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Enabling the development of PKB inhibitors as novel cancer therapeutics

Summary of the impact

PKB (protein kinase B), also known as AKT, is an enzyme in the PI3 kinase/mTOR intracellular signalling pathway, which is deregulated in many cancers. Professor David Barford's team at the ICR solved the crystal structure of PKB03b2 using innovative protein engineering. The ICR has licensed six international pharmaceutical companies with reagents to enable them to begin PKB drug discovery programmes. The Barford team has also used their structural biology expertise to advance the ICR's own PKB inhibitor drug discovery programme. Two series of inhibitors were developed that were licensed to AstraZeneca and Astex and are now both in clinical trials.

Submitting Institution

Institute of Cancer Research

Unit of Assessment

Biological Sciences

Summary Impact Type

Technological

Research Subject Area(s)

Biological Sciences: Biochemistry and Cell Biology

Discovery of a new class of cancer drugs: HSP90 inhibitors

Summary of the impact

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.

Submitting Institution

Institute of Cancer Research

Unit of Assessment

Clinical Medicine

Summary Impact Type

Technological

Research Subject Area(s)

Biological Sciences: Biochemistry and Cell Biology
Medical and Health Sciences: Neurosciences

Developing inhibitors of the PI3 kinase enzymes as novel therapeutics

Summary of the impact

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.

Submitting Institution

Institute of Cancer Research

Unit of Assessment

Clinical Medicine

Summary Impact Type

Technological

Research Subject Area(s)

Biological Sciences: Biochemistry and Cell Biology
Medical and Health Sciences: Oncology and Carcinogenesis

RAS/RAF/MEK/ERK signalling and identifying BRAF as a key target for the development of novel cancer therapeutics

Summary of the impact

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.

Submitting Institution

Institute of Cancer Research

Unit of Assessment

Biological Sciences

Summary Impact Type

Technological

Research Subject Area(s)

Biological Sciences: Biochemistry and Cell Biology
Medical and Health Sciences: Oncology and Carcinogenesis

Developing and disseminating conformal radiotherapy and intensity modulated radiotherapy

Summary of the impact

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.

Submitting Institution

Institute of Cancer Research

Unit of Assessment

Clinical Medicine

Summary Impact Type

Health

Research Subject Area(s)

Physical Sciences: Other Physical Sciences
Medical and Health Sciences: Oncology and Carcinogenesis

BRCA genes in cancer; improved screening regimes and novel therapies

Summary of the impact

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.

Submitting Institution

Institute of Cancer Research

Unit of Assessment

Biological Sciences

Summary Impact Type

Technological

Research Subject Area(s)

Biological Sciences: Biochemistry and Cell Biology
Medical and Health Sciences: Oncology and Carcinogenesis

Aromatase inhibitors in breast cancer treatment

Summary of the impact

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.

Submitting Institution

Institute of Cancer Research

Unit of Assessment

Clinical Medicine

Summary Impact Type

Technological

Research Subject Area(s)

Medical and Health Sciences: Oncology and Carcinogenesis

Development of abiraterone for the treatment of castration-resistant prostate cancer

Summary of the impact

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.

Submitting Institution

Institute of Cancer Research

Unit of Assessment

Clinical Medicine

Summary Impact Type

Technological

Research Subject Area(s)

Medical and Health Sciences: Clinical Sciences, Oncology and Carcinogenesis

Establishing the spin out company Domainex to exploit novel protein expression technology

Summary of the impact

The Institute of Cancer Research (ICR) founded the spin out company Domainex in 2002 in collaboration with UCL and Birkbeck. The company was set up on the basis of novel research into the expression of soluble protein domains to provide services to a range of bioscience-based companies. Within the period 2008-2013, Domainex has established profitability and positioned itself as a successful company employing over 30 scientists at its laboratories in Cambridge. It has established programmes and contracts with over 20 international clients in medicinal chemistry, drug discovery, monoclonal antibody development and agrochemical science, making a major commercial impact in all these fields.

Submitting Institution

Institute of Cancer Research

Unit of Assessment

Biological Sciences

Summary Impact Type

Technological

Research Subject Area(s)

Chemical Sciences: Analytical Chemistry
Biological Sciences: Biochemistry and Cell Biology
Agricultural and Veterinary Sciences: Fisheries Sciences

Uncovering the PKB signalling cascade and the development of PKB inhibitors for the treatment of cancer.

Summary of the impact

The protein kinase PKB (also known as Akt) is a key regulator of cell proliferation and survival that is commonly dysregulated in human cancers. Work at the University of Dundee in the late 1990s identified key components of this signaling pathway and established the mechanism by which PKB becomes activated through phosphorylation. Structural studies at the University provided important insights for the design of small molecules permitting targeted inhibition of this enzyme. PKB is a firmly established focus for pharmacological intervention and several clinical trials are underway testing the antineoplastic activity of PKB inhibitors in a variety of cancers.

Submitting Institution

University of Dundee

Unit of Assessment

Biological Sciences

Summary Impact Type

Technological

Research Subject Area(s)

Biological Sciences: Biochemistry and Cell Biology

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