Mancini Andrea, Colapietro Alessandro, Cristiano Loredana, Rossetti Alessandra, Mattei Vincenzo, Gravina Giovanni Luca, Perez-Montoyo Héctor, Yeste-Velasco Marc, Alfon Jose, Domenech Carles, Festuccia Claudio
Laboratory of Radiobiology, Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy.
Department of Clinical Medicine, Public Health, Life Sciences, University of L'Aquila, L'Aquila, Italy.
Front Oncol. 2022 Nov 2;12:943064. doi: 10.3389/fonc.2022.943064. eCollection 2022.
Glioblastoma 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.
The aim of this study was to investigate and the potential of ABTL0812, an oral anticancer compound currently in phase II clinical stage, as a novel therapy for GBM.
We 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 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.
Overall, 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.
多形性胶质母细胞瘤（GBM）是最恶性的成人脑肿瘤。当前的标准治疗方法疗效非常有限，患者的总生存期为14个月，2年生存率低于10%。因此，GBM的治疗是一项亟待满足的临床需求。
本研究的目的是调查目前处于II期临床阶段的口服抗癌化合物ABTL0812作为GBM新疗法的潜力。
我们发现ABTL0812在多种GBM细胞系和患者来源的胶质母细胞瘤干细胞（GSCs）中抑制细胞增殖，半数最大抑制浓度（IC50）范围为15.2µM至46.9µM。此外，ABTL0812减少了GSCs神经球的形成。GBM细胞的侵袭性与向一种分化程度较低的表型的转分化过程有关，这种表型称为神经上皮向间充质转变（PMT）。研究表明，ABTL0812可逆转PMT，并诱导GBM细胞系和GSCs向恶性程度较低的表型分化，从而减少细胞侵袭。如先前在其他癌症类型中所示，我们证明ABTL0812在胶质母细胞瘤中的分子作用机制涉及通过TRIB3的过表达抑制Akt/mTORC1轴，以及激活内质网（ER）应激/未折叠蛋白反应（UPR）。这两种作用共同导致自噬介导的细胞死亡。使用皮下和原位脑内异种移植肿瘤模型研究了ABTL0812的抗癌疗效。我们证明ABTL0812可抑制肿瘤生长，并延长小鼠的无病生存期和总生存期。此外，肿瘤的组织学分析表明ABTL0812可减少血管生成。最后，我们在原位模型中研究了ABTL0812与GBM标准治疗方法放疗和替莫唑胺的联合使用，发现ABTL0812可增强两种治疗方法的疗效，并且ABTL0812+放疗+替莫唑胺三联组合的效果最强。
总体而言，本研究证明了ABTL0812作为单一药物以及与GBM标准治疗方法联合使用在胶质母细胞瘤模型中的抗癌疗效，并支持将ABTL0812作为这种侵袭性脑肿瘤类型的潜在新疗法进行临床研究。
