Translating today’s science into tomorrow’s medicine

In drug discovery and development, Cancer Research UK can be compared to a medium to large biotechnology company. The record of our success — from Carboplatin to Abiraterone — and the size of our current portfolio, plus the infrastructure and expertise that we have built up within CRUK, are often the envy of industry.

But we are very different from a biotechnology company, and we are not in competition with industry. Our models of academic drug discovery and of drug development which draws on our academic research community are unique in the world, and it is our diverse portfolio of world-class basic research which gives our translational research its strength and unique flavour.

Much of our drug discovery record can be attributed to the core-funded academic Drug Discovery Units (DDUs) at our centres and institutes. But in 2014 we created a new committee to oversee the diversification of our drug discovery activities, and to review applications to new response-mode funding schemes. We have also been partnering with industry in order to experiment with the format of our funding schemes.

Building bridges between academia and industry is also the goal of Discovery Laboratories (CRT-DL) within our commercialisation arm, Cancer Research Technology. CRT-DL has in-house capabilities which enable it to translate research into commercially attractive projects. But it is in building alliances with the right industry and academic groups that the CRT-DL excels, and we’re currently excited by the progress of one such collaboration which in 2014 produced a novel highly selective inhibitor of an atypical Protein Kinase C.

Also in 2014, our Drug Development Office became the CRUK Centre for Drug Development (CDD), reflecting the extent of the Centre’s activities and the in-house infrastructure and expertise in early-phase drug development that has been built in the Centre. The Centre has recently celebrated successful outcomes from its Clinical Development Partnerships programme, bringing new life to agents which had been deprioritised by industry, and has built a unique initiative for investigating novel drugs in combination with the Combinations Alliance.

Changing discovery

In 2014 we created the Drug Discovery Committee, chaired by Professor Stephen Frye, to oversee the expansion and diversification of our drug discovery activities. At the same time we introduced new funding schemes reflecting the priorities set out in our Research Strategy. We have recently funded the first round of awards through these new schemes, including creating our first two biotherapeutics research programmes.

In addition to the biotherapeutics awards, we are addressing gaps in the UK’s immunotherapy research infrastructure through our partnership with MedImmune, the global biologics research and development arm of AstraZeneca. The CRUK-MedImmune Alliance Laboratory is now up and running in Cambridge, providing access to MedImmune’s world-class antibody engineering platform for CRUK researchers looking to translate their work. The priority for the Alliance is to support research into novel therapeutic and diagnostic antibodies, but the lab also has the ability to produce reagents for research where this may provide new therapeutic insights.

“This is an innovative collaboration where CRUK’s Principal Investigators will propose novel oncology targets as candidates for MedImmune’s antibody generating technology. Within the laboratory, MedImmune and CRUK scientists will work together to generate medicines which will transform the lives of oncology patients for the future.”
Maria Groves, Lab Head for the CRUK/MedImmune Alliance

We have also been experimenting with the format of response-mode funding of drug discovery through the Bayer co-funded Drug Discovery Grant, which combines the resources from industry with the breath of ideas that can only come from a response mode funding call. Established with Cancer Research Technology, a major goal for this partnership was to foster collaboration between academic researchers and drug discovery scientists from industry. The partnership has enabled CRUK to increase the funding available for drug discovery projects and allow applicants access to Bayer’s in-house technology and expertise.

Dr Paul Wilcock, Research Funding Manager for the scheme, explained: “One of the most successful innovations we pioneered with this scheme was partnering applicants with a Bayer scientist who helped the investigator develop their proposal and will provide expertise throughout the duration of the project. This is extremely beneficial for both the investigator and the project.

“And by partnering with industry in drug discovery,” Wilcock adds, “we also ensure that projects are really focussed on the goal of helping patients sooner, and promising agents will be able to exploit Bayer’s expertise in drug development.”

We awarded funding to four projects in November 2014, and we are now monitoring the progress of these against their agreed milestones, in order to assess the impact that access to Bayer scientists and infrastructure has had for the projects and to inform the development of future funding schemes.

Drug Discovery Units

“In the past few years pharma has been closing research sites,” says Professor Martin Drysdale. “They’re concentrating much more on being development companies. That means the whole field is much more reliant on the discovery research happening in the not-for-profit and academic environment to keep the pipeline flowing. What CRUK has is really an exemplar model for doing this now, funding core drug discovery groups with a lot of diverse expertise in drug discovery, but most importantly having access to all that world-class basic biology.”

CRUK fund three of these DDUs — the DDUs at the Cancer Research UK Beatson Institute and the Cancer Research UK Manchester Institute, and the Institute of Cancer Research (ICR) Cancer Therapeutics Unit — with a total annual investment of £17.8 million. In addition to working with groups at their host institutes, these units work as a network with complementary skill sets, and are open to collaboration with the whole CRUK community. Researchers with Small Molecule Project Awards, for example, often collaborate with a DDU, but the teams are also always on the lookout for breakthroughs in basic biology.

“The DDUs are really here to work with CRUK researchers to help them translate their work. We want researchers to be coming to us with potential targets, and then we’ll try to set up a collaboration in which we’ll help with the target validation, the work that’s required to show that something really is a hot target rather than a biological curiosity, and if it looks good then derisk the target and identify potential inhibitors.”

One of the best examples of the DDUs’ work is the HSP90 story, says Drysdale. The potential of the target was first identified by Laurence Pearl’s structural biology and signal transduction team at the ICR, working with Paul Workman at the ICR Unit. Further discovery work was conducted in collaboration with Vernalis. Their work leading to the HSP90 inhibitor AUY922 won the ICR team the 2013 Cancer Research UK Translational Research Prize.

“HSP90 is the kind of target that we love to work on,” says Drysdale. “What gets us really excited is when we get a target like that, before anybody else has spotted its potential. HSP90 is now everyone’s favourite target, but because CRUK was doing the basic research, it was in on the game from the start. It can be a risk being the first, and it can be hard work, but when it goes right it’s very rewarding to work on.

“And ultimately it’s what we’re all here for. If we don’t translate and do drug discovery well then we’re not doing what people put 50p in a bucket for.”

The Centre for Drug Development

With a portfolio of 28 preclinical and early-phase projects, the CDD ranks alongside the top five pharmaceutical companies for cancer drugs in development. But the Centre is unique says director Dr Nigel Blackburn.

“We can take the risks where industry might hesitate,” says Blackburn. “Because we are free of this profit burden we get to be more innovative, we can try new things and take more risks, and so the rewards are potentially greater. But nor does any other charity do anything like this; we are the only charitably funded drug development group in the world — and that’s an exciting place to be.”

The Centre’s Clinical Development Partnerships (CDP) scheme brings new life to promising agents which have been deprioritised by industry, helping to jumpstart research on promising drugs. The scheme has seen three success stories so far, with perhaps the best example being the development of IMA950, an immunotherapeutic vaccine for glioblastoma, through phase I trials (see box). The innovative risk-reward model means that we are taking on the development of the agents at our risk — but have received milestone payments from the successful projects, and have revenue-sharing agreements in place for agents which make it to the clinic. Most importantly, though, the aim is to ensure that patients benefit from new treatments sooner.

Currently creating excitement at the Centre is MOv18, a first in class IgE antibody against folate receptor ɑ. “The hope is that these types of molecules might harness a unique set of effector cells and might be more powerful in attacking tumour cells than traditional IgG molecules,” says Chief Drug Development Scientist Dr Robert Williams. “But industry has shied away from this area because IgE antibodies can be involved in allergic reactions. By working with the immunology experts in the academic community — led by James Spicer’s group at King’s College — we were able to do the preclinical work to mitigate that risk and satisfy the regulator so that it has now been taken into phase I trials in patients with advanced solid tumours.”

As well as carrying out early stage trials, the CDD also runs Combinations Alliance, a matchmaking service for academic researchers seeking novel drug combinations. “Here, we don’t necessarily fund the trials,” explains Blackburn. “Industry partners open up their portfolios of phase 2 and 3 drugs, and we act like a dating agency, providing the framework, resources and knowledge to help partners find potentially exciting new matches. We also offer preclinical funding to help investigators acquire the data they need to carry out a new combination trial. This service could really help advance cancer therapy, and is only possible because we are a charity.”

The Pioneer Fund

A more conventional development approach is the CRT Pioneer Fund. The £50 million fund was created in 2012 by CRT and the European Investment Fund to take projects with a high level of scientific novelty and clear patient benefit into Phase II trials. In December 2014, Battle Against Cancer Investment Trust Limited (BACIT) joined the Fund, and committed to increase funding by £20 million.

Although only three years old, the fund has already seen some success, with five investments made (see table). Particularly exciting are MPS1 inhibitors discovered at the CRUK Cancer Therapeutics Unit at the ICR. These mitotic kinases are part of the spindle assembly checkpoint, and inhibitors lead to errors in chromosome segregation ultimately resulting in mitotic catastrophe and cell death.

CRT Discovery Labs: a proven partner for progressing academic research to clinical trials

Cancer Research Technology’s Discovery Laboratories (CRT-DL) have successfully worked with CRUK scientists and industry partners to discover a first-in-class, orally-active, and highly selective Protein Kinase C (PKC) inhibitor which is now progressing towards Phase 1 trials. The drug targets PKC iota (PKCι), a key player in cell growth, establishment and maintenance of cellular polarity, and migration, and which is often found to be amplified in many carcinomas.

The potential of PKCι as a target was identified by Professors Peter Parker and Neil McDonald working on PKCι signalling pathways and its structural biology at the Francis Crick Institute. They turned to CRT-DL and its collaboration partner, Teva Pharmaceutical Industries, who designed a drug discovery programme leading to a clinical candidate that could successfully modulate PKCι.

The drug discovery collaboration was highly iterative, explains Parker, involving the Crick teams throughout. “The remit of our academic positions is to deepen knowledge and insight. Hence we can invest time and effort into extracting this depth of understanding and then contribute this to create a well informed development and trial activity.”

“I believe this is the first research collaboration to demonstrate that selective small molecule inhibitors against a key regulator of cellular polarity can be efficacious in models of human cancer”, says Dr Jon Roffey from the CRT-DL. “A significant breakthrough has been to identify a set of small molecules that possess strong anti-cancer activity, yet are well tolerated in animal models and maintain suitable properties for further development.”

Several other important outputs have come from the project, including early on solving the co-crystal structure of PKCι and the identification of its binding motifs.

Additionally, using an inhibitor-resistant mutant of PKCι, the team has invented a novel methodology for kinase substrate identification, dubbed Kinase Identification of Proximal Substrates (KIPS). The method enables the identification of kinase activity biomarkers, removing a significant barrier to drug discovery and development.

Finally, some of the well characterised compounds discovered during the collaboration have been fed back into academic research as declared tool compounds. The PKCι inhibitors provide a means of acutely blocking protein function and exploitation of these in model organisms is having a profound impact on understanding the cellular functions of PKCι. These tool compounds are now accessible to the wider academic community.

Ignyta have now licensed the programme, and Parker is actively involved in facilitating the progression of the inhibitor to Phase 1 trials. Parker hopes that the compound could be effective in inhibition of tumour growth and metastatic spread in a broad range of carcinomas. “By working in collaboration with CRT and our industry partners, we are seeing a drug candidate progress to its first patients in the coming months, something that otherwise may not have occurred for years.”

“There are currently more than four and a half thousand potential drug treatments in pharmaceutical companies, waiting for the resources to be developed. Any one of them could be effective in treating cancer. That’s where we come in — to take the most promising ones forward.”
Dr James Ritchie, Drug Development Scientist, Cancer Research UK

Unblocking drug development bottlenecks

IMA950, a cancer vaccine for glioblastoma (GBM), has met the two primary endpoints of safety and immunogenicity in a trial conducted by the CDD. We’ve now entered into a licence agreement with immatics biotechnologies GmbH which will continue to develop this cancer vaccine for GBM, the most common and lethal adult brain tumour.

The decision is based on positive results from a Phase I trial conducted by the CDD under the Clinical Development Partnerships (CDP) scheme, a joint initiative between CRUK and CRT. Without the support and expertise of the CDD, and the CDP scheme, it is highly unlikely that such a trial could have gone ahead.

IMA950 is a vaccine that has been specifically developed to treat GBM that contains 11 different tumour-associated peptides (TUMAPs). The TUMAPs, identified by immatics using its proprietary drug discovery platform XPRESIDENT®, are over-expressed on the surface of GBM tumours. They are designed to trigger the patient’s immune system to recognise and kill tumour cells while leaving healthy cells unharmed.

IMA950 is the first therapeutic vaccine developed under our CDP initiative. Under the scheme, companies retain rights to their drugs while allowing the CDD to undertake early clinical development work to assess each treatment’s benefit to cancer patients. These partnerships offer a unique collaboration that gives a second chance to potential cancer therapies that would otherwise be stuck on the shelf.

This story was originally published in Pioneering Research: Cancer Research UK’s annual research publication for 2014/15. Find more at cruk.org/pioneeringresearch

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