Details

Autor(en) / Beteiligte

• Felip, Isidre
• Moiola, Cristian Pablo
• Megino-Luque, Cristina
• Lopez-Gil, Carlos
• Cabrera, Silvia
• Solé-Sánchez, Sonia
• Muñoz-Guardiola, Pau
• Megias-Roda, Elisabet
• Pérez-Montoyo, Héctor
• Alfon, José
• Yeste-Velasco, Marc
• Santacana, María
• Dolcet, Xavier
• Reques, Armando
• Oaknin, Ana
• Rodríguez-Freixinos, Victor
• Lizcano, José Miguel
• Domènech, Carles
• Gil-Moreno, Antonio
• Matias-Guiu, Xavier
• Colas, Eva
• Eritja, Nuria

Titel

Therapeutic potential of the new TRIB3-mediated cell autophagy anticancer drug ABTL0812 in endometrial cancer

Ist Teil von

• Gynecologic oncology, 2019-05, Vol.153 (2), p.425-435

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2019

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• The PI3K/AKT/mTOR pathway is frequently overactivated in endometrial cancer (EC). We assessed the efficacy of ABTL0812, a novel first-in-class molecule presenting a unique mechanism of action inhibiting this pathway. We investigated the effects of ABTL0812 on proliferation, cell death and modulation of intracellular signaling pathways in a wide panel of endometrioid and non-endometrioid cell lines, an inducible PTEN knock-out murine model, and two patient-derived xenograft murine models of EC. Then, TRIB3 expression was evaluated as potential ABTL0812 pharmacodynamic biomarker in a Phase 1b/2a clinical trial. ABTL0812 induced an upregulation of TRIB3 expression, resulting in the PI3K/AKT/mTOR axis inhibition and autophagy cell death induction on EC cells but not in healthy endometrial cells. ABTL0812 treatment also impaired PTEN knock-out cells to progress from hyperplasia to cancer. The therapeutic effects of ABTL0812 were demonstrated in vivo. ABTL0812 increased TRIB3 mRNA levels in whole blood samples of eight EC patients, demonstrating that TRIB3 mRNA could be used as a pharmacodynamic biomarker to monitor the ABTL0812 treatment. ABTL0812 may represent a novel and highly effective therapeutic agent by inducing TRIB3 expression and autophagy in EC patients, including those with poorer prognosis. [Display omitted] •ABTL0812 is a small molecule inhibitor and is an effective therapeutic option for high-risk endometrial cancer patients.•ABTL0812 acts by inducing TRIB3 expression, inhibiting the PI3K/AKT/mTOR axis, and promoting autophagy cell death.•In preclinical models, ABTL0812 kills endometrial cancer cells but not healthy endometrial cells.•ABTL0812 stops hyperplasic lesions to progress to cancer.