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

The biopharmaceutical company Ability Pharmaceuticals SL announced today that the full description of the mechanism of action of ABTL0812 has been published in the prestigious Autophagy journal (impact +11). The findings confirm a new strategy to tackle cancer based on the Reticular Stress (ER stress) that ABTL0812 induces in tumors, causing cell destruction by cytotoxic autophagy.

ABTL0812 is currently being tested in phase 2 open-label clinical trial in Spain and France in patients with endometrial cancer or squamous cell lung cancer, as a first-line treatment in combination with chemotherapy and as a maintenance treatment after the chemotherapy cycles. In fact, in the publication, the authors also describe for the first time the detection of mRNAs of two ER stress - related proteins (CHOP and TRIB3) in blood samples from patients undergoing this clinical trial, supporting their use as pharmacodynamic biomarkers.

This work will be also presented by AbilityPharma at the American Association for Cancer Research (AACR) 2020 Congress. “The description of this mechanism of action is a very important step for AbilityPharma, and shows the excellent collaboration engaged by our company and the INc-UAB. Besides, it supports a broader use of ABTL0812 in other cancer paradigms, apart from endometrial and squamous lung carcinoma” explains Carles Domènech, AbilityPharma’s executive chairman.

The research team was coordinated by Jose Miguel Lizcano from the INc-UAB and the UAB Biochemistry and Molecular Biology Department. For the past years, this team has investigated how ABTL0812 exerts its antitumor action. “Cancer cell death comes from a severe stress of the endoplasmic reticulum, a cellular organelle in charge of protein synthesis, resulting in the accumulation of defective proteins. As a consequence, cells activate a compensatory response, called Unfolded Protein Response (UPR). This response, when sustained in time, can induce autophagy that results in cancer cell death”, says Jose Miguel Lizcano.

The study also explains why ABTL0812 does not affect non-cancer cells: “The main advantage of this molecule lies in its specificity for tumor cells. To survive the hostile environment, cancer cells overtake it by having elevated levels of ER stress and UPR activity. Our drug provokes cancer cells to overpass the stress level in which this response has protective effects, causing their death, while healthy cells still have a wider margin”, says Pau Muñoz, researcher at the INc-UAB and first author of the article.

The study was performed in strong collaboration with the Bioactive Molecules Research Unit at the Institute for Advanced Chemistry of Catalonia (IQAC-CSIC). Several researchers from the following institutions also collaborated in this work: the Complutense University of Madrid (UCM), the Catalan Institute of Oncology (ICO), the Vall d’Hebron Research Institute (VHIR), the Vall d’Hebron Institute of Oncology (VHIO) and the Bellvitge Biomedical Research Institute (IDIBELL).

The research was funded by grants from the Spanish Ministry for the Economy and Competitiveness (MINECO) and the European Regional Development Fund (ERDF), the agency for business competitiveness ACCIÓ (Government of Catalonia), the Centre for the Development of Industrial Technology (CDTI) and the Empresa Nacional de Innovación, Sociedad Anónima (ENISA).

Original article
Muñoz-Guardiola P, Casas J, Megías-Roda E, Solé S, Perez-Montoyo H, Yeste-Velasco M, Erazo T, Diéguez-Martínez N, Espinosa-Gil S, Muñoz-Pinedo C, Yoldi G, Abad JL, Segura MF, Moran T, Romeo M, Bosch-Barrera J, Oaknin A, Alfón J, Domènech C, Fabriàs G, Velasco G, Lizcano JM. The Anti-Cancer Drug ABTL0812 Induces ER Stress-Mediated Cytotoxic Autophagy by Increasing Dihydroceramide Levels in Cancer Cells. Autophagy 2020 May 13. doi: 10.1080/15548627.2020.1761651.