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

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

Research output: Contribution to journalArticleResearch

10 Citations (Scopus)

Abstract

© 2019 Elsevier Inc. Objectives: 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. Methods: 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. Results: 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. Conclusions: ABTL0812 may represent a novel and highly effective therapeutic agent by inducing TRIB3 expression and autophagy in EC patients, including those with poorer prognosis.
Original languageEnglish
Pages (from-to)425-435
JournalGynecologic Oncology
Volume153
DOIs
Publication statusPublished - 1 May 2019

Keywords

  • ABTL0812
  • Endometrial cancer
  • PI3K/AKT/mTOR1 pathway
  • Small molecule inhibitor
  • TRIB3

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