Treating Multiple Myeloma and Diffuse Large B Cell Lymphoma by Targeting the NF-kB Pathway with the First-in-Class GADD45b/MKK7 Inhibitor, DTP3

Professor Guido Franzoso and his colleagues at Imperial College London have discovered a new way of tackling multiple myeloma, an incurable cancer of the white blood cells, which are normally responsible for producing 'antibodies,' that attacks and destroys bone, which could offer a cure for this disease. The treatments that currently exist for multiple myeloma have severe side effects that limit the doses that can be given to patients. The most recent treatment, bortezomib (Velcade), cannot completely destroy the cancer, allowing some of the cancer cells to escape this treatment and so, whilst the disease can be temporarily stabilised, relapse is unfortunately inevitable. Because of an increased number of antibody-producing white blood cells, patients generally have high levels of a single type of antibody called 'M-protein' in their blood and/or urine. These patients often also have reduced blood cell counts and decreased amounts of normal antibodies, which compromises their body's immune defenses against infection. As a result of these and other complications, most of the 110,000 people diagnosed each year with the disease in the US, Europe and Japan will die within about five years of diagnosis. This blood borne cancer cannot be treated using radiotherapy or surgery and so the options are restricted to chemotherapy or bone marrow transplant.

Prof. Franzoso's team discovered a new protein, called Gadd45b, which forms one half of a crucial signalling point within cells. An enzyme called MKK7 controls traffic through a second signalling pathway (JNK) that forms the other half of this focal signalling point. When bound together, the two Gadd45b and MKK7 proteins stop the signals that tell the cancerous cells to activate a form of cellular suicide known to specialists as 'apoptosis', thus allowing them to multiply uncontrollably.

The team has since developed a novel compound molecule, DTP3, which specifically disrupts the relationship and interaction between Gadd45b and MKK7, and in so doing kills the cancerous cells effectively but, perhaps most importantly, completely lacks toxicity to the normal cells. This unique property makes DTP3 an exciting starting point in the search for a new effective drug therapy against multiple myeloma.

The goal of the research team is now to progress DTP3 to an early stage clinical study in patients suffering from multiple myeloma in order to test the drug in man and ultimately develop an effective therapy with no toxicity, alongside a diagnostic test, for multiple myeloma and potentially other cancers where the Gadd45b and MKK7 proteins are responsible for keeping the tumour cells alive.

Multiple myeloma (MM) and diffuse large B cell lymphoma (DLBCL) are distinct B cell cancers. Despite several new therapies, MM remains incurable. Similarly, over 40% of DLBCL patients do not respond to therapy or relapse and most of them die from their disease, with worst outcomes in cases of activated B-cell (ABC)-DLBCL. NF-kB is a promising therapeutic target in MM/ABC-DLBCL. Yet, despite a 30-year global effort, no specific NF-kB inhibitor has been clinically approved, due to the toxicities of systemic NF-kB blockade. Several MM/lymphoma agents, e.g. proteasome inhibitors, block NF-kB, but also many other pathways, lack cancer-cell specificity and do not exert their clinical effect via NF-kB. Thus, an attractive alternative to blocking NF-kB would be to target the essential, cancer-specific downstream effectors of the NF-kB oncogenic function. We identified the complex formed by the product of the NF-kB target gene, GADD45B, and the JNK kinase, MKK7, as an actionable target in MM/DLBCL. GADD45b is stably upregulated by NF-kB and promotes MM/DLBCL cell survival by blocking MKK7/JNK-driven apoptosis. Further, we developed the GADD45b/MKK7 inhibitor, DTP3, which kills MM/ABC-DLBCL cells via JNK-mediated apoptosis ex vivo and in mice and is not toxic to normal cells (G0901436). Due to this cancer-selective specificity, DTP3 has similar efficacy to the standard bortezomib in MM cells and xenograft models, but a >100-fold higher ex vivo therapeutic index and far wider safety margin in vivo, ablating MM/DLBCL xenografts without adverse effects. GLP studies established the on-target pharmacology, tolerability and good PK/ADME profile of DTP3 (MR/L005069/1). Early trial data demonstrated no adverse events, with initial efficacy and cancer-specific PD signals in relapsed MM patients, warranting further clinical evaluation. We now aim to conduct a follow-on trial of DTP3 to deliver PoC for a safe and effective NF-kB-targeting therapy and address the unmet needs in MM/DLBCL.