Vall d'Hebron Talks by VHIR 'Fine-tuning endoplasmic reticulum stress and autophagy in cancer: Discovery and preclinical/clinical development of ABTL0812'

Speaker: Jose Miguel Lizcano De Vega, Head of group Protein kinases in cancer research (VHIR)

Summary: I will present the preclinical and clinical development of ABTL0812 (2-hydroxylinoleic acid), a first-in-class anticancer molecule. ABTL0812 selectively kills cancer cells by inducing endoplasmic reticulum (ER) stress and the UPR-mediated cytotoxic autophagy, without affecting healthy cells. Mechanistically, ABTL0812 inhibits desaturase-1, the last enzyme in the ceramide biosynthesis pathway, leading to an accumulation of long-chain dihydroceramides. This, in turn, results in the activation of ER stress and the unfolded protein response (UPR), ultimately inducing cytotoxic autophagy in cancer cells. This represents a novel therapeutic approach, highlighting the potential of ER stressors as effective anticancer agents.
Clinical trial data demonstrate that ABTL0812 has a favourable safety and tolerability profile. Phase 2 clinical trials have shown that ABTL0812 enhances the efficacy of standard chemotherapy regimens in patients with advanced squamous non-small cell lung cancer (NSCLC) and advanced endometrial cancer. ABTL0812 is currently in Phase 2b clinical trial, as a first-line therapy in combination with FOLFIRINOX, for patients with advanced or metastatic pancreatic cancer. Additionally, I will present supporting preclinical data that provide a rationale for this clinical trial.