In a paper published today in the journal Cancer Cell, the researchers report how the drug, known as DTP3, kills myeloma cells in laboratory tests in human cells and mice, without causing any toxic side effects, which is the main problem with most other cancer drugs. The new drug works by stopping a key process that allows cancer cells to multiply.
The team have been awarded Biomedical Catalyst funding from the Medical Research Council (MRC) to take the drug into a clinical trial in multiple myeloma patients, scheduled to begin in late 2015.
Multiple myeloma is an incurable cancer of the bone marrow, which accounts for nearly two per cent of all cancer deaths.
Professor Guido Franzoso, from the Department of Medicine at Imperial College London, who led the research, said: ?Lab studies suggest that DTP3 could have therapeutic benefit for patients with multiple myeloma and potentially several other types of cancer, but we will need to confirm this in our clinical trials, the first of which will start next year.?
The new drug was developed by studying the mechanisms that enable cancer cells to outlive their normal lifespan and carry on multiplying. In the 1990s, a protein called nuclear factor kappa B (NF-?B), which plays an important role in inflammation, and the immune and stress response systems, was discovered to be overactive in many types of cancer, and responsible for switching off the normal cellular mechanisms that naturally lead to cell death. This enables the cancer cells to survive.
The pharmaceutical industry and scientists around the world have invested heavily in research into NF-?B inhibitors, but such compounds have not been successfully developed as therapies because they also block the many important processes controlled by NF-?B in healthy cells, causing serious toxic side effects.
The Imperial researchers took a different approach, looking for target genes downstream of NF-?B that might be responsible for its role in cancer specifically.
By studying cells from multiple myeloma patients, they identified a protein complex, named GADD45?/MKK7, that appeared to play a critical role in allowing the cancer cells to survive.
Searching for a safe way to target the NF-?B pathway, they screened over 20,000 molecules and found two that disrupted the protein complex. Further refinements led to the experimental drug, DTP3, which tests showed kills cancer cells very effectively but appears to have no toxicity to normal cells at the doses that eradicate the tumours in mice.
We had known for many years that NF-?B is very important for cancer cells, but because it is also needed by healthy cells, we did not know how to block it specifically. The discovery that blocking the GADD45?/MKK7 segment of the NF-?B pathway with our DTP3 peptide therapeutic selectively kills myeloma cells could offer a completely new approach to treating patients with certain cancers, such as multiple myeloma,? Professor Franzoso said.
A spinout company, Kesios Therapeutics, was formed to commercialise DTP3 and other drug candidates based on Professor Franzoso?s research, with support from Imperial Innovations, a technology commercialisation company focused on developing the most promising UK academic research.
The significant progress made by Professor Franzoso in multiple myeloma is one of the many cancers we believe his signal transduction research could be applied to. To help develop this ground-breaking research further, Imperial Innovations created the spin out Kesios Therapeutics,? explained Dayle Hogg from the Healthcare Ventures team at Imperial Innovations.
This research has been funded by the MRC, the US National Institutes of Health, and Cancer Research UK.
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Notes to editors:
1. L. Tornatore et al. ?Cancer-selective targeting of the NF-?B survival pathway with GADD45?/MKK7 inhibitors.? Cancer Cell, 13 October 2014.
2. About Imperial College London
Consistently rated amongst the world’s best universities, Imperial College London is a science-based institution with a reputation for excellence in teaching and research that attracts 14,000 students and 6,000 staff of the highest international quality. Innovative research at the College explores the interface between science, medicine, engineering and business, delivering practical solutions that improve quality of life and the environment – underpinned by a dynamic enterprise culture.
Since its foundation in 1907, Imperial’s contributions to society have included the discovery of penicillin, the development of holography and the foundations of fibre optics. This commitment to the application of research for the benefit of all continues today, with current focuses including interdisciplinary collaborations to improve global health, tackle climate change, develop sustainable sources of energy and address security challenges.
In 2007, Imperial College London and Imperial College Healthcare NHS Trust formed the UK’s first Academic Health Science Centre. This unique partnership aims to improve the quality of life of patients and populations by taking new discoveries and translating them into new therapies as quickly as possible.
3. About DTP3 and the Cancer Cell Publication Data
DTP3, a D-tripeptide, specifically disrupts the GADD45?/MKK7 complex found within a discrete loop of the NF-?B pathway, and in so doing, kills multiple myeloma cells from patients, without toxicity to normal cells. In human cell models, DTP3 was found to have a similar anti-cancer potency to that of the clinical standard, bortezomib, but with a more than 100-fold higher cancer-cell specificity, and interestingly retained full therapeutic efficacy in cell lines that were resistant to standard multiple myeloma treatments. Crucially, in mice, DTP3 was found to eradicate myeloma tumors, with no apparent side-effects at the effective doses.
4. About Imperial Innovations
Imperial Innovations creates, builds and invests in pioneering technologies developed from the academic research of the UK’s four leading Universities. The Group supports scientists and entrepreneurs in the commercialisation of their ideas and intellectual property by leading the formation of new companies, providing facilities in the early stages, providing investment and encouraging co-investment to accelerate development, providing operational expertise and recruiting high-calibre management teams. It also runs an Incubator in London that is the initial home for many of its technology spin-outs.
Originally formed as the Technology Transfer office for Imperial College – a role it still carries out today, Innovations also invests in opportunities arising from intellectual property developed at, or associated with, Cambridge University, Oxford University and University College London. These are the top four research intensive universities in Europe with a research income of over ?1.3 billion per annum.
Innovations invests in the most promising opportunities from whichever technology sector they arise, but has built particular expertise in the key sectors of: therapeutics, medtech, engineering and materials, and ICT.
During the period from the admission of its shares to trading on AIM in 2006 to 31 January 2014, Innovations has invested a total of ?160.9 million across its portfolio companies, which have raised collectively investment of over ?750.0 million.
5. The Biomedical Catalyst is a funding programme run jointly by the Medical Research Council and Innovate UK (formerly the Technology Strategy Board). It provides early translational funding to UK academics and SMEs to help bridge the gap between discovery science and commercialisation of new treatments and technologies. http://www.mrc.ac.uk/funding/science-areas/translation/biomedical-catalyst/