Anticancer effects of ABTL0812, a clinical stage drug inducer of autophagy-mediated cancer cell death, in glioblastoma models

by Selleckchem | Dec 07 2023

Background: 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.

Methods: The 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.

Results: 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 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.

Conclusions: 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.

Comments:

The study you described provides valuable insights into the potential of ABTL0812 as a novel therapy for glioblastoma multiforme (GBM), a highly malignant adult brain tumor with limited treatment options and poor prognosis. Here's a summary of the key findings and implications of the study:

**Background:**
- **GBM Challenge:** GBM is a highly aggressive brain tumor with limited treatment options and poor survival rates.
- **Current Standard of Care:** Existing treatments have limited efficacy, and there is a pressing need for more effective therapies.

**Methods:**
- **Study Objective:** The study aimed to investigate the potential of ABTL0812, an oral anticancer compound in phase II clinical trials, as a therapy for GBM.
- **Approach:** The researchers conducted in vitro and in vivo experiments to assess ABTL0812's effects on GBM cell lines and patient-derived glioblastoma stem cells (GSCs).

**Results:**
- **Inhibition of Cell Proliferation:** ABTL0812 inhibited cell proliferation in various GBM cell lines and GSCs.
- **Reduction of Aggressiveness:** ABTL0812 reversed the process of proneural to mesenchymal transition (PMT), decreasing cell invasion and promoting a less malignant phenotype.
- **Mechanism of Action:** ABTL0812 inhibited the Akt/mTORC1 axis, induced endoplasmic reticulum (ER) stress and unfolded protein response (UPR), leading to autophagy-mediated cell death.
- **In Vivo Efficacy:** ABTL0812 impaired tumor growth, increased disease-free survival, and overall survival in mouse models of GBM. It also reduced angiogenesis in tumors.
- **Combination Therapy:** ABTL0812, when combined with standard treatments (radiotherapy and temozolomide), enhanced the efficacy of these therapies, particularly in the triple combination approach.

**Conclusions:**
- **Clinical Implications:** The study supports the clinical investigation of ABTL0812 as a potential therapy for GBM, either as a single agent or in combination with existing standard treatments.
- **Significance:** ABTL0812 demonstrated promising anticancer efficacy in preclinical models, offering hope for a much-needed advancement in GBM treatment options.
- **Future Research:** Further clinical trials are warranted to validate these findings in human patients and to assess the safety and efficacy of ABTL0812 in real-world scenarios.

This research provides a strong foundation for the development of ABTL0812 as a potential breakthrough in the treatment of GBM, addressing the urgent unmet clinical need for more effective therapies for this aggressive brain tumor type.