Researchers from the Translational Research group on Cancer in Childhood and Adolescence of the Vall d'Hebron Research Institute (VHIR), in collaboration with the laboratory of Dr. José Miguel Lizcano (Autonomous University of Barcelona) and the biopharmaceutical company AbilityPharma (Cerdanyola del Vallès, Barcelona), have tested the therapeutic potential of the antitumor drug ABTL0812 in models of neuroblastoma, one of the most aggressive childhood solid tumours and with a poor prognosis when in advanced stages. These results, published in the journal Cell Death & Disease, suggest a new therapeutic strategy for the treatment of one of the tumours with fewer therapeutic options."Neuroblastoma is one of the most common solid tumours of childhood. They represent between 8 and 10 percent of all solid tumours and have a similar incidence in boys and girls. Despite all therapeutic efforts, high-risk neuroblastomas continue to have a poor prognosis. In addition, patients who overcome the disease can suffer significant side effects as a result of the disease itself or due to the treatment, a serious situation that demands new therapies", underline the coordinators of the team, Dr. Soledad Gallego and Dr. Josep Sánchez de Toledo, heads of the Translational Research group on Cancer in Childhood and Adolescence.ABTL0812 is a first-in-class compound that, through a unique mechanism of action, activates cytotoxic autophagy, an innovative strategy to specifically kill tumour cells, without harming normal cells, making it a safe treatment, explains Dr. Carles Domènech, chief scientific officer of AbilityPharma, which is conducting research and development of ABTL0812 to become a new therapeutic option for the treatment of cancer. To date, ABTL0812 has been shown to exert a potent antitumor effect in preclinical models in different types of cancers. In 2016, a phase 1 clinical trial was successfully completed in advanced adult tumours, demonstrating high safety and minimal toxicity, in addition, the first signs of therapeutic efficacy were detected. In 2020, AbilityPharma has completed a phase 2 study in endometrial and lung cancer patients, where ABTL0812 combined with chemotherapy, has demonstrated superior therapeutic efficacy than chemotherapy and also high safety. Also in 2020, approval was obtained in the US and Spain to start a phase 2b study in pancreatic cancer.This work, led by Dr. Miguel Segura, researcher at the Neural Tumour Laboratory within the VHIR Translational Research Group on Cancer in Childhood and Adolescence, is the first to investigate the therapeutic potential of ABTL0812 in childhood cancer models. The results of the study confirm the therapeutic effect of ABTL0812 in preclinical neuroblastoma models as a single therapy or in combination with other therapies currently in use for the treatment of neuroblastomas. Its high safety and low toxicity have also been demonstrated in these models, a very important aspect, especially in pediatric cancers, comments Dr. Miquel Segura, principal investigator of this study. These studies have led to the obtaining of Orphan Drug Designation (ODD) by the European and American drug agencies (EMA and FDA), which facilitates and accelerates the process for ABTL0812 to be approved as a therapy for neuroblastoma.The social impact of this research by the VHIR Translational Research on Childhood and Adolescent Cancer group and AbilityPharma may have a great impact on the treatment of childhood cancer. In this sense, Mr. Joaquín José Molí, president of the NEN Association (Association of Relatives and Friends of Children with Neuroblastoma) has added, "from the NEN Association we support various research projects related to the treatment of Neuroblastoma, as in the case of AbilityPharma. We are very happy to see how the project with ABTL0812 continues to advance, and to see that the recently published results open the door to new research to make ABTL0812 a new therapeutic option for patients with neuroblastoma".ABTL0812ABTL0812 is an orally administered, fully differentiated, first-in-class antitumor compound that causes cancer cell death by autophagy (self-digestion).ABTL0812 has positively completed an open phase 2a clinical study in Europe in patients with endometrial cancer or squamous lung cancer, as first-line treatment in combination with chemotherapy and as chronic maintenance treatment after chemotherapy cycles, providing an increase in efficiency. The study has been carried out in leading cancer hospitals in Spain and France.Currently, the Spanish Agency for Medicines and Health Products (AEMPS) and the US FDA have authorized an international multicenter, placebo-controlled, phase 2b clinical trial in pancreatic cancer to investigate ABTL0812 in combination with FOLFIRINOX chemotherapy. ABTL0812 also has the Orphan Drug Designation (ODD) for pancreatic cancer, biliary cancer and pediatric neuroblastoma cancer approved by the FDA in the United States and by the EMA in Europe.A phase 1/1b clinical trial (29 patients with advanced solid tumours) was previously conducted, in which ABTL0812 showed great safety and tolerability and no dose-limiting toxicities were identified. Signs of efficacy were observed, notably two patients had long-term stabilizations of the disease, for more than a year (14 and 18 months). Furthermore, ABTL0812 showed action on biomarkers with a dose-response effect.The mechanism of action of ABTL0812 is unique. ABTL0812 is a targeted therapy that kills cancer cells by robust induction of cytotoxic autophagy. ABTL0812 binds and activates the transcriptional activity of the nuclear receptors PPAR&alpha, and PPAR&gamma,, leading to the induction of endoplasmic reticular stress (ER-stress) and the blocking of the activation of Akt, the central kinase of the PI3K/Akt/mTOR pathway. This double action of activation of ER-stress and blocking of the Akt/mTOR axis converge to induce autophagy, which leads to the death of cancer cells. The mechanism of action was published partially in Clinical Cancer Research in May 2016, and fully in the journal Autophagy in May 2020.In preclinical cancer models, ABTL0812 is effective as a single agent with an excellent safety profile in a broad spectrum of cancer types: lung, endometrial and pancreatic cancer, neuroblastoma, and glioma. It also enhances chemotherapy (taxanes, platinum compounds and gemcitabine) with a synergistic effect without increasing its toxicity.Ability PharmaceuticalsAbility Pharmaceuticals is a biopharmaceutical company with one product, ABTL0812, in phase 2 clinical studies focused on improving the future of oncology by developing innovative therapies that address unmet medical needs. In April 2016, AbilityPharma entered into a territorial license agreement for ABTL0812 with SciClone Pharmaceuticals to develop and market the product in China.