Abstract 922: ABTL0812: A new drug class with oral antitumor action inhibiting mTOR activity and DHFR expression

• Published in: Cancer research (Chicago, Ill.) Ill.), 2012-04, Vol.72 (8_Supplement), p.922-922
• Main Authors: Alfon, Jose, Espadaler, Jordi, García-Martínez, Jose A., Lizcano, Jose Miguel, Domènech, Carles
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2012-922

ABTL0812* is a lipid analogue that has shown high efficacy by the oral route in mouse models of cancer. Here we show that two clinically validated targets are responsible for the cytotoxic effect of ABTL0812: mTOR (mammalian target of rapamycin), as shown by the dramatic reduction in S6 phosphorylation, and dihydrofolate reductase (DHFR), as shown by its reduced expression, resulting in autophagic cell death. Moreover, the compound's cellular potency increases with incubation time, and it has a long lasting cytotoxic effect after removing the compound from the incubation medium. In vivo efficacy was determined in a human lung cancer xenograft model by subcutaneously injecting A549 human lung adenococarcinoma cells into nu/nu mice. ABT0812 was administered daily at two dose levels and its impact on tumor volume was measured. ABT0812 showed a similar efficacy to docetaxel but with much lower toxicity, and better efficacy than erlotinib. Histological analysis of the tumors revealed increased necrotic area, more inflammatory cells and fewer cells undergoing mitosis. Additionally, plasma levels of ABTL0812 were inversely correlated with tumor volume, reinforcing the concentration-effect relationship. A parallel study was performed to evaluate ABTL0812 efficacy in a pancreatic cancer model. Nu/nu mice were subcutaneously injected with MiaPaCa-2 cells and the volume of xenograft was used as a measurement of efficacy. Again, ABTL0812 showed a statistically significant reduction of tumor volume, increased tumor cell death, and better tolerance than gemcitabine in the mice. DMPK properties in rats and dogs showed very low in vitro hepatic metabolism, ∼50% bioavailability and half lives that calculate to single daily oral administration. Safety pharmacology studies with very high doses of the compound showed no impact on the central nervous system. Ongoing toxicological studies show that the margin between efficacy and toxicity is broad. In conclusion, ABTL0812 is a lipid analogue that hits two clinically validated targets: mTOR and DHFR. This multitarget property increases antitumor efficacy and reduces drug resistance. In addition, preliminary in vivo results indicate that the potential therapeutic margin will be high. * Protected by PCT WO 2010/106211, by Escribá Ruiz PV, et al., licensed to AB-Therapeutics, SL. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 201