Join us for the first instalment of the 2021 Almroth Wright lecture series with Professor Paul Workman FRS.
Please register in advance if you would like to attend. This event will be hosted via Microsoft Teams; once you have registered, you will receive a calendar invitation and link via email.
For more information about the Almroth Wright lecture series, please visit our website.
One in two people will develop cancer in their lifetime. The UK’s cancer survival has doubled over the last four decades such that around half of patients now survive over ten years. However, outcomes for cancers such as lung, liver, brain and pancreas remain very poor. The discovery and development of personalised medicines have been underpinned by our enhanced mechanistic understanding of cancer biology and genetics, accelerated by genome sequencing. However, a major challenge to drug treatment is the extensive cellular and genetic heterogeneity of tumours and the ability of cancer cells to adapt, evolve and become resistant. I will briefly cover this background before describing examples of our recent research to discover new molecularly targeted drugs. I will also interweave examples of my other major personal research interest, which is the discovery of high-quality small-molecule chemical probes to investigate the role of specific proteins in fundamental biology and disease pathology.
Following our discovery of Heat Shock Protein 90 molecular chaperone inhibitors and progression of luminespib to the clinic (with Vernalis and Novartis), we switched our attention to discover inhibitors of the transcription factor Heat Shock Factor 1 or HSF1. HSF1 plays an important role in oncogenesis and the maintenance of the cancer state. HSF1 is itself hard to drug directly and so we adopted an approach based on phenotypic screening. I will describe our more than ten-year journey from the initial screen to the discovery of a chemical probe and then a clinical candidate HSF1 pathway inhibitor that shows particular potential for the treatment of ovarian clear cell carcinoma and multiple myeloma.
In collaborative studies, we have progressed to a first-in-child clinical trial evaluation of the dual-selective cyclin-dependent kinase (CDK) 9/2 inhibitor fadraciclib (CYC065). This drug was discovered by our team at ICR in collaboration with Cyclacel. We then discovered its therapeutic potential in models of aggressive paediatric neuroblastoma that is driven by another transcription factor, MYCN. Like HSF1, MYCN is also hard to drug directly, but its expression is decreased by fadraciclib’s inhibition of the transcriptional kinase CDK9. The additional inhibition of CDK2 by fadraciclib induces apoptotic cell death in MYCN neuroblastoma cells and produces prolonged tumour response and survival in mouse models.
About the speaker
Paul Workman is Chief Executive and President of The Institute of Cancer Research (ICR), London, and Harrap Professor of Pharmacology and Therapeutics at the ICR. He was the Founding Director of the ICR/Imperial Cancer Centre of Excellence and the ICR/Imperial CRUK Convergence Science Centre. Paul is a Fellow of the Royal Society, Academy of Medical Sciences, Royal Society of Chemistry, Royal Society of Biology and the European Academy of Cancer Sciences. He is also a Cancer Research UK (CRUK) Life Fellow.
Trained in biochemistry and cancer pharmacology, Paul is a leader in the discovery of molecularly targeted cancer drugs for personalised treatment and the identification of small-molecule chemical probes to investigate protein function in fundamental biology and disease pathology. At AstraZeneca, he led the biology of the team that discovered gefitinib (Iressa), approved in EGFR mutant lung cancer. As Director of ICR’s CRUK Cancer Therapeutics Unit, Paul oversaw the discovery of 20 drug candidates, eleven of which have progressed into the clinic. Paul is especially renowned for his innovative personal research in the discovery, chemical biology, and molecular pharmacology of drugs acting on protein kinases, PI3 kinases and the molecular chaperone HSP90, and he is the originator of the widely used Pharmacologic Audit Trail framework for biomarker-led drug development. He was a scientific founder of Piramed Pharma (acquired by Roche) and Chroma Therapeutics and is Executive Director of the non-profit Chemical Probes Portal.
Paul has published more than 500 scientific articles, receiving over 45,000 citations. He has received numerous personal honours and awards. He led the ICR/Royal Marsden team that won the 2012 American Association of Cancer Research Team Science Award, and under his leadership, the ICR was awarded a 2017 Queens’ Anniversary Prize for its outstanding track record in cancer drug discovery. Paul writes, lectures and blogs about cancer research and drug discovery.