Anticancer effects of ABTL0812, a clinical stage drug inducer of autophagy-mediated cancer cell death, in glioblastoma models
BackgroundGlioblastoma multiforme (GBM) is the most malignant adult brain tumor. Current standard of care treatments have very limited efficacy, being the patients´ overall survival 14 months and the 2-year survival rate less than 10%. Therefore, the treatment of GBM is an urgent unmet clinical need...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-11-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2022.943064/full |
| _version_ | 1797991148166316032 |
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| author | Andrea Mancini Alessandro Colapietro Loredana Cristiano Alessandra Rossetti Vincenzo Mattei Giovanni Luca Gravina Giovanni Luca Gravina Héctor Perez-Montoyo Marc Yeste-Velasco Jose Alfon Carles Domenech Claudio Festuccia |
| author_facet | Andrea Mancini Alessandro Colapietro Loredana Cristiano Alessandra Rossetti Vincenzo Mattei Giovanni Luca Gravina Giovanni Luca Gravina Héctor Perez-Montoyo Marc Yeste-Velasco Jose Alfon Carles Domenech Claudio Festuccia |
| author_sort | Andrea Mancini |
| collection | DOAJ |
| description | BackgroundGlioblastoma multiforme (GBM) is the most malignant adult brain tumor. Current standard of care treatments have very limited efficacy, being the patients´ overall survival 14 months and the 2-year survival rate less than 10%. Therefore, the treatment of GBM is an urgent unmet clinical need.MethodsThe aim of this study was to investigate in vitro and in vivo the potential of ABTL0812, an oral anticancer compound currently in phase II clinical stage, as a novel therapy for GBM.ResultsWe showed that ABTL0812 inhibits cell proliferation in a wide panel of GBM cell lines and patient-derived glioblastoma stem cells (GSCs) with half maximal inhibitory concentrations (IC50s) ranging from 15.2 µM to 46.9 µM. Additionally, ABTL0812 decreased GSCs neurosphere formation. GBM cells aggressiveness is associated with a trans-differentiation process towards a less differentiated phenotype known as proneural to mesenchymal transition (PMT). ABTL0812 was shown to revert PMT and induce cell differentiation to a less malignant phenotype in GBM cell lines and GSCs, and consequently reduced cell invasion. As previously shown in other cancer types, we demonstrated that the molecular mechanism of action of ABTL0812 in glioblastoma involves the inhibition of Akt/mTORC1 axis by overexpression of TRIB3, and the activation of endoplasmic reticulum (ER) stress/unfolded protein response (UPR). Both actions converge to induce autophagy-mediated cell death. ABTL0812 anticancer efficacy was studied in vivo using subcutaneous and orthotopic intra-brain xenograft tumor models. We demonstrated that ABTL0812 impairs tumor growth and increases disease-free survival and overall survival of mice. Furthermore, the histological analysis of tumors indicated that ABTL0812 decreases angiogenesis. Finally, we investigated the combination of ABTL0812 with the standard of care treatments for GBM radiotherapy and temozolomide in an orthotopic model, detecting that ABTL0812 potentiates the efficacy of both treatments and that the strongest effect is obtained with the triple combination of ABTL0812+radiotherapy+temozolomide.ConclusionsOverall, the present study demonstrated the anticancer efficacy of ABTL0812 as single agent and in combination with the GBM standard of care treatments in models of glioblastoma and supports the clinical investigation of ABTL0812 as a potential novel therapy for this aggressive brain tumor type. |
| first_indexed | 2024-04-11T08:48:00Z |
| format | Article |
| id | doaj.art-cb7a5d13492143b0b02a9cc3d74d5cbd |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-04-11T08:48:00Z |
| publishDate | 2022-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-cb7a5d13492143b0b02a9cc3d74d5cbd2022-12-22T04:33:55ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2022-11-011210.3389/fonc.2022.943064943064Anticancer effects of ABTL0812, a clinical stage drug inducer of autophagy-mediated cancer cell death, in glioblastoma modelsAndrea Mancini0Alessandro Colapietro1Loredana Cristiano2Alessandra Rossetti3Vincenzo Mattei4Giovanni Luca Gravina5Giovanni Luca Gravina6Héctor Perez-Montoyo7Marc Yeste-Velasco8Jose Alfon9Carles Domenech10Claudio Festuccia11Laboratory of Radiobiology, Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, ItalyLaboratory of Radiobiology, Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, ItalyDepartment of Clinical Medicine, Public Health, Life Sciences, University of L'Aquila, L'Aquila, ItalyLaboratory of Radiobiology, Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, ItalyBiomedicine and Advanced Technologies Rieti Center, “Sabina Universitas”, Rieti, ItalyLaboratory of Radiobiology, Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, ItalyDivision of Radiation Oncology, Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L’Aquila, ItalyR&D Department, Ability Pharmaceuticals, Parc Tecnològic del Vallès, Cerdanyola del Vallès, Barcelona, SpainR&D Department, Ability Pharmaceuticals, Parc Tecnològic del Vallès, Cerdanyola del Vallès, Barcelona, SpainR&D Department, Ability Pharmaceuticals, Parc Tecnològic del Vallès, Cerdanyola del Vallès, Barcelona, SpainR&D Department, Ability Pharmaceuticals, Parc Tecnològic del Vallès, Cerdanyola del Vallès, Barcelona, SpainLaboratory of Radiobiology, Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, ItalyBackgroundGlioblastoma multiforme (GBM) is the most malignant adult brain tumor. Current standard of care treatments have very limited efficacy, being the patients´ overall survival 14 months and the 2-year survival rate less than 10%. Therefore, the treatment of GBM is an urgent unmet clinical need.MethodsThe aim of this study was to investigate in vitro and in vivo the potential of ABTL0812, an oral anticancer compound currently in phase II clinical stage, as a novel therapy for GBM.ResultsWe showed that ABTL0812 inhibits cell proliferation in a wide panel of GBM cell lines and patient-derived glioblastoma stem cells (GSCs) with half maximal inhibitory concentrations (IC50s) ranging from 15.2 µM to 46.9 µM. Additionally, ABTL0812 decreased GSCs neurosphere formation. GBM cells aggressiveness is associated with a trans-differentiation process towards a less differentiated phenotype known as proneural to mesenchymal transition (PMT). ABTL0812 was shown to revert PMT and induce cell differentiation to a less malignant phenotype in GBM cell lines and GSCs, and consequently reduced cell invasion. As previously shown in other cancer types, we demonstrated that the molecular mechanism of action of ABTL0812 in glioblastoma involves the inhibition of Akt/mTORC1 axis by overexpression of TRIB3, and the activation of endoplasmic reticulum (ER) stress/unfolded protein response (UPR). Both actions converge to induce autophagy-mediated cell death. ABTL0812 anticancer efficacy was studied in vivo using subcutaneous and orthotopic intra-brain xenograft tumor models. We demonstrated that ABTL0812 impairs tumor growth and increases disease-free survival and overall survival of mice. Furthermore, the histological analysis of tumors indicated that ABTL0812 decreases angiogenesis. Finally, we investigated the combination of ABTL0812 with the standard of care treatments for GBM radiotherapy and temozolomide in an orthotopic model, detecting that ABTL0812 potentiates the efficacy of both treatments and that the strongest effect is obtained with the triple combination of ABTL0812+radiotherapy+temozolomide.ConclusionsOverall, the present study demonstrated the anticancer efficacy of ABTL0812 as single agent and in combination with the GBM standard of care treatments in models of glioblastoma and supports the clinical investigation of ABTL0812 as a potential novel therapy for this aggressive brain tumor type.https://www.frontiersin.org/articles/10.3389/fonc.2022.943064/fullABTL0812glioblastomaTRIB3AktmTORER stress |
| spellingShingle | Andrea Mancini Alessandro Colapietro Loredana Cristiano Alessandra Rossetti Vincenzo Mattei Giovanni Luca Gravina Giovanni Luca Gravina Héctor Perez-Montoyo Marc Yeste-Velasco Jose Alfon Carles Domenech Claudio Festuccia Anticancer effects of ABTL0812, a clinical stage drug inducer of autophagy-mediated cancer cell death, in glioblastoma models Frontiers in Oncology ABTL0812 glioblastoma TRIB3 Akt mTOR ER stress |
| title | Anticancer effects of ABTL0812, a clinical stage drug inducer of autophagy-mediated cancer cell death, in glioblastoma models |
| title_full | Anticancer effects of ABTL0812, a clinical stage drug inducer of autophagy-mediated cancer cell death, in glioblastoma models |
| title_fullStr | Anticancer effects of ABTL0812, a clinical stage drug inducer of autophagy-mediated cancer cell death, in glioblastoma models |
| title_full_unstemmed | Anticancer effects of ABTL0812, a clinical stage drug inducer of autophagy-mediated cancer cell death, in glioblastoma models |
| title_short | Anticancer effects of ABTL0812, a clinical stage drug inducer of autophagy-mediated cancer cell death, in glioblastoma models |
| title_sort | anticancer effects of abtl0812 a clinical stage drug inducer of autophagy mediated cancer cell death in glioblastoma models |
| topic | ABTL0812 glioblastoma TRIB3 Akt mTOR ER stress |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2022.943064/full |
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