Publications

The anti-cancer drug ABTL0812 induces ER stress-mediated cytotoxic autophagy by increasing dihydroceramide levels in cancer cells.

Pau Muñoz-Guardiola,Josefina Casas,Elisabet Megías-Roda,Sònia Solé,Héctor Perez-Montoyo,Marc Yeste-Velasco,Tatiana Erazo,Nora Diéguez-Martínez,Sergio Espinosa-Gil,Cristina Muñoz-Pinedo,Guillermo Yoldi,Jose L Abad,Miguel F Segura,Teresa Moran,Margarita Romeo,Joaquim Bosch-Barrera,Ana Oaknin,Jose Alfón,Carles Domènech,Gemma Fabriàs,Guillermo Velasco & Jose M Lizcano

Posted online: 13 May 2020
https://doi.org/10.1080/15548627.2020.1761651

Abstract:

ABTL0812 is a first-in-class small molecule with anti-cancer activity, which is currently in clinical evaluation in a phase 2 trial in patients with advanced endometrial and squamous non-small cell lung carcinoma (NCT03366480). Previously, we showed that ABTL0812 induces TRIB3 pseudokinase expression, resulting in the inhibition of the AKT-MTORC1 axis and macroautophagy/autophagy-mediated cancer cell death. However, the precise molecular determinants involved in the cytotoxic autophagy caused by ABTL0812 remained unclear. Using a wide range of biochemical and lipidomic analyses, we demonstrated that ABTL0812 increases cellular long-chain dihydroceramides by impairing DEGS1 (delta 4-desaturase, sphingolipid 1) activity, which resulted in sustained ER stress and activated unfolded protein response (UPR) via ATF4-DDIT3-TRIB3 that ultimately promotes cytotoxic autophagy in cancer cells. Accordingly, pharmacological manipulation to increase cellular dihydroceramides or incubation with exogenous dihydroceramides resulted in ER stress, UPR and autophagy-mediated cancer cell death. Importantly, we have optimized a method to quantify mRNAs in blood samples from patients enrolled in the ongoing clinical trial, who showed significant increased DDIT3 and TRIB3 mRNAs. This is the first time that UPR markers are reported to change in human blood in response to any drug treatment, supporting their use as pharmacodynamic biomarkers for compounds that activate ER stress in humans. Finally, we found that MTORC1 inhibition and dihydroceramide accumulation synergized to induce autophagy and cytotoxicity, phenocopying the effect of ABTL0812. Given the fact that ABTL0812 is under clinical development, our findings support the hypothesis that manipulation of dihydroceramide levels might represents a new therapeutic strategy to target cancer.

LATEST NEWS

09.06.2020

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AbilityPharma publishes full characterization of mechanism of action of ABTL0812, a Phase II clinical inducer of cytotoxic autophagy in cancer cells, in Autophagy journal + info
25.03.2020

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AbilityPharma awarded €5 million from the Horizon Europe EIC Accelerator Pilot Program to conduct a Phase 2b clinical trial with ABTL0812 in patients with advanced pancreatic cancer + info
12.09.2019

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AbilityPharma rises € 3.5 million in a financing round to complete the current oncologic phase 2 clinical trial and license ABTL0812 to an international pharmaceutical company + info
31.05.2019

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Ability Pharmaceuticals Announces the Presentation of the First Results of ABTL0812 as First Line in Patients with Endometrial or Lung Cancer at 2019 ASCO Annual Meeting + info
04.02.2019

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Ability Pharmaceuticals Announces the Approval in China of a Clinical Study in Pancreatic Cancer with ABTL0812 + info
30.01.2019

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Ability Pharmaceuticals is attending the BIOMED EVENT® by INVEST SECURITIES and the Cholangiocarcinoma Foundation Annual Conference + info
05.12.2018

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AbilityPharma ha superado el millón de euros en la ronda de crowdfunding que abrió el pasado mes de septiembre + info
07.11.2018

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Ability Pharmaceuticals Announces FDA-Orphan Drug Designation for ABTL0812 in Biliary Tract Cancer + info
19.09.2018

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Ability Pharmaceuticals anuncia la inclusión del primer paciente en el estudio clínico de la fase 2 de ABTL0812 en Francia + info
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