ABTL0812 enhances antitumor effect of paclitaxel and reverts chemoresistance in triple‐negative breast cancer models

Abstract

R ABTL0812 enhances antitumor effect of paclitaxel and reverts chemoresistance in triple-negative breast cancer modelsDear Editor, Triple-negative breast cancer (TNBC) accounts for 20% of all breast carcinomas and lacks a validated targeted therapy; thus, currently, cytotoxic chemotherapy is the treatment of choice [1]. Compared with other breast cancer types, patients with TNBC are younger, have larger tumors, a higher risk of metastasis, and a higher rate of recurrence [2]. Among all the subtypes described by Lehmann et al.[3], mesenchymal-like and mesenchymal stem-like (MSL) subtypes had the lowest 5-year distant metastasis-free survival rates. Therefore, the aggressiveness and poor prognosis of TNBC call for new and more effective therapies.ABTL0812 is a novel first-in-class anticancer agent. It was initially selected for preclinical development based on its anti-proliferative effect on different human cancer cell lines and its safety profile in animal models as both single therapy and in combination with chemotherapy [4][5][6][7][8]. A first-in-human phase I clinical trial with ABTL0812 was successfully completed, showing a high safety profile and signs of efficacy in patients with advanced solid tumors who had received ABTL0812 orally after several chemotherapy lines (NCT02201823). Based on these findings, a phase I/IIa clinical trial was performed whereby ABTL0812 was administered as first-line therapy in combination with paclitaxel and carboplatin in patients with advanced/recurrent endometrial and metastatic squamous non-small cell lung cancers (NSCLC). The trial results observed improved efficacy without increasing toxicities, compared to chemotherapy alone (NCT03366480).

Anticancer effects of ABTL0812, a clinical stage drug inducer of autophagy-mediated cancer cell death, in glioblastoma models

“…Statistical analysis showed no difference in IC50 calculated for glioblastoma compared to GSC cell lines ( Supplementary Figures S1A, B ). Importantly, in astrocytes and human brain derived endothelial cells (HBMVECs) the calculated IC50 values were 380 μM and 225 μM, respectively ( Figure 1C ), confirming previous published data showing that non-cancer cells are viable at the same ABTL0812 concentrations that are cytotoxic for cancer cells ( 13 – 18 ). Morphological changes were observed after administration of ABTL0812 with the acquisition of a more differentiated astrocyte phenotype, which was evident at ABTL0812 concentrations between 10 and 20 μM.…”

“…Very importantly, ABTL0812 anticancer effects were also detected in glioblastoma stem cells, which are more resistant to chemotherapy and radiotherapy, at similar concentrations as for glioblastoma non-stem cells. Also noteworthy is the fact that ABTL0812 at supratherapeutic concentrations did not affect non-tumoral brain cells, as previously detected in other models ( 13 – 18 ).…”

“…The decrease of p-Akt Ser473, and also p-Akt Thr308, was confirmed by ELISA in U251, U87MG, A172 and GSC-5 cells ( Figure 5B ). Moreover, it was previously shown that ABTL0812 induces sustained ER stress that results in activation of unfolded protein response (UPR) via PERK-eIF2α-ATF4-CHOP-TRIB3 ( 16 – 18 ). Immunoblotting analysis of this pathway showed that ABTL0812 induced pPERK, peIF2α, ATF4 and CHOP in a concentration-dependent manner in U87MG cells.…”

“…Both actions converge to induce a robust and persistent autophagy that results in cancer cell death, while non-tumoral cells are spared. ABTL0812 anticancer activity as a single agent by oral route has been demonstrated in preclinical animal models, including pancreatic cancer ( 13 , 14 ), endometrial cancer ( 15 ), non-small cell lung carcinoma (NSCLC) ( 13 , 14 , 16 ), neuroblastoma ( 17 ) and breast cancer ( 18 ). Moreover, in these models ABTL0812 potentiates chemotherapy activity without increasing its toxicity ( 15 , 16 , 18 ).…”

“…ABTL0812 anticancer activity as a single agent by oral route has been demonstrated in preclinical animal models, including pancreatic cancer ( 13 , 14 ), endometrial cancer ( 15 ), non-small cell lung carcinoma (NSCLC) ( 13 , 14 , 16 ), neuroblastoma ( 17 ) and breast cancer ( 18 ). Moreover, in these models ABTL0812 potentiates chemotherapy activity without increasing its toxicity ( 15 , 16 , 18 ). At clinical level, to date ABTL0812 has successfully completed a first-in-human phase 1 clinical trial showing a high safety profile and signs of efficacy in patients with advanced solid tumors (NCT02201823) ( 19 ).…”