Pierre Galka

         Cyclic peptides mediated genes regulation, a new way in cancer therapy.

            The regulation of gene expression is one of the most exciting and enigmatic processes involved at all steps of cellular life, especially during normal or abnormal cell differentiation and proliferation. For this principal reason, it is extensively studied in developmental and oncologic contexts.
The oncogenic character of protein Pbx1a (PreB-cell leukemia transcription factor 1a) is well established and suggests its implication not only in leukemia but also in numerous other cancers (pancreas, liver, breast or prostate). This ubiquitous implication in cancers together with our bioinformatics analyses showing 100% conservation in mammalian sequences of Pbx1a suggest a hub position of the protein in transcriptional events of normal cell development and cancerogenesis.
Started in January 2012, our research project aims at developing a new method for interfering with transcriptional regulation by screening millions of biosynthetic cyclic peptides obtained with an intein-based method. The principal work hypothesis is that some peptides in these genetic libraries can act as disruptors of the ternary transcriptional enhancer complex formed between Pbx1a, its cofactor protein Hoxa1 and a specific target DNA sequence (HoxB1-Auto Regulatory Element).
Active peptides screening involve not only their direct activity to interfere with Pbx1a/Hoxa1/HoxB1-ARE transcriptional complex formation but also stability of molecules in physiological conditions and ability to reach intracellular targets and especially to enter the nuclear compartment.  So investigated first in bacteria, our project was designed and is actually in adaptation phase to S.cerevisiae, an eukaryotic host extensively used as model organism for gene regulation investigations.
By all these aspects, our project aims at opening completely new therapeutic perspectives in which small genetically encoded molecules will be able to target the transcriptional activation of specific genes of interest.