TY - JOUR
T1 - Therapeutic potential of the new TRIB3-mediated cell autophagy anticancer drug ABTL0812 in endometrial cancer
AU - Felip, Isidre
AU - Moiola, Cristian Pablo
AU - Megino-Luque, Cristina
AU - Lopez-Gil, Carlos
AU - Cabrera, Silvia
AU - Solé-Sánchez, Sonia
AU - Muñoz-Guardiola, Pau
AU - Megias-Roda, Elisabet
AU - Pérez-Montoyo, Héctor
AU - Alfon, José
AU - Yeste-Velasco, Marc
AU - Santacana, María
AU - Dolcet, Xavier
AU - Reques, Armando
AU - Oaknin, Ana
AU - Rodríguez-Freixinos, Victor
AU - Lizcano, José Miguel
AU - Domènech, Carles
AU - Gil-Moreno, Antonio
AU - Matias-Guiu, Xavier
AU - Colas, Eva
AU - Eritja, Nuria
N1 - Publisher Copyright:
© 2019 Elsevier Inc.
PY - 2019/5
Y1 - 2019/5
N2 - 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.
AB - 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.
KW - ABTL0812
KW - Endometrial cancer
KW - PI3K/AKT/mTOR1 pathway
KW - Small molecule inhibitor
KW - TRIB3
UR - http://www.scopus.com/inward/record.url?scp=85062438329&partnerID=8YFLogxK
U2 - 10.1016/j.ygyno.2019.03.002
DO - 10.1016/j.ygyno.2019.03.002
M3 - Article
C2 - 30853360
AN - SCOPUS:85062438329
SN - 0090-8258
VL - 153
SP - 425
EP - 435
JO - Gynecologic Oncology
JF - Gynecologic Oncology
IS - 2
ER -