16 March 2014

Cancer therapy may be too targeted

Genetic landscape of rare cancer acts as a guide for future clinical trials

Driver variants in angiosarcoma. Likely driver variants are indicated by colored squares.

Driver variants in angiosarcoma. Likely driver variants are indicated by colored squares. [Doi: 10.1038/ng.2921]

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Researchers have identified two novel cancer genes that are associated with the development of a rare, highly aggressive, cancer of blood vessels. These genes may now act as markers for future treatments and explain why narrowly targeted therapies that are directed at just one target fail.

Angiosarcoma is a rare cancer of blood vessels. It occurs either spontaneously or can appear after radiotherapy treatment. Although quite rare, with approximately 100 people diagnosed with the cancer in the UK each year, the survival outcomes for the cancer are poorer than many other cancer types.

Scientists have previously developed drugs against angiosarcoma that target specific cellular pathways involved in the formation of blood vessels. However, these drugs have had little or no success.

In this study, the team found that 40 per cent of angiosarcomas carry mutations in genes that control blood vessel growth, including two novel cancer genes, PTPRB and PLCG1.

"Because this cancer doesn't respond well to traditional chemotherapy and radiotherapy, it makes sense to develop drugs that target pathways that control blood vessel formation," says Dr Peter Campbell, co-lead author from the Wellcome Trust Sanger Institute "We found two novel cancer genes that control blood vessel formation which are mutated in this cancer and which could be targeted for treatment of this highly aggressive cancer."

" We found two novel cancer genes that control blood vessel formation which are mutated in this cancer and which could be targeted for treatment of this highly aggressive cancer. "

Dr Peter Campbell

However, in some patients, the team found multiple mutations in the pathway that controls blood vessel growth. These multiple mutations may make drugs developed for a single target ineffective in some patients. This study emphasises the need to take into account the effects multiple, co-operating mutations can have when designing targeted treatments for patients.

"This indicates that we may need to think more broadly to find a suitable treatment," adds Dr Campbell.

"This study really highlights the power that a limited number of samples can have to influence the clinical and biological understanding of a rare disease, in this case angiosarcoma," says Professor Adrian Harris, co-lead author from the University of Oxford. "Not only does our study change the way people view the biology of this tumour, it acts as a guide for future drug trials in angiosarcoma patients."

Because so few people are affected by angiosarcoma, clinical trials can be very difficult to conduct. With this new information researchers now need to determine if existing drugs could be effective against this detrimental cancer.

"It's extremely important that we continue to study rare cancers such as angiosarcomas," says Dr Sam Behjati, first author from the Wellcome Trust Sanger Institute. "Not only will this help the many patients with these cancers and improve treatment strategies, but it will help us understand the full landscape of cancer-causing mutations and the underlying biology."

Notes to Editors

Publication details

  • Recurrent PTPRB and PLCG1 mutations in angiosarcoma.

    Behjati S, Tarpey PS, Sheldon H, Martincorena I, Van Loo P, Gundem G, Wedge DC, Ramakrishna M, Cooke SL, Pillay N, Vollan HK, Papaemmanuil E, Koss H, Bunney TD, Hardy C, Joseph OR, Martin S, Mudie L, Butler A, Teague JW, Patil M, Steers G, Cao Y, Gumbs C, Ingram D, Lazar AJ, Little L, Mahadeshwar H, Protopopov A, Al Sannaa GA, Seth S, Song X, Tang J, Zhang J, Ravi V, Torres KE, Khatri B, Halai D, Roxanis I, Baumhoer D, Tirabosco R, Amary MF, Boshoff C, McDermott U, Katan M, Stratton MR, Futreal PA, Flanagan AM, Harris A and Campbell PJ

    Nature genetics 2014;46;4;376-9

Funding

This work was supported by funding from the Wellcome Trust.

Participating Centres

  • Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK
  • Department of Paediatrics, University of Cambridge, Hills Road, Cambridge, CB2 2XY, UK
  • he Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, OX3 9DS, UK
  • Human Genome Laboratory, Department of Human Genetics, VIB and KU Leuven, B-3000 Leuven, Belgium
  • Histopathology, Royal National Orthopaedic Hospital NHS Trust, Stanmore, Middlesex, HA7 4LP, UK
  • University College London Cancer Institute, Huntley Street, London, WC1E 6BT, UK
  • Departments of Oncology and Genetics, Oslo University Hospital, N-0310 Oslo, Norway
  • The K.G. Jebsen Center for Breast Cancer Research, University of Oslo, N-0424 Oslo, Norway
  • Institute of Structural and Molecular Biology, Division of Biosciences, University College London, London WC1E6BT, UK
  • Division of Molecular Structure, MRC-National Institute for Medical Research, Mill Hill, London NW7 1AA, UK
  • Department of Pathology, John Radcliffe Hospital, Oxford, OX3 9DS, UK
  • M. D. Anderson Cancer Center, The University of Texas, 1901 East Road, Houston, Texas 77054, USA
  • Bone Tumour Reference Centre, Institute of Pathology, University Hospital Basel, Basel, Institute for Applied Cancer Science, Switzerland
  • Pfizer Oncology, 10555 Science Center Dr, La Jolla, CA, 92121
  • Department of Haematology, Addenbrooke's Hospital, Cambridge, UK
  • Department of Haematology, University of Cambridge, Hills Road, Cambridge, CB2 2XY, UK

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