Determination of recommended phase II dose of ABTL0812, a novel regulator of Akt/mTOR axis, by pharmacokinetic-pharmacodynamic modelling

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

“…Interestingly, these blood cells were healthy and viable regardless having high expression levels of UPR genes. In agreement with this observation, patients treated with ABTL0812 did not show decrease in peripheral blood cell counts during previous clinical phase 1 (32) Notably, we propose the expression of TRIB3 and DDIT3 mRNAs in blood as pharmacodynamic biomarkers for ABTL0812 therapy of patients enrolled in the ongoing Phase 2 clinical trial ( Figure 4 and Fig. S5).…”

“…Human blood samples from patients enrolled in the clinical trial were used for the pharmacodynamic biomarker studies (32). Briefly, total RNA was isolated from whole blood using the RiboPure RNA purification kit for whole blood (Thermo Fisher Scientific, AM1928).…”

Therapeutic Potential of Autophagy Modulation in Cholangiocarcinoma

“…This is the case for some drugs such as tetrahydrocannabinol (THC), which exerts its antitumoral action by inducing ER-stress-mediated apoptotic cell death [149,165,166] and has shown anticancer efficacy in CCA [167]. ABTL0812 is the autophagy inductor currently being evaluated in CCA models with the most complete description of its mechanism of action, and it already showed preliminary clinical efficacy on a CCA patient derived from a phase I trial in patients with solid tumors [160,168]. In xenograft models, ABTL0812 potentiated gemcitabine plus cisplatin anticancer efficacy by upregulating TRIB3 and CHOP levels, two markers that have been validated for the first time as surrogate pharmacodynamic biomarkers in endometrial and lung cancer patients [158,160,169,170].…”