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Clinical research led by The Institute of Cancer Research (ICR) has resulted in new standardised curative radiotherapy dose-fractionation regimens being adopted across the UK for over 25,000 women per year with early breast cancer. As a direct result of the trials led by the ICR, NICE introduced new guidance in 2009 recommending a 15-fractions-over-3-weeks radiotherapy regimen (hypofractionation) instead of the previous 25-fractions-over-5-weeks schedule. Patient welfare is substantially improved with savings in travel time and costs for attending treatment, and the NHS benefits from reduced treatment costs. This new treatment schedule is now being adopted internationally.
The Institute of Cancer Research (ICR) has made seminal contributions to the development and dissemination of conformal radiotherapy and intensity modulated radiotherapy (IMRT), leading to changes in clinical practice, reduced treatment complications and improved cure rates. ICR researchers developed conformal radiotherapy, which allowed better shaping of the high-dose radiation volume around a tumour, and they then refined this technique to create IMRT, which makes possible the definition of a high dose volume with a concave border allowing further sparing of critical normal tissue. IMRT is now the approved treatment regime for many cancers such as prostate, breast and head and neck in the USA, the UK and many European countries.
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.
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.
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.
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.
Scientists at The Institute of Cancer Research (ICR) have identified a breast cancer susceptibility gene, BRCA2, and advanced the understanding of the function of the BRCA genes. Following the discovery and cloning of BRCA2, further research demonstrated that BRCA mutations are also associated with ovarian, prostate and pancreatic cancers. BRCA testing is now routinely used by health services worldwide to identify those at high risk of developing cancer and advise them on preventative strategies. ICR research showed that magnetic resonance imaging (MRI) was more sensitive than X-ray mammography when screening for tumours in BRCA carriers, and this is now the standard of care in the UK. Through further research on BRCA function, ICR scientists demonstrated that PARP inhibitors were effective in treating breast cancer in mutant BRCA carriers. This has led to the rapid development of poly-ADP-ribose polymerase (PARP) inhibitors as drugs for targeted use against breast and ovarian cancers with a BRCA mutation as well as a recent submission to regulatory authorities for approval and registration in Europe for the use of the PARP inhibitor olaparib for maintenance treatment of BRCA mutated ovarian cancer.
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).
Laboratory research at Imperial College supported the concept of switching adjuvant treatment of breast cancer (i.e. tamoxifen for 2-3 years to exemestane for 2-3 years) which has now been shown in Imperial-led clinical trials to improve overall survival of breast cancer patients for at least 5 years post-switching. In association with this, the effects of switching on endometrial, skeletal and joint function have shown few long-term deleterious effects. This way of treating breast cancer has now gained acceptance worldwide, as being more efficacious and resulting in fewer longterm, serious side effects. It is the recommended treatment in international guidelines.
As part of a 20 year partnership with AstraZeneca, Professor John Robertson, University of Nottingham, has made the largest and most consistent contribution by a clinical academic to the development of the most recent endocrine agent licensed for breast cancer, fulvestrant (Faslodex®). [text removed for publication]. Since 2008, fulvestrant 250mg has continued to be registered and launched in a number of countries based on Robertson's work, and Robertson has enhanced the clinical uptake of fulvestrant 250mg through training. His research has also been instrumental in the development and uptake of the more efficacious fulvestrant 500mg, including registration in 2010.