Elicits Anti-Glioma Activity and Enhances the Therapeutic Effects of Anti-Angiogenetic Compounds in Preclinical Murine Models.

Author information

1
Department of Biotechnological and Applied Clinical Sciences, Division of Radiation Oncology, University of L'Aquila, 67100 L'Aquila, Italy. giovanniluca.gravina@univaq.it.
2
Department of Biotechnological and Applied Clinical Sciences, Laboratory of Radiobiology, University of L'Aquila, 67100 L'Aquila, Italy. mancio_1982@hotmail.com.
3
Department of Biotechnological and Applied Clinical Sciences, Laboratory of Radiobiology, University of L'Aquila, 67100 L'Aquila, Italy. alecolapietro@gmail.com.
4
Department of Biotechnological and Applied Clinical Sciences, Laboratory of Cellular Biology, University of L'Aquila, 67100 L'Aquila, Italy. simona.dellemonache@univaq.it.
5
Department of Biotechnological and Applied Clinical Sciences, Laboratory of Human Anatomy, University of L'Aquila, 67100 L'Aquila, Italy. roberta.sferra@univaq.it.
6
Department of Biotechnological and Applied Clinical Sciences, Laboratory of Human Anatomy, University of L'Aquila, 67100 L'Aquila, Italy. pompili.simona@virgilio.it.
7
Department of Biotechnological and Applied Clinical Sciences, Laboratory of Neurophysiology, University of L'Aquila, 67100 L'Aquila, Italy. floravitale86@Hotmail.it.
8
Department of Biotechnological and Applied Clinical Sciences, Laboratory of Cellular Biology, University of L'Aquila, 67100 L'Aquila, Italy. s.martellucci@sabinauniversitas.it.
9
Laboratory of Experimental Medicine and Environmental Pathology, University Hub "Sabina Universitas", 02100 Rieti, Italy. s.martellucci@sabinauniversitas.it.
10
Department of Radiological, Oncological and Pathological Sciences, Sapienza University of Rome, 00118 Rome, Italy. francesco.marampon@uniroma1.it.
11
Laboratory of Experimental Medicine and Environmental Pathology, University Hub "Sabina Universitas", 02100 Rieti, Italy. Vincenzo.mattei@uniroma1.it.
12
Department of Biotechnological and Applied Clinical Sciences, Laboratory of Experimental Oncology, University of L'Aquila, 67100 L'Aquila, Italy. leda.biordi@univaq.it.
13
Sherris Pharma Partners, Jamaica Plain, MA 02130, USA. davidsherris@gmail.com.
14
Department of Biotechnological and Applied Clinical Sciences, Division of Radiation Oncology, University of L'Aquila, 67100 L'Aquila, Italy. claudio.festuccia@univaq.it.

Abstract

Background. Glioblastoma multiforme (GBM) is a devastating disease showing a very poor prognosis. New therapeutic approaches are needed to improve survival and quality of life. GBM is a highly vascularized tumor and as such, chemotherapy and anti-angiogenic drugs have been combined for treatment. However, as treatment-induced resistance often develops, our goal was to identify and treat pathways involved in resistance to treatment to optimize the treatment strategies. Anti-angiogenetic compounds tested in preclinical and clinical settings demonstrated recurrence associated to secondary activation of the phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathway. Aims. Here, we determined the sensitizing effects of the small molecule and oral available dual TORC1/TORC2 dissociative inhibitor, RES529, alone or in combination with the anti-VEGF blocking antibody, bevacizumab, or the tyrosine kinase inhibitor, sunitinib, in human GBM models. Results. We observed that RES529 effectively inhibited dose-dependently the growth of GBM cells in vitro counteracting the insurgence of recurrence after bevacizumab or sunitinib administration in vivo. Combination strategies were associated with reduced tumor progression as indicated by the analysis of Time to Tumor Progression (TTP) and disease-free survival (DSF) as well as increased overall survival (OS) of tumor bearing mice. RES529 was able to reduce the in vitro migration of tumor cells and tubule formation from both brain-derived endothelial cells (angiogenesis) and tumor cells (vasculogenic mimicry). Conclusions. In summary, RES529, the first dual TORC1/TORC2 dissociative inhibitor, lacking affinity for ABCB1/ABCG2 and having good brain penetration, was active in GBM preclinical/murine models giving credence to its use in clinical trial for patients with GBM treated in association with anti-angiogenetic compounds.

KEYWORDS:

RES529; TORC1/TORC2 inhibitor; bevacizumab; glioblastoma

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