Journal
HAEMATOLOGICA
Volume 102, Issue 11, Pages 1878-1889Publisher
FERRATA STORTI FOUNDATION
DOI: 10.3324/haematol.2017.173419
Keywords
-
Categories
Funding
- Associazione Italiana per la Ricerca sul Cancro (AIRC) [IG-17314]
- Italian Ministry of Health (Bando Giovani Ricercatori) [GR-2011-02349282, GR-2011-02346826]
- Leukemia and Lymphoma Society [6465-15]
- ImmuneTarget Inc.
- ImmuneTarget Inc. [IT-901]
Ask authors/readers for more resources
IT-901 is a novel and selective NF-kappa B inhibitor with promising activity in pre-clinical models. Here we show that treatment of chronic lymphocytic leukemia cells (CLL) with IT-901 effectively interrupts NF-kappa B transcriptional activity. CLL cells exposed to the drug display elevated mitochondrial reactive oxygen species, which damage mitochondria, limit oxidative phosphorylation and ATP production, and activate intrinsic apoptosis. Inhibition of NF-kappa B signaling in stromal and myeloid cells, both tumor-supportive elements, fails to induce apoptosis, but impairs NF-kappa B-driven expression of molecules involved in cell-cell contacts and immune responses, essential elements in creating a pro-leukemic niche. The consequence is that accessory cells do not protect CLL cells from IT-901-induced apoptosis. In this context, IT-901 shows synergistic activity with ibrutinib, arguing in favor of combination strategies. IT-901 is also effective in primary cells from patients with Richter syndrome (RS). Its anti-tumor properties are confirmed in xenograft models of CLL and in RS patient-derived xenografts, with documented NF-kappa B inhibition and significant reduction of tumor burden. Together, these results provide pre-clinical proof of principle for IT-901 as a potential new drug in CLL and RS.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available