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Pharmacogenomics failing to reach developing countries Pharmacogenomic research failed to pro­ duce sufficient studies focusing on rare, orphan and tropical diseases prevalent in developing countries between 1997 and 2010, according to a study published in the journal Global Public Health. To study the extent to which pharmaco­ genomics research has addressed these neglected diseases, lead investigator Cath­ erine Olivier (University of Montreal, Can­ ada) identified the focus of studies published between 1997 and 2010. A total of 626 stud­ ies, published in 171 different journals were identified. Each study was analyzed accord­ ing to the type of disease investigated, the authors’ origins and affiliations with phar­ maceutical companies, if applicable. “The information collected allowed us to draw a map showing current and historical trends in the development of pharmacogenomic research,” explained Olivier.

The ana­lysis revealed a total of 401 pharmacogenomic publications between 1997 and 2003 in the PubMed database, this number doubled between 2003 and 2010. However, the number of original articles was found to decline after 2002, with more non-original articles being pub­ lished. During the period analyzed, 23% of published studies focused on oncology, 14.7% on psychological disorders and 13.6% on cardiovascular disorders. Rare diseases, tropical infections and maternal health only represented 3.8% of published studies.

“Of the 65 publications from BRICS countries – Brazil, Russia, India, China and South Africa – only two concerned rare diseases and tropical infections.”

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News & Views – News Of concern to Olivier is the lack of inter­ est in such topics even in developing stud­ ies. “Of the 65 publications from BRICS countries – Brazil, Russia, India, China and South Africa – only two concerned rare ­d iseases and tropical infections,” stated Olivier. It would appear that pharmacogenomic research is a long way from fulfilling its promise of aiding the United Nation’s

Millennium Declaration of reducing global health inequalities. – Written by Hannah Wilson Sources: Olivier C, Williams-Jones B. Global pharmaco­genomics: where is the research taking us? Global Public Health 9(3), 312–324 (2014); University of Montreal news: www.nouvelles. umontreal.ca/udem-news/news/20140402pharmocogenomic s-has- not-fulfilled-it spromise-to-developing-countries.html

New collaboration aims to aid target validation and drive drug discovery A pioneering public–private research initia­ tive between GlaxoSmithKline (UK), the European Bioinformatics Institute (UK) and the Wellcome Trust Sanger Institute (UK) is being set up with the aim of har­ nessing the power of genome sequencing and big data to improve the success rate for novel drug discovery. The newly formed Centre for Therapeutic Target Validation (CTTV) aims to address a wide range of human dis­ eases and will share its data openly with a vision towards accelerating drug discovery. The CTTV aims to make use of cut­ ting-edge developments in genetic research to help scientists with the crucial first step in exploring new medicines – finding a starting point. Target validation requires a clear definition of the role of a biologi­ cal process in disease before a new drug can be developed to tackle it. Current esti­ mates state that 90% of compounds enter­ ing clinical trials fail to demonstrate the required efficacy and safety requirements, and never reach patients. This can often

be linked back to a lack of understanding of the biological target. “The CTTV is a transformative collabo­ ration to improve the process of discovering new medicines,” explains CTTV interim head Ewan Birney. “The precompetitive nature of the center is critical: the collabo­ ration of the European Bioinformatics Insti­ tute and the Sanger Institute with Glaxo­ SmithKline allows us to make the most of commercial research and development practice, but the data and information will be available to everyone. It is truly exciting to apply so many different areas of exper­ tise, from data integration to genomics, to the challenge of creating better medicines.” Scientists working with the CTTV will combine their expertise to explore and inter­ pret large volumes of genomic, proteomic, chemical and disease data. It is hoped that this new approach will complement existing target validation methods by drawing on the diverse, specialized skills from scientific institutes and the pharmaceutical industry.

Open data will be a cornerstone of the collaboration with collaborators having agreed that sequence data and informa­ tion gathered within the CTTV will be shared to benefit the wider scientific community. Professor Dame Janet Thornton, Direc­ tor of the European Bioinformatics Insti­ tute, summarizes the CTTV’s mission stating: “Maximizing our use of ‘big data’ in the life sciences is critical for solving some of society’s most pressing problems. This collaboration gives us an opportunity to translate this complex information into biomedical discoveries. As biology becomes increasingly data-driven, precompetitive collaborations such as the CTTV have become crucial for improving efficiencies, driving down costs and providing the best opportunities to deliver beneficial results.” – Written by Hannah Wilson Source: EMBL-EBI press release: www.ebi.ac.uk/ about/news/press-releases/CTTV-launch

New high-risk gene mutation for hereditary melanoma development identified The Wellcome Trust Sanger Institute (UK) has recently announced the discov­ ery of mutations in the POT1 gene, which appear to be responsible for a hereditary form of melanoma. Approximately one in every 20 patients diagnosed with mela­ noma has family history of the disease 732

and identification of causative genetic factors such as this may allow identifica­ tion of those who should be part of mela­ noma surveillance programmes. The study appears online in Nature Genetics. “Genomics is on the verge of transform­ ing the healthcare system – this study Pharmacogenomics (2014) 15(6)

highlights the potential clinical benefits that can be gained through genomic studies and offers potential strategies to improve patient care and disease manage­ ment,” commented David Adams, cosenior author from the Wellcome Trust Sanger Institute. “With this discovery we should future science group

News – be able to determine who in a family is at risk, and in turn, who should be regularly screened for early detection.”

“…research is making a real difference to understanding what causes melanoma and ultimately therefore how to prevent and treat melanoma and is a prime example of how genomics can transform public health.” Previously identified mutations such as deleterious germline variants in CDKN2A and variants in CDK4, BRCA2 and BAP1 account for approximately 40% of inher­ ited melanoma. In an attempt to identify new high-penetrance susceptibility genes that might be involved in the other 60% of cases, the team sequenced the genomes of

184 individuals with hereditary melanoma of unknown genetic cause. Their results indicated that those with inactivating mutations in POT1 were at an extremely high risk of developing mela­ noma. It was further established that the mutations prevent POT1 from maintaining telomere length and integrity. Evidence of the mutations was also noted in some cases of other cancer types in families, including leukemias and brain tumors. “Our research is making a real difference to understanding what causes melanoma and ultimately therefore how to prevent and treat melanoma and is a prime example of how genomics can transform public health,” explained Julia Newton Bishop, cosenior author from the University of Leeds (Leeds, UK). “This study would not have been pos­ sible without the help and patience from the

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families that suffer from these devastating, inherited forms of melanoma.” The researchers plan to further their work into POT1 variants and melanoma predisposition by developing cells and mice with an inactive POT1 gene in which to test potential drug therapies. – Written by Emily Brown Sources: Robles-Espinoza CD, Harland M, Ramsay AJ et al. POT1 loss-of-function variants predispose to familial melanoma. Nat. Genet. doi:10.1038/ng.2947 (2014) (Epub ahead of print); Wellcome Trust Sanger Institute press release: www.nature.com/ng/journal/vaop/ ncurrent/full/ng.2947.html

Regulatory gene linked to progression and relapse of triple-negative breast cancer “Patients with the triple negative form of breast cancer are those who most desper­ ately need new approaches to treat their disease,” comments Laurie H Glimcher of Weill Cornell Medical College (NY, USA). Glimcher is the senior author of a new report published in Nature, describ­ ing how a gene previously not associated with mammary epithelial tumors appears to play a pivotal role in the tumorigenicity and progression of triple-negative breast cancer. Representing approximately 20% of all cancer diagnoses, triple-negative breast cancer is a particularly deadly strain of the disease that typically sees patients relapse within 1–3 years of treatment. This study has determined that the gene XBP1, a critical regulator of immune and meta­ bolic functions, is central to the ability of the cancer to thrive in the oxygen- and nutrient-deprived tumor environment. “This pathway was activated in about two-thirds of patients with this type of breast cancer. Now that we better under­ stand how this gene helps tumors prolifer­ ate and then return after a patient’s initial treatment, we believe we can develop more

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effective therapies to shrink their growth and delay relapse,” continues Glimcher. The research group, which consisted of investigators from across nine institutions, examined breast cancer cell lines and deter­ mined that XBP1 was notably active in basal-like breast cancer cells from culture and triple-negative breast cancer cells iso­ lated from patients. XBP1 depletion both in vitro and in animal models resulted in inhibited tumor growth and tumor relapse, particularly when combined with the use of the chemotherapeutic agents doxorubi­ cin or paclitaxel. The investigators suggest that their results implicate XBP1 in the control of the behavior of tumor-initiat­ ing cells and support the hypothesis that combination therapy could be an effective treatment for triple-negative breast cancer. The work also indicates that XBP1 and another transcriptional regulator known to be hyperactivated in triple negative breast cancers termed HIF1-a interact to form a transcriptional complex that activates cancer-driving proteins. As lead author Xi Chen (Weill Cornell) explains, this “shows the interaction between two critical path­ ways to make the cells better able to deal

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with a hostile microenvironment, and in that way offers new strategies to target triple-negative breast cancer.” While these results may provide a new target for consideration in therapy develop­ ment for this aggressive subtype of breast cancer, further study is required to vali­ date the findings and to ascertain how the information may best help women with the disease. “Obviously we need to know now whether what our group saw in models is what we’ll see in patients,” said coauthor Jenny Chang, Professor of Medicine at Weill Cornell and director of the Hous­ ton Methodist Cancer Center (TX, USA). “We are very excited about the prospect of moving this research forward as soon as possible for the benefit of patients.” – Written by Emily Brown Sources: Chen X, Iliopoulos D, Zhang Q et al. XBP1 promotes triple-negative breast cancer by controlling the HIF1a pathway. Nature 508(7494), 103–107 (2014); Weill Cornell Medical College press release: http://weill. cornell.edu/news/pr/2014/03/gene-implicatedin-progression-and-relapse-of-deadly-breastcancer-nature-laurie-glimcher-xi-chen.html

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Pharmacogenomics failing to reach developing countries.

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