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DNA Therapeutics Reports a Novel Mechanism of Action and a Biomarker of its Lead Molecule Dbait That Open an Innovative Pathway-Targeting in Molecular Cancer Therapy
Thursday, April 12, 2007
Evry, France -- DNA Therapeutics S.A. an emerging pharmaceutical company specialized in innovative cancer therapy announces today the elucidation of a new mechanism of action and the identification of a biomarker of its first-in-class antitumoral lead molecule Dbait. It will be presented at the forecoming American Association for Cancer Research annual meeting 2007. Its abstract is now available online. The presentation itself will be available from April 16th onwards at http://www.dna-therapeutics.com/doc/File/pdf/AACR2K7.pdf
Background: Most of the cancer therapies induce directly or indirectly DNA double strand breaks (DSBs), but unfortunately cells possess DNA repair complexes specialized in repairing these lethal lesions, which are responsible of lessened efficacy, or refractoriness of classical therapies.
A new family of anticancer drugs, named short inhibiting DNA (siDNA), has been designed by DNA Therapeutics' scientific founder team to inhibit these repair activities. The first lead, named Dbait, mimics DSBs, diverts DSB repair system from their primary objective, and facilitates cancer cells killing by traditional therapies.
The proof of concept work was presented last November at the 18th EORTC-NCI-AACR Symposium "Molecular Targets and Cancer Therapeutics" (Prague): the median survival of nude mice grafted with human tumor cell lines treated by intra-tumoral injection of Dbait, in association with radiotherapy, is significantly increased in a dose-dependent manner. MRI and cytology analysis of tumors shows that Dbait strongly enhances irradiation-induced necrosis and apoptosis.
New finding: The present study aims at deciphering the underlying mechanism of action of Dbait at molecular and cellular levels, and in particular its impact on DSB repair foci organization at chromatin level.
It is known that the kinases ATM/ATR and DNA-PK are involved in the general cellular response to DNA damage by signaling proteins that control cell cycle, apoptosis and DNA repair. In particular, ATM and DNA-PK both phosphorylate the H2AX, an isoform of the histone H2A, after exposure to ionizing radiation. The appearance of the phosphorylated H2AX, called gamma-H2AX, in cell nuclei is an indicator of DSB repair foci.
Our data provides evidence that Dbait specifically activates DNA-PK but not ATM kinase activity, as the phosphorylation of H2AX is in a DNA-PK dependent manner. Dbait-induced H2AX phosphorylation persists more than 6 days as compared to 1 day for irradiation. Cell imaging shows that the global distribution of gamma-H2AX in the nucleus of the cells transfected by Dbait was radically different of the gamma-H2AX foci organization observed when H2AX phosphorylation was triggered by irradiation alone. This indicates that DSB repair system is dramatically disorganized in Dbait transfected cells, and points out a new mechanism of action.
In addition, the amount of gamma-H2AX is proportional to that of Dbait in cultured cells and in the cells from tumor samples. gamma-H2AX appears to be a specific biomarker of Dbait in cells. It can be easily used to monitor the bioactivity of Dbait molecules in further preclinical and clinical development.
M. Dutreix who conducted this study said "this additional mechanism of antitumoral action of Dbait molecules confirms that the use of Dbait which baits, hijacks the enzyme complexes that repair DSBs and disorganizes DSB repair system, is a novel and attractive pathway-targeting approach in molecular cancer therapy".
J.S. Sun, CEO of DNA Therapeutics comments "The elucidation of Dbait's mechanisms of action and the identification of gamma-H2AX as a specific biomarker of Dbait activity are important milestones of DNA Therapeutics' development". He adds "DNA Therapeutics is currently raising series A to finance regulatory preclinical, and phase I/IIb trial anticipated to be initiated in Q4 2008".
About DNA Therapeutics: http://www.dna-therapeutics.com
DNA Therapeutics S.A., founded in May 2006, as a spinoff from the Institut Curie, the CNRS, the INSERM (French NIH) and the Museum National d'Histoire Naturelle, is the premier corporation developing DNA baits to trap enzyme complexes involved in DNA repair and inhibit their DNA repair capacity, as an innovative approach to enhance conventional anticancer therapy. It is headquartered in the Genopole Biocluster (Evry, France). DNA Therapeutics is being granted a portfolio of worldwide exclusive license from the parent institutions on DNA bait and related technologies.
Contacts: Pr. Jian-Sheng Sun, Ph.D. Chairman and CEO Phone: +33-624-753-239 Email: sun@dna-therapeutics.com
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