Image: Dr Susan Lindquist. Source: Wikimedia, CC BY-SA 3.0.
Like so many, I was shocked and saddened to hear of the untimely death from cancer on October 27, 2016, of Dr Susan Lindquist.
Sue was a true scientific pioneer and innovator, specialising in the field of protein folding and its role in cancer and neurodegenerative diseases. She was also a great advocate for women in STEM.
Her cutting edge research and radical ideas were not only trailblazing but often viewed as controversial at the time and met with initial disbelief.
Sue’s impact on both basic and translational research was immense. Of particular relevance to my own research and that of The Institute of Cancer Research, London, was her work on the molecular chaperone HSP90 (Heat Shock Protein 90), another heat shock protein and chaperone HSP70 and the transcription factor HSF1 (Heat Shock Factor 1).
An ebook dedicated to the life and work of Sue Lindquist, edited by Marc Mendillo, David Pincus and Ruth Scherz-Shouval, has just been published with the title ‘HSF1 and Molecular Chaperones in Biology and Cancer’.
This project was initiated at a meeting in Sue's honour in Madrid that I co-organized with Nabil Djouder, Wilhelm Krek and Xiaohong Helena Yang.
Individual chapters are listed in PubMed as articles published in Advances in Experimental Medicine and Biology.
I was honoured to contribute the closing chapter of the monograph, writing what was very much a personal reflection on the translational aspects of the field of molecular chaperones and the discovery and development of inhibitors of HSP90, HSP70 and HSF1.
Sue spent the initial part of her career at the University of Chicago and then later was at the Whitehead Institute in Boston, where she was also Professor of Biology at the Massachusetts Institute of Technology (MIT), and latterly also an associate member of the Broad Institute of MIT and Harvard University.
Earlier, Sue earned an undergraduate degree in microbiology from University of Illinois at Urbana-Champaign and a PhD in biology from Harvard.
Drugging HSP90, HSP70 and HSF1
Sue’s research into the biological function of HSP90 provided valuable background to our own research to discover small-molecule inhibitors of chaperones, culminating in the discovery in the Cancer Research UK Cancer Therapeutics Unit at the ICR, in collaboration with UK biotech company Vernalis, of the clinical candidate luminespib – also previously known as VER52296 and AUY922 – which was licensed to Novartis and has shown clinical activity in breast and non small cell lung cancer.
This therapeutic activity is based on the role of HSP90 in ‘chaperoning’ or stabilising many cancer-causing proteins – for example the product of the HER2 gene which is amplified and drives the growth of many breast (and other) cancers and the product of mutated forms of the ALK and EGFR genes that drive many non small cell lung cancers.
Sue had carried out crucial early work to understand the features of HSP90 that allow it to chaperone both kinases and also transcription factors such as the glucocorticoid receptor.
Inhibition of HSP90 blocks its ability to chaperone and stabilise HER2 and mutant EGFR and ALK protein kinases, leading to their destruction by the cell’s waste disposal system for proteins, known as the proteasome.
At least 17 small-molecule HSP90 inhibitors have entered clinical trials. However, to date none have been approved. This may be because we have not as yet found the way to use these drugs most optimally – especially in combination with other agents.
In leading one of the teams that championed HSP90 as a drug target, in collaboration with Professor Laurence Pearl’s lab in ICR’s Division of Structural Biology, I was impressed by HSP90’s ability to chaperone many different proteins that contribute to cancer’s growth and spread.
And we reasoned that by inhibiting the function of HSP90 we would be able to eliminate multiple cancer-causing proteins and therefore not only to block cancer growth but also to reduce its ability to adapt and evolve to become resistant to treatment.
This thinking was an extension into the oncology domain of Sue’s pioneering and at times controversial research demonstrating that HSP90 could act as a kind of genetic capacitor in phenotypic variation and so-called ‘morphological evolution’ – initially buffering hidden genetic variants before releasing, under conditions of environmental stress, potentially useful forms for selection in evolutionary bursts.
In addition to HSP90, HSP70 family members have also been validated as drug targets. Hence we and others have also designed and synthesized inhibitors of heat shock proteins and chaperones in HSP70 family. HSP70 proteins are, however, technically much tougher to drug.
Prior to her work on HSP90, Sue had been involved in the very early work to understand how elevated temperatures trigger the 'heat shock response' mediated by HSF1 – leading to the production of heat shock proteins, many of which are chaperones like HSP90.
Furthermore, in later years Sue’s lab contributed hugely to understanding the important role of HSF1 in cancer and provided important validation that helped underpin our subsequent discovery of small-molecule inhibitors of the HSF1 pathway.
'An astonishing list of achievements'
Among her many awards and accolades, Sue was in 2015 elected as a Foreign Member of the UK’s Royal Society for which her biography reads:
‘Susan Lindquist has transformed our understanding of how protein folding shapes biological systems. She has made groundbreaking contributions in genetics, cell biology and biochemistry, using organisms as diverse as fungi, fruit flies, mustard plants and mammals.
‘She discovered the functions of heat-shock proteins, identified prions as conduits of protein-based inheritance, and pioneered new platforms for neurodegenerative disease. She established the key role of the heat-shock proteins in tumour progression and the evolution of fungal drug resistance. She discovered that protein-folding buffers and releases genetic variation in response to environmental stress, providing the first plausible explanation for rapid bursts of evolution.’
This an astonishing list of achievements.
In addition to the application of her discoveries to cancer, Sue’s pioneering work on the inheritance of proteins – with new, self-perpetuating shapes, as distinct from new DNA sequences – has great relevance to understanding and potentially treating neurological illnesses such as Alzheimer's, Parkinson's, Huntington's and Creutzfeldt–Jakob disease.
To accelerate the discovery of treatments for these diseases, Sue co-founded two biotech companies – FoldRx Pharmaceuticals (acquired by Pfizer) and Yumanity.
Overall, Sue Lindquist’s research has made an enormous contribution to our understanding of protein folding in health and disease.
At the end of my article in the monograph dedicated to her life in science, I express the profound hope that our clinical candidate inhibitor of the HSF1 pathway – which is showing promising activity in models of ovarian cancer – will make a real difference to the treatment of this disease which cruelly took Sue away from us far too early.
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