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The ICR has a world-leading role in identifying, characterising and clinically exploiting genetic factors that predispose to cancer. This has had a direct and significant impact on public health and patient care; over 250,000 clinical tests for gene modifications that were identified at ICR are performed annually worldwide. Many thousands of families have benefited through optimised treatments for individuals with cancer and improved cancer risk estimation, targeted screening and risk-reducing measures for their relatives. Cancer genes discovered at the ICR include breast cancer genes (BRCA2, CHEK2, BRIP1, PALB2), ovarian cancer genes, (BRCA2, RAD51D, PPM1D), a renal cancer gene (FH) and childhood cancer genes (BUB1B, PALB2, EZH2).
Scientists at The Institute of Cancer Research (ICR) have played a central role in analysing the RAS/RAF/MEK/ERK cell signalling pathway and defining targets for novel cancer therapeutics. Their research work was key in stimulating an international effort to develop MEK inhibitors. Subsequently, ICR scientists predicted that the BRAF protein would be a key node in this pathway and they made the significant discovery that mutant BRAF is an oncogene. This prompted an international search for BRAF inhibitors, which was facilitated by the ICR's structural biology studies of BRAF. As a result, two novel drugs are now on the market.
The PI3 kinase (PI3K) enzymes play a significant role in AKT-mTOR intracellular signalling, a key pathogenic pathway in many cancers. The ICR has discovered first-in-class inhibitors of class I PI3K and these are now being commercially developed by Genentech and are in clinical trials, having demonstrated clinical safety, as well as target inhibition and antitumour activity. To accelerate the commercial development of its PI3K inhibitors, the ICR founded the spin-out company Piramed Pharma, which was subsequently acquired by Roche for a total of $175million. The ICR's published research and its development of a tool compound has underpinned the worldwide effort by pharmaceutical companies to develop these novel cancer therapeutics.
Work by Professor Andrew Tutt at King's College London (KCL), has had the following major impacts: (i) it has provided proof through first-in-man clinical trials (in collaboration with the Royal Marsden/ICR Phase I Clinical Trials Unit) and Phase II clinical trials designed and led by Professor Tutt that poly(ADP ribose) polymerase (PARP) inhibitors have an anti-cancer action in breast and ovarian cancers with BRCA mutations; (ii) it has demonstrated that the concept of `synthetic lethality' can be applied to the selective targeting of cancer cells in humans; (iii) it has paved the way for a major programme of investment by the pharmaceutical industry (over $1 billion to date) in PARP inhibitors for the treatment of BRCA-related cancers (which are currently being tested in a range of cancers in Phase III trials); and (iv) it has been incorporated into UK, European, US and other international guidelines on genetic testing for breast and ovarian cancers that run in families.
HSP90 is a key molecular chaperone protein, and cancer cells are particularly dependent on its function. However, given its wide-ranging action, many doubted it would be possible to produce an effective and safe HSP90 inhibitor. Multidisciplinary research at the ICR has validated HSP90 as an oncology target and defined useful biomarkers leading to HSP90 currently being one of the most actively pursued targets in the drug industry. ICR's own drug candidate, AUY922, was licensed to Novartis and is now in late stage clinical trials. It has shown promising therapeutic activity, especially in HER2-positive breast and non-small cell lung cancers, including drug resistant cases. HSP90 inhibitors could be used against a wide range of other cancers including breast, lung, prostate, ovarian and colon.
Abiraterone (trade name Zytiga) was designed, synthesised and developed by a multidisciplinary team of academic chemists, biologists and clinicians at The Institute of Cancer Research (ICR). Following ICR-led phase I, II and III clinical trials, which demonstrated prolonged survival and improved quality of life for patients with castration-resistant prostate cancer (following cytotoxic therapy), abiraterone was granted approval by the FDA, EMA and NICE. In 2011-2012, abiraterone worldwide sales reached $2.755 billion. In 2012-13, FDA and EMA approval was extended to use in the treatment of metastatic castration-resistant prostate cancer in men who have not received standard chemotherapy.
The Institute of Cancer Research (ICR) conducted pioneering translational research into the use of aromatase inhibitors (AIs) in breast cancer. Novel assays were developed that enabled the effects of AIs to be measured accurately and facilitated their rapid entry into large scale clinical trials and subsequent widespread availability. The ICR showed how AIs should be used clinically and helped to establish international guidelines; in some indications AIs are now the accepted standard of care. Research at the ICR has also led to the evaluation and development of novel predictive tests to determine the prognosis of patients on these drugs.
Basic and applied research at the University of Cambridge has culminated in a widely-used risk prediction algorithm ("BOADICEA") for familial breast and ovarian cancer. This user-friendly web-based tool predicts the likelihood of carrying mutations in breast and ovarian cancer high-risk genes (BRCA1 and BRCA2), and the risks of developing breast or ovarian cancer. BOADICEA has been adopted by several national bodies including NICE in the UK (2006 until present), the American Cancer Society and the Ontario Breast Screening Program (both since 2011) for identifying women who would benefit from BRCA1/2 mutation screening, intensified breast cancer screening and chemoprevention.
Basic, clinical and applied research at the University of Cambridge has culminated in a widely-used risk prediction algorithm ("BOADICEA") for familial breast and ovarian cancer. This web-based, user-friendly tool predicts the likelihood of carrying mutations in breast and ovarian cancer high risk genes (BRCA1 and BRCA2), and the risk of developing breast or ovarian cancer. In 2006, BOADICEA was been recommended by the UK National Institutes of Health and Clinical Excellence (NICE: CG41, 2006) and the American Cancer Society (since 2011). In June 2013, NICE recommended BOADICEA in subsequent guidance (CG164). Furthermore, several national bodies have designated BOADICEA as the standard tool to assess eligibility for high risk breast cancer screening.
Protein kinase B (PKB), also known as AKT, is an enzyme in the PI3 kinase/mTOR intracellular signalling pathway, which is found to be deregulated in many forms of cancer. Professor David Barford's team at the ICR solved the crystal structure of PKB03b2 using innovative protein engineering and licensed six international pharmaceutical companies with reagents to enable them to begin PKB drug discovery programmes. The ICR also initiated its own PKB drug discovery programme: two series of inhibitors were developed that were licensed to AstraZeneca and Astex and are now both in clinical trial. The ICR's work helped to establish PKB as a valid cancer therapeutic target. The ICR is involved in clinical research studies of multiple PI3 kinase and PKB inhibitors, and this research has led to the definition of useful clinical pharmacodynamic biomarkers.