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Stay on target – building a better resource for drug target evaluation

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by Cancer Research UK | Analysis

12 September 2023

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When drug discovery scientist Craig MacKay searched for an overview of drug target databases, what information they contained and how they could be used, he came up empty handed. Given how much time and resource can be saved with good target evaluation, there was only one thing to do – it was time to roll up his sleeves and get to work…

As cancer focussed drug discovery scientists, the concept of what we do is really quite simple. We work with researchers to identify targets (most commonly, but not always, proteins) that are involved in biological processes supporting cancer progression. We then develop therapeutic agents that modulate such processes to inhibit progression of cancer in the clinical setting.

However, this simple concept is anything but in practice. As you may know, it takes an average of 10-15 years from target identification to approval and in many cases can be much longer. Recent approvals of small molecules that target the oncogene KRAS have come off the back of more than four decades of effort. This requires significant investment, with average costs in the region of $2 billion to develop a new drug.

Development of new products in any field can result in failures but in cancer drug discovery, the attrition rate is as high as 90%. This can be caused by any number of factors, including lack of effect on disease progression in the patient population, unacceptable level of toxicity or challenges developing an agent that effectively modulates target biology.

There is an under-utilised wealth of datasets from cell lines, animal models and patient samples that are publicly available, free to access and that can be used to support cancer target evaluation.

Acceleration needs good evaluation

At Cancer Research Horizons, our aim is to accelerate the discovery and development of new therapeutics, ensuring we bring new treatments to patients faster. One of the ways in which we aim to do this is by reducing the attrition associated with our target portfolio. This means we robustly evaluate novel targets and prioritise those we believe have the best chance of progressing towards clinical testing and ultimately approval.

When we do this, we want to understand our ability to prosecute a drug discovery programme, the target function in a non-cancer setting, what patient population we expect to benefit from a drug and the level of confidence we have that target modulation will inhibit cancer progression. Clearly generating the data required to assess these factors is impractical to do for every target evaluated and published literature providing this information is often limited for novel targets. There is however an under-utilised wealth of datasets from cell lines, animal models and patient samples that are publicly available, free to access and that can be used to support cancer target evaluation.

Our target review process incorporates an appraisal of outputs from these publicly available datasets to inform target evaluation and direct subsequent in-house studies. However, the potential of these publicly available datasets is not being fully realised in the wider cancer research community as many scientists are not aware what databases are available, how or when they should be used and how to interpret the output.

It quickly became apparent through literature searches that there was not a single article or resource with a comprehensive overview of what databases were available, what information they contained and how they could be used or where we could direct anyone interested in learning more.

Rolling up sleeves…

So, in May 2022, I proposed that Cancer Research Horizons scientists write the review ourselves. I worked with my colleagues Daniel Croft, Puja Lodhia and Sofia Lourenco, to generate an outline structure of what we would like to include and identify journals that may be interested in publishing such a review.

However, publishing a review is often not a straightforward process. Many journals operate on a “review by invitation only” policy, and so we worked on a pre-submission enquiry detailing what the review would include, why it would be of interest to the cancer research community and why the experience we had that meant we were the right people to write this review. After discussions with the editor of NAR Cancer, we were invited to submit our review eight months later.

Eight months may sound like a long time but if you have written reviews before, you’ll know that time can get eaten up very easily. Background reading, draft writing, figure generation, feedback from colleagues and re-drafting, whilst continuing to work on existing projects, mean that efficiency is the order of the day. If you’ve not produced a review article as a team before, here is a top tip: Dividing the workload between the authors and setting regular deadlines for updates meant that we could ensure we made the progress required to meet the target submission date.

And there was another benefit for our team as well. As part of our preparation, we identified new databases we were not previously aware of and updates to existing databases that offered new functionalities. Writing the review therefore provided an excellent opportunity to update our current processes as well as the primary aim of providing information to the wider community.

The article was accepted as an “Editor’s Choice review” in June 2023, just over one year since the review was initially proposed.

We hope that the resulting review is a resource that is of interest to the wider cancer research community and contributes towards Cancer Research Horizons aim of expediting the delivery of patient benefit.

Read the review here.

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Craig MacKay

Craig is Group Lead, Biosciences, at Cancer Research Horizons