Innovations Strategic and Portfolio Awards: projects we've funded
Detecting treatment response in cancer using hyperpolarised magnetic resonance imaging (MRI)
Patients with similar tumour types can show very different responses to the same therapy. The development of new treatments would benefit, therefore, from the introduction of imaging methods that allow an early assessment of treatment response in individual patients, allowing rapid selection of the most effective treatment.
Conventional Magnetic Resonance Imaging (MRI), which produces images of tissue morphology by mapping the distribution of water molecules, can be used to detect tumours and monitor their responses to treatment by measuring reduction in tumour size. However, changes in tumour size may take many weeks to become manifest, and with some treatments may not occur at all despite a positive response to treatment. MRI can also be used to detect tumour metabolites in vivo, using magnetic resonance spectroscopic imaging techniques. However, these metabolites are present at ~10,000x lower concentration than tissue water, which makes them hard to detect and difficult to image, except at relatively low resolution.
Professor Kevin Brindle and his colleagues in Cambridge have been developing a technique in collaboration with GE Healthcare, termed “hyperpolarisation”, which increases the sensitivity of MRI by 10,000 – 100,000x. With this technique they inject a hyperpolarised 13C-labelled molecule and now have sufficient sensitivity to image its distribution in the body and the distribution of the metabolites produced from it, effectively providing a real-time readout of tissue metabolism. They have shown, in preclinical studies, that they can detect very early evidence of treatment response in tumours by using this technique to monitor changes in tumour metabolism. The team have been awarded ~£4.3M of translational funding to take this technology from the laboratory to the clinic, where they will investigate its potential for detecting early evidence of treatment response in lymphoma, glioma and breast cancer patients.
Development of Wolbachia as an effective and sustainable approach to reduce dengue
The Eliminate Dengue program, led by Professor Scott O’Neill of Monash University, is developing a new way to control dengue fever. Dengue is caused by a virus that is transmitted between people by mosquitoes.
The program team has found that a common bacterium (Wolbachia) found in many insects naturally, but not the mosquito that transmits dengue, will reduce the ability of mosquitoes to transmit dengue and other viruses when it is introduced. Initial trials have demonstrated that the Wolbachia technology can be practically deployed at a limited scale, is stable in the field, is acceptable to communities and regulators, and is predicted by modelling to have a major impact on dengue transmission. The technology, if it functions as envisioned, will provide an area-wide solution to dengue transmission control, capable of spreading and maintaining itself without the need for reapplication and without need for human behaviour change.
Improved control of endemic foot-and-mouth disease by development of virus like particle vaccines
Foot-and-mouth disease (FMD) is a highly contagious, acute viral disease of cloven-hoofed, domesticated and wild animals. The disease is much feared as the virus can spread extremely rapidly, has the potential to cause enormous economic losses and is the single most important constraint to international trade in livestock and animal products. Current vaccines are made of inactivated virus and induce a protective antibody response but only for a short duration and only against viruses that are closely related to the vaccine strain.
Leading researchers from the Pirbright Institute, the University of Oxford, the Diamond Light Source and the University of Reading have developed methods to produce stabilised FMDV capsids in insect cells which do not require expensive high disease containment facilities. This new capsid production platform will allow modification of the structures to enhance the short duration of immunity and the narrow spectrum of the protective immune responses.
The consortium, which also includes the University of Dundee and MSD Animal Health, will identify methods to enhance the cellular immune responses to the capsids and so stimulate prolonged antibody responses. In addition, they will establish which parts of the viral capsid structure are the most important to use in new vaccines to protect against a wide range of viruses. Once identified these common structures can be engineered for enhanced prominence in new vaccines designed to induce widely cross-protective responses.
A pipeline of drugs for leishmaniasis and Chagas disease
Visceral leishmaniasis and Chagas disease are neglected tropical diseases that cause substantial suffering and an estimated 60,000 deaths each year. Current medicines are inadequate – issues include limited efficacy and unacceptable toxicity. There is a need for new, effective and safe drugs to save lives and improve quality of life for people in low-income countries with these diseases.
Our fully-integrated team, led by Professor Paul Wyatt, Dr Jose Fiandor and colleagues at the University of Dundee and at GSK has the substantial leadership, experience and infrastructure required to develop drug candidates suitable for clinical trials.
We are already making substantial progress: we have identified two candidate drugs for visceral leishmaniasis and improved the methodology and systems to develop drugs for this and Chagas disease. But a greater pipeline of candidate drugs is required to ensure clinical success.
Our goal over the next five years is to deliver at least two, potentially three, new drug candidates suitable for clinical trials for either of these diseases.
An integrated target validation and drug discovery platform for the identification of novel agents targeting genome stability for the treatment of cancer
With more than 3.2 million new cases and 1.7 million deaths each year, cancer remains an important public health problem in Europe. Furthermore, the strong association of cancer risk with age will result in a major increase in cancers in the coming years. Identifying treatments that specifically target cancer cells with minimal impact on normal proliferating cells remains the overriding goal of cancer research. Conventional chemotherapies are widely known to be toxic to healthy cells as well as cancer cells, often resulting in intolerable side effects. Most, if not all, cancers have tumour-specific defects in one or more of the multiple genome stability pathways (processes that maintain the integrity of our DNA). Recent research has discovered that developing new drugs to target genome stability can be very effective at killing cancer cells in certain patients. This has been recently demonstrated with the approval of the DDR-mechanism drug olaparib (Lynparza), which has been used successfully to treat patients with advanced breast cancer, showing reduced side effects.
Professor Simon Ward and colleagues at the University of Sussex will aim to use the expertise on genome stability from within the university to discover and develop the next generation of cancer treatments that would selectively kill cancer cells and so be better tolerated and more effective therapeutic agents.
Discovery of new drug candidate for the treatment of human African trypanosomiasis
Human African trypanosomiasis (HAT) disease elimination is tentatively within reach but achieving this goal is highly dependent on the availability of drugs with pharmacological profile far superior to the current therapies. The ideal target product profile for a disease elimination therapy is a safe and inexpensive oral drug with a short dosing regimen able to cure stage 1 and 2 HAT patients. Following up on a large high-throughput screen, the Novartis Institute for Tropical Diseases (NITD) and its collaborators have identified a portfolio of lead scaffolds with favorable drug-like properties and showing potent anti-trypanosomal activity through novel mechanisms of action. The key objectives of this next stage of development is to carry out the medicinal chemistry optimisation of these compounds to achieve pharmacological properties compatible with a short oral treatment course, rapid and complete clearance of parasites in all tissues including the brain, and no requirement for intensive safety monitoring. NITD will evaluate, early on, the potential for drug combinations through in vitro and in vivo combinatorial activity studies with all early leads as well as HAT drug candidates that are currently being developed. This strategy aims to deliver clinical candidates that, when used in combination, will simplify and shorten treatment, enabling aggressive and sustainable disease elimination strategies.
Community for Open Antimicrobial Drug Discovery (CO-ADD)
Multi-drug resistant (MDR) microbes are a serious health threat as the approval of new antibiotics has dropped alarmingly. To find new classes of antimicrobials, novel chemical diversity needs to be accessed. The Community for Open Antimicrobial Drug Discovery (CO-ADD) is an ‘open access’ compound screening initiative.
CO-ADD will uncover novel antibiotic and antifungal compounds from the untapped chemical diversity residing with synthetic organic chemists in academic laboratories in all countries.CO-ADD has established capacity for antimicrobial testing, hit-confirmation and validation, resistance determination, target identification, and ADME/T in one facility located at the University of Queensland, Australia.
A focused initiative will benefit the antimicrobial research community and end-users by identifying new antibiotic and anti-fungal chemotypes, as well as providing valuable information on the physicochemical and structural properties of a compound required for antimicrobial activity. The global reach of the initiative necessitates support from a visionary organisation committed to the advancement of human health worldwide. National academic and commercial funding models would not be in a position to support the scope of this project.
CO-ADD will pioneer an 'open access' screening initiative to challenge conventional thinking on the antimicrobial discovery process. They will determine if: i) there are novel antibiotic chemotypes in chemistry laboratories that have not been identified simply because they have never been tested, ii) the chemical space of compounds synthesised outside corporate collections differ significantly from libraries already screened, iii) an 'open access' approach to antimicrobial discovery targeting synthetic chemists can re-invigorate antimicrobial discovery. CO-ADD will screen compounds from academic research groups from anywhere in the world for antimicrobial activity for free.