A recent paper from the Immunogenetics group demonstrates that a novel NF-kB inhibitor is effective in pre-clinical models of chronic lymphocytic leukemia and Richter syndrome
NF-kB plays critical roles in inflammation, immune responses, proliferation and cell survival. In tumor cells, NF-kB promotes tumor growth by inducing proliferation of cancer cells and by shaping the tumor microenvironment. Deregulated NF-kB pathway is a common feature in most B lymphoid malignancies, including chronic lymphocytic leukemia (CLL) where the p65 subunit of the complex is highly active and relevant for transcription. In this paper published in Haematologica Vaisitti and colleagues show that IT-901, a novel and selective NF-kB inhibitor, effectively interrupts the pathway in CLL cells, resulting in increased mitochondrial reactive oxygen species levels, reduced oxidative phosphorylation and activation of apoptosis. Moreover, inhibition of NF-kB by IT-901 in stromal and myeloid cells, both tumor supportive elements, fails to induce apoptosis but results in the modulation of the expression of molecules involved in cell-cell contact and immune responses. The final result is that accessory cells do not protect CLL cells from IT-901-induced apoptosis.
IT-901 is also effective in primary cells from patients with Richter syndrome (RS), the transformation of CLL into an aggressive lymphoma. Its anti-tumor effects are confirmed in xenograft models of CLL and in RS patient-derived xenografts, with inhibition of NF-kB and a significant reduction of tumor burden.
These results provide a proof of principle for IT-901 as a novel potential drug in CLL and RS.