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

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 Gadd45-Beta, 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 Gadd45-Beta 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 Gadd45-Beta 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 Gadd45-Beta and MKK7 proteins are responsible for keeping the tumour cells alive.

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.

Multiple myeloma is an incurable malignancy of plasma cells. At present, it accounts for 10% of all haematological malignancies and ~2% of all cancer deaths in the Western World. The median age at diagnosis is approximately 68 years, and the disease is more common in men than in women. Approximately 4,000 people are diagnosed with multiple myeloma in the UK and it affects 110,000 patients in US, Europe and Japan each year. The worldwide pharmaceutical market for multiple myeloma was valued at $4.4 billions in 2013 and is currently forecasted to reach $7 billions by 2017.

The NF-kB pathway is arguably one of the most promising targets for drug development in multiple myeloma and other cancers. Despite the Biotech and pharmaceutical industries' aggressive pursuit of NF-kB inhibitors dating back to the early 90s, no such inhibitor has been clinically approved to this day. Proteasome inhibitors with clinical indication in multiple myeloma, such as bortezomib and more recently carfilzomib, do not specifically target cancer cells, resulting in dose-limiting toxicities and low therapeutic indices. Thus, whilst they show a clear clinical benefit, these and other drugs currently used for the treatment of myeloma patients, fail to induce lasting remissions, inevitably leading to relapse and/or refractory disease. These limitations reveal a need for a radically new therapeutic approach, one that is more specific, safer and, hence, more effective.

To deliver this urgent, unmet medical need, we have developed a novel D-tripeptidic compound, DTP3, which selectively targets a non-redundant and cancer-specific axis of the NF-kB pathway (i.e. the Gadd45b/MKK7 axis), rather than NF-kB globally. We have shown that DTP3 kills multiple myeloma cells very effectively and, importantly, lacks toxicity to normal cells, even when used at very high concentrations. Due to this cancer-selective target specificity, DTP3 displays similar potency to bortezomib, the current gold standard treatment, in multiple myeloma cells, but a more than 100-fold higher therapeutic index in vitro and far superior tolerability and therapeutic index in vivo.

DTP3 also has excellent physicochemical properties, such as high stability in serum and high aqueous solubility, favourable pharmacokinetic profile with good distribution to the bone marrow, the target tissue, and excellent tolerability in vivo.

With the current application, we aim to progress DTP3 to regulatory preclinical evaluation followed by a Phase 1 clinical trial in patients with advanced multiple myeloma in order to achieve clinical Proof of Concept for a therapeutic strategy to selectively target the NF-kB pathway in cancer by the use of Gadd45b/MKK7 inhibitors. Desirably, we also aim to progress a first-in-class candidate therapeutic targeting the Gadd45b/MKK7 axis towards development of a new, effective therapy for multiple myeloma and potentially other cancers where NF-kB promotes survival via Gadd45b.

Along with this trial, we propose to develop and validate a companion diagnostic test, based on a simple and cost-effective qRT-PCR assay, to establish a more informed approach to therapeutic strategy and improve clinical protocols with the aim of reducing unnecessary exposure to medicines' risk and enhancing clinical benefit.

On successful completion of clinical evaluation and market authorisation, we envisage DTP3 being used initially to treat hospitalised, relapsed and/or refractory myeloma patients for whom there is no alternative option, in order to extend remissions and improve quality of life, an area where existing therapies fail. Subsequently, we believe DTP3 may form the basis of a frontline multiple myeloma therapy used either alone or in combination with other therapies. Ultimately, DTP3 may find potential indication also in other areas on unmet need within oncology, such in diffuse large B cell lymphoma, and inflammatory and autoimmune diseases.