Reflections from our chief clinician: The essential role of our research community

Cancer

As Cancer Research UK celebrates 20 years since its formation, our chief clinician Charlie Swanton gives some of his personal reflections on how far research has come and why sustained investment is so important for the therapies of the future…          

20 years ago, I was a junior doctor in training. We were just beginning to see the introduction of targeted therapies into the clinic.

I remember a conversation with my registrar on call one night about a new drug to treat a previously untreatable tumour – Imatinib in gastrointestinal stromal tumours with a specific mutation in the receptor tyrosine kinase c-KIT – and marvelling at the future potential of this field. Of course, this was just the beginning and since then we have seen many successes in the field of precision oncology.

“Progress requires sustained investment in research, tolerance of risk and an acceptance that failure is an important component of defining the right path for patients.”

As we celebrate 20 years of Cancer Research UK (CRUK), it is a perfect time to reflect on the progress we have made in clinical and discovery research and the impact this has had on patient lives. In a short article like this, I couldn’t possibly do justification to the thousands of scientists, clinician scientists, cancer trialists and hospital staff who work tirelessly to improve the lives of patients. We owe them a huge debt of gratitude for their dedication to building a future where cancer diagnoses are rarer and earlier and cures are more likely.

It is helpful to consider just what is involved to develop effective medicines and how much effort our research community dedicates, over decades, to improve patient lives. Progress requires sustained investment in research, tolerance of risk and an acceptance that failure is an important component of defining the right path for patients. Maintaining a diverse research portfolio, fostering long term investment in our research community, growing careers and supporting leaders of the future drives breakthroughs from unexpected quarters that are today delivering real benefit for patients.

Making the impossible, possible

Targeting the EGFR/HER2 pathway has resulted in impressive advances in the treatment of colorectal, lung and breast cancer, among others. Delivering benefit for patients however, is often built on decades of prior research.

In the context of the EGFR pathway, much of the research to understand the roles of this receptor tyrosine kinase family and its downstream signalling molecules has been funded by CRUK’s legacy charities, the Imperial Cancer Research Fund (ICRF) and the Cancer Research Campaign (CRC). In fact, my postdoc supervisor, Julian Downward, played a major role in the discovery of EGFR in the 1980s during his PhD. It wasn’t until 25 years later that the first truly positive lung cancer trial – IPASS – demonstrated the benefit of targeting EGFR in a select population with EGFR mutations.

Cancer research has subsequently elucidated how clonal evolution selects for resistance events following EGFR targeting. A decade later, we now have a third generation EGFR inhibitor that overcomes a downstream resistance mechanism, prolonging benefit and patient lives. Thanks to decades of research into understanding the cell signalling protein K-Ras and its downstream effectors, we even have small molecules that target a specific activating mutation, previously considered un-targetable. Scientific investments really do transform the impossible to the possible.

Today’s progress, tomorrow’s treatments

A year before CRUK was formed, Tim Hunt and Paul Nurse won a Nobel Prize for their discoveries of the human cyclin-dependent kinase, CDC2, and unravelling the orchestration of the cell cycle governing when and how cells divide. We now know, thanks to major global cancer sequencing efforts, that most solid tumours have one or more defects in genes that regulate timely transition through the cell cycle, particularly in genes that regulate transition into S phase from G1. Three decades later, G1 phase specific cyclin-dependent kinase inhibitors are demonstrating real benefit for patients with breast cancer.

When viewed in a moment of time, progress – in the context of patient outcomes – can appear depressingly slow. But behind the scenes, activity in the fields of basic science, through to drug discovery and development, really are driving the cures of the future.

One Friday evening shortly before CRUK was founded, I remember Professor Martin Gore, a mentor to so many oncologists and cancer nurses in the NHS today, saying how tired he was of treating melanoma. It was then a field that had not advanced in his 30-year career. Martin was reflecting on the treatment of melanoma and the depressing outcomes at the time, and the fact that he was still using the same cancer chemotherapy drug, DTIC, that he used as a junior doctor. Less than a decade later, CRUK supported clinicians were at the forefront of the development of cancer immune-therapy drugs in this disease. These checkpoint inhibitors now offer real potential for long term benefit, and even ‘cures’ in a disease that was previously intractable.

Undoubtedly, some of the scientific breakthroughs made by our researchers today will lead to the drugs of the future, accelerating improvements in patient outcome that will be reported 30 years from now at CRUK’s 50th Anniversary.

The principle that “nature does not make jumps” underpinned Darwin’s work in his Origin of Species. But when it comes to progress against cancer, history clearly shows that jumps and sudden advances are made, with breakthroughs from unexpected areas – and this is thanks to the extraordinary endeavours of our scientific and clinical communities.

Professor Charles Swanton is Cancer Research UK’s chief clinician. He is a clinician scientist, focusing his work on understanding the challenges inherent in the management of metastatic cancer and their drug resistant and incurable nature.

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