28 March 2012

The path to personalised cancer treatment

Researchers identify genetic markers of drug sensitivity in cancer cells

A volcano plot representation of MANOVA results showing the magnitude and significance of all drug-gene associations. Each circle represents a single drug-gene interaction and the size is proportional to the number of mutant cell lines screened.

A volcano plot representation of MANOVA results showing the magnitude and significance of all drug-gene associations. Each circle represents a single drug-gene interaction and the size is proportional to the number of mutant cell lines screened. [10.1038/nature1100]

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In the largest study of its kind, researchers have profiled genetic changes in cancer with drug sensitivity in order to develop a personalised approach to cancer treatments. The study is published in Nature on Thursday 29 March 2012.

The team uncovered hundreds of associations between mutations in cancer genes and sensitivity to anticancer drugs. One of the key responses the team found was that cells from a childhood bone cancer, Ewing's sarcoma, respond to a drug that is currently used in the treatment of breast and ovarian cancers. The lowered toxicity of this treatment may mean it is a safer alternative therapy for children and young adults with this aggressive cancer.

There is an intimate relationship between the way a drug works and the genetic changes present in cancers. This study found that sensitivity to most anti-cancer drugs is influenced by mutations in cancer genes and establishes the utility of using large-scale studies to identify these associations and build them into improved patient treatment.

"Our key focus is to find how to use cancer therapeutics in the most effective way by correctly targeting patients that are most likely to respond to a specific therapy," explains Dr Mathew Garnett, first author from the Wellcome Trust Sanger Institute. "We studied how genetic changes in a panel of more than 600 cancer cell lines effects responses to 130 anti-cancer drugs, making it the largest study of this type to date."

The team identified biological markers of drug sensitivity to a broad range of cancer drugs. Most of the cancer genes analysed, including those that are not known directs targets of the drugs tested, were associated with either sensitivity or resistance to at least one of the drugs analysed.

" Our key focus is to find how to use cancer therapeutics in the most effective way by correctly targeting patients that are most likely to respond to a specific therapy. "

Dr Mathew Garnett

"Our research has taken us down unknown paths to find associations that are completely novel," says Dr Cyril Benes, senior author from Massachusetts General Hospital Cancer Centre. "We have identified hundreds of associations, many of which we still don't fully understand. We identified a novel indication for the use of PARP inhibitors, anti-cancer drugs currently used to treat breast and ovarian cancers, for the treatment of Ewing's sarcoma."

Ewing's sarcoma is a cancer of children and young adults with a 15% five-year survival rate in patients where the cancer has spread or they have relapsed after chemotherapy. The use of PARP inhibitors could represent a new treatment option for Ewing's sarcoma patients and these compounds will now be tested in clinical trials to assess their therapeutic benefit.

"Advances in next-generation sequencing technologies are already being translated into the large-scale detection of cancer gene mutations in the clinic," says Dr Ultan McDermott, senior author from the Wellcome Trust Sanger Institute. "There is a compelling need to identify, in a systematic fashion, whether observed mutations affect the likelihood of a patient's response to a given drug treatment. We have therefore developed a unique online open-access resource for the research and medical community that can be used to optimise the clinical application of cancer drugs as well as the design of clinical trials of investigational compounds being developed as treatments."

The team hopes their open-access database will be an important resource for the cancer research community and which will ultimately lead to improved treatments for patients. This research program is a unique Wellcome Trust funded 5-year collaboration between The Cancer Genome Project at the Wellcome Trust Sanger Institute and the Center for Molecular Therapeutics, Massachusetts General Hospital Cancer Center.

"Our work is helping to move cancer therapeutics away from the conventional tissue-based treatment to a more molecular-based treatment," says Professor Daniel Haber, senior author from Massachusetts General Hospital Cancer Centre. "The next steps for this collaborative project are to evaluate some of the key findings using tumour samples and test new candidate therapeutic strategies in clinical trials so we can hopefully improve the way we treat cancer patients. We are continuing our screening effort, in particular using drug combinations to discover innovative and better therapeutic options."

Notes to Editors

Publication details

  • Systematic identification of genomic markers of drug sensitivity in cancer cells.

    Garnett MJ, Edelman EJ, Heidorn SJ, Greenman CD, Dastur A, Lau KW, Greninger P, Thompson IR, Luo X, Soares J, Liu Q, Iorio F, Surdez D, Chen L, Milano RJ, Bignell GR, Tam AT, Davies H, Stevenson JA, Barthorpe S, Lutz SR, Kogera F, Lawrence K, McLaren-Douglas A, Mitropoulos X, Mironenko T, Thi H, Richardson L, Zhou W, Jewitt F, Zhang T, O'Brien P, Boisvert JL, Price S, Hur W, Yang W, Deng X, Butler A, Choi HG, Chang JW, Baselga J, Stamenkovic I, Engelman JA, Sharma SV, Delattre O, Saez-Rodriguez J, Gray NS, Settleman J, Futreal PA, Haber DA, Stratton MR, Ramaswamy S, McDermott U and Benes CH

    Nature 2012;483;7391;570-5

Funding

This work was supported by a grant from the WellcomeTrust and by grants from the National Institutes of Health. S.R. is supported by a Physician-Scientist Early Career Award fromthe Howard Hughes Medical Institute. U.M. is supported by a Cancer Research UK Clinician Scientist Fellowship.

Participating Centres

A list of participating centres can be found in the paper

The Genomics of Drug Sensitivity in Cancer project

The Genomics of Drug Sensitivity in Cancer project is an academic research program to identify molecular features of cancers that predict response to anti-cancer drugs. The Genomics of Drug Sensitivity in Cancer Project is a collaboration between The Cancer Genome Project at the Wellcome Trust Sanger Institute (UK) and the Center for Molecular Therapeutics, Massachusetts General Hospital Cancer Center.

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Massachusetts General Hospital

Massachusetts General Hospital founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $750 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, reproductive biology, systems biology, transplantation biology and photomedicine.

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The Wellcome Trust Sanger Institute

The Wellcome Trust Sanger Institute is one of the world's leading genome centres. Through its ability to conduct research at scale, it is able to engage in bold and long-term exploratory projects that are designed to influence and empower medical science globally. Institute research findings, generated through its own research programmes and through its leading role in international consortia, are being used to develop new diagnostics and treatments for human disease.

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The Wellcome Trust

The Wellcome Trust is a global charitable foundation dedicated to achieving extraordinary improvements in human and animal health. We support the brightest minds in biomedical research and the medical humanities. Our breadth of support includes public engagement, education and the application of research to improve health. We are independent of both political and commercial interests.

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