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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.
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.
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.
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.
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.
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.
Research carried out at King's College London (KCL) has raised awareness of the potential risks associated with certain hormone therapies used to treat prostate cancer. The group found that such hormone therapy can raise the risk of heart attack by 24% and the risk of dying from heart disease by 21%. However, for men receiving anti-androgen hormone therapy, the risk of dying from heart disease was lower compared to other hormone therapies such as gonadotropin-releasing hormone agonists. With anti-androgen hormone therapy there was a chance of heart failure but the risk was 5% compared to 34% for other hormone therapies which reduce testosterone production.
The research has had very considerable impact in terms of reach, as over 600 articles have been published in newspapers and other media which refer to the KCL finding that men with prostate cancer treated with certain hormone therapies have a higher risk of heart disease and strokes.
The findings had a very significant impact on US Food and Drug Administration (FDA) advice to healthcare professionals on the benefits and risks of hormone therapy. The FDA also required manufacturers of certain hormone therapy drugs to add safety information to labels.
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 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).
ProtecT (Neal, Cambridge; Donovan, Bristol; Hamdy, Oxford), funded by NIHR in 1999, is the largest randomised controlled trial in localised prostate cancer; and compares a deferred conservative approach (Active Monitoring — developed by the Trial PIs) with surgery and radiotherapy. Avoiding "over-treatment" in low risk cancer is important and Active Monitoring (AM) and Surveillance (AS) have now had a major impact on patients and on national health policy through NICE guidance, which recommends such management approaches. The linked bio-repository was critical to characterising the genetic pre-disposition alleles (SNPs) in prostate cancer, which are now being used to identify high risk populations.