Periodic Reporting for period 1 - TARGEPILIVER (Characterization of Key Epigenetic Targets in Hepatic Fibrosis and Hepatocellular Carcinoma Development. Generation of New Antifibrotic and Antitumoral Drugs.)
Periodo di rendicontazione: 2015-12-01 al 2017-11-30
The exploration of the epigenetic mechanisms involved in hepatocarcinogenesis processes can open the door to the development of promising new therapies. This has been a pioneering project in the field of hepatic tumor disease, in which, in addition to identifying and characterizing new epigenetic targets, new pharmacological agents potentially capable of preventing and / or treating hepatic fibrosis and HCC have been developed. The weight of chronic liver diseases in Europe has increased greatly in recent decades, assuming a clinical and economic problem, and the prognosis is that they continue to increase in the coming years. Liver cirrhosis along with HCC cause 220,000 deaths a year in the European Union (http://www.easl.eu/_eu-policy/publications) highlighting the need to develop effective therapies.
The objectives of this project have been to address this problem with an innovative technology and a multidisciplinary approach and can therefore be susceptible to further clinical development. Our proposal presented two general objectives: i) a comprehensive analysis of the expression and pathological significance of two epigenetic modifiers, the DNA and histone methyltransferases DNMT1 and G9a, in experimental fibrosis, HCC and ii) the development of novel and efficacious DNMT1 and G9a specific inhibitors with a good safety profile, which is critical when treating patients with compromised liver function. These new epigenetic pharmacological tools may be further developed into drugs to prevent chronic liver diseases progression, and to treat HCC alone or in combination with existing drugs.
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Conclusion: Combined targeting of G9a/DNMT1 with compounds like CM-272 is a promising strategy for HCC treatment. Our findings also underscore the potential of differentiation therapy in HCC.
First, we demonstrated the coordinated overexpression of G9a and DNMT1, along with their key adaptor UHRF1, in human HCC tissues. The pathophysiological relevance of this matched overexpression is suggested by its significant association with molecular, histological and clinical characteristics indicative of aggressive disease and poor prognosis. The rationale for the simultaneous inhibition of G9a/DNMT1 in HCC was further established by the synergistic anti-proliferative action of combined G9a and DNMT1 specific antagonists. Thus, CM-272 exerted a very potent antiproliferative effect in a wide panel of human HCC cell lines, which also showed a
close correlation in the expression of G9a, DNMT1 and the UHRF1 adaptor. CM-272 inhibited HCC cells growth in vivo in the absence of apparent toxicity. The high specificity of CM-272 for G9a/DNMT1, and a mechanism of action based on the reversible inhibition of G9a and DNMT1 binding to their substrates, but not to Sadenosylmethionine, may contribute to explain its lack of off-target effects and systemic toxicity.
A patent application for the small molecules mentioned in this project was initially filed (June 2014), covering chemical series for these compounds and finally accepted (Agirre, X. et al. Novel compounds as dual inhibitors of histone methyltransferases and DNA methyltransferases. WO2015192981A1, 30 March (2015). Any potential new application derived of these findings will be also susceptible to be protected from IP perspective. If the output of this research is amenable for industrial development it will be readily transferred to interested companies, with positive repercussions for the advancement of this research line, the university's wealth and the scientific and patient’s community at large.