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Treating Multiple Myeloma by Targeting the NF-Kappa-B Pathway with Gadd45-Beta/MKK7 Inhibitors

Guido Franzoso

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Medical Research Council (MRC)
The NF-kB pathway is aberrantly upregulated in many cancers, where it promotes survival. A paradigm of these cancers is Multiple Myeloma (MM), an incurable plasma cell malignancy. Existing MM treatments fail to induce lasting remissions, leading to relapse and/or refractory disease. NF-kB is a promising therapeutic target in MM. Despite the industry's long-standing pursuit of NF-kB inhibitors, however, no such inhibitor has been clinically approved to this day. Likewise, proteasome inhibitors with MM indication, such as bortezomib, inhibit NF-kB and other cellular functions, and do not specifically target cancer cells, resulting in low therapeutic indices and dose-limiting toxicities. We reasoned that an attractive alternative to globally targeting NF-kB would be to block the non-redundant, cancer-specific effectors of NF-kB-dependent survival. Recently, we identified the interaction between the NF-kB-regulated gene product, Gadd45b, and the JNK kinase, MKK7, as a novel therapeutic target in MM. Gadd45b is elevated in MM cells relative to healthy tissue and promotes survival therein by suppressing MKK7/JNK-induced apoptosis. Further, with MRC support, we developed a novel D-tripeptide, DTP3, which specifically disrupts the Gadd45b/MKK7 interaction, kills MM cells at low-nM concentrations and, importantly, completely lacks toxicity to normal cells. Due to this cancer-selective target specificity, DTP3 has similar anti-MM activity to bortezomib, but more than 100-fold higher therapeutic index in vitro. DTP3 also has excellent tolerability and far greater therapeutic index than bortezomib in vivo. Consequently, it virtually eradicates MM xenografts in mice without apparent side effects. We currently aim to progress DTP3 to a Phase 1 trial to deliver clinical PoC for a cancer-selective NF-kB-targeting strategy and an effective therapy with no preclusive toxicity, alongside a diagnostic test, for MM and potentially other cancers where NF-kB promotes survival via Gadd45b.

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