6533b82bfe1ef96bd128dcf7

RESEARCH PRODUCT

Functional characterisation of the first HSP110 inhibitors.

subject

description

Heat shock proteins are molecular chaperones highly expressed in haematological malignancies. My laboratory has shown that the heat shock protein HSP110 is a new and important therapeutic target In colorectal cancer and in non-Hodgkin's lymphoma. As there were no existing inhibitors of HSP110, a screening strategy of a chemical library was carried out and allowed the identification of two molecules capable of specifically inhibiting the chaperone activity of HSP110. My thesis objective was to characterise and functionally validate these newly identified molecules in diffuse large cell B lymphomas. I have shown that one of these molecules limits the interaction of HSP110 with the SYK signalling protein, an essential kinase in the BCR signalling pathway in activated diffuse B-cell lymphoma. These molecules reduce the growth of these lymphoma cells in vitro and in vivo. They reduce the activation of the NF-κB pathway, an essential survival pathway. Finally, I have shown that inhibition of this pathway by our inhibitor, in combination with inhibitors of the PI3K pathway, completely blocks tumour growth in vivo.