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NIH, Japanese Scientists Discuss Global Alliance Aimed to Advance PGx Research

The National Institutes of Health and the Center for Genomic Medicine in Japan announced plans this week to establish a Global Alliance for Pharmacogenomics, an effort that will aim to identify the genetic underpinnings for drug response and serious adverse reactions. 
From the US, members of the NIH Pharmacogenetics Research Network will join the alliance. The PGRN is a consortium of research groups studying how people's genotypes influence their metabolism of certain drugs.
In a separate interview discussing NIH's recent solicitation for stakeholders to weigh in on the challenges to pharmacogenomics research, Rochelle Long, Chief of the Pharmacological & Physiological Sciences Branch at the NIGMS, told Pharmacogenomics Reporter, that the PGRN has $30 million in funding for fiscal year 2008. The PGRN will be a major source of funding for the studies conducted under the alliance. 
Japanese researchers will contribute from the newly created Center for Genomic Medicine, which is affiliated with the RIKEN Yokohama Institute and conducts high-throughput analyses of human genes involved in diseases and drug responses.
“We expect this international agreement to speed scientific discovery and the translation of results into improved treatments for cancer, heart disease, and other serious conditions,” NIH Director Elias Zerhouni said in a statement announcing the alliance. “Ultimately, physicians worldwide will be able to tailor the treatment of each patient — one of the great frontiers of health care today.”
Initial PGx projects will focus on: understanding genetic factors affecting the effectiveness of aromatase inhibitors in breast cancer treatment; optimizing the length of treatment for cyclophosphamide and either doxorubicin or paclitaxel to treat early stage breast cancer; discovering new genetic factors linked to serious adverse reactions from treatment with gemcitabine and bevacizumab in pancreatic cancer; studying the genetic basis for drug-induced long QT syndrome; and working with the International Warfarin Consortium to genetically tailor starting doses of the anticoagulant warfarin.
The alliance received DNA samples for its studies from the National Cancer Institute's Clinical Trials Cooperative Groups, the International Warfarin Pharmacogenomics Consortium, and the Foundation Leducq, Alliance Against Sudden Cardiac Death.
The alliance will function under the stewardship of a steering committee that will meet twice a year to discuss progress, future projects, intellectual property issues, the approval of additional members, and communication with the public. Data yielded from the alliance will be made public and published in peer-reviewed journals.
In an interview with Pharmacogenomics Reporter this week, Mark Ratain, chair of the PGRN, Kathy Giacomini, a PGRN leader, and Yusuke Nakamura, director of the RIKEN Center for Genomic Medicine, discussed the plans for the alliance and the forthcoming projects that US and Japanese researchers will collaborate on.
The following is an edited transcript of the interview.

Why did you launch the alliance at this time?
Mark Ratain: I think it's a great time in genomics and the potential of genomics has not been fully implemented yet in pharmacogenomics. The timing was really precipitated by the fact that some larger clinical trials were maturing to the point that the samples were ready for analysis. The opportunity to work with Dr. Nakamura, who has one of the best genomics labs in the world, became available. And it was just a great opportunity to create an international alliance and collaboration.
Yusuke Nakamura: We are running a very huge research project called Biobank Japan. We collected 300,000 samples in our DNA bank, and sharing information between two countries can help patients quite a lot.
Which disease states will you be primarily focusing on in this collaboration?
YN: We are focusing on many diseases. We collected [DNA] for 47 different kinds of diseases. Our major focus is cancer. We have more than 15,000 [samples] from cancer patients, those containing the data for adverse reactions. So, more than 2,000 patients show ... higher adverse reactions. But basically this data needs to be verified using another set of samples, and this is the benefit of sharing data between two countries.
Could you discuss your initial projects?
Kathy Giacomini: For this particular alliance, we are starting with five studies. Three of them are on anti-cancer drugs. One of them is on drug-induced cardiac arrhythmias, and there are multiple drugs that cause this. The final study is on warfarin bleeding. It's an anticoagulant so the adverse reaction is bleeding. So, those are the first five studies.
Our plan, since this is the beginning of our alliance, is that it may develop into other drug areas.
What is the design of the studies?
MR: These are all genome-wide association studies.
YN: We are planning to screen more than 600,000 genetic variations in the human genome. We will be looking for genetic links to the drug's efficacy or the drug's adverse reactions.
Do you plan to share this data?
KG: An important part of our collaborative studies is that we publish and that we make all of our data publicly available. This will facilitate other researchers from doing their studies as well. First, they can use our data to replicate their findings. Or, they can use our data to see if our findings are true for their set of patients.
At what stage are your initial projects?
MR: The genotyping for the first study [in pancreatic cancer involving the drugs gemcitabine and bevacizumab] has been completed. We're currently analyzing the data.
Have any pharmaceutical companies expressed an interest in contributing to or replicating the alliance's efforts?
MR: We've not had any formal discussions about that. Genentech is aware that we're doing this. Bevacizumab is their drug, and I have mentioned it to them, but there have not been any formal discussions and there is no formal relationship.
Could you describe the interest in pharmacogenomics among healthcare stakeholders in Japan?
YN: I don't think there is much interest in pharmacogenomics in Japan. But we [at the Center for Genomic Medicine] have continued to express the importance of pharmacogenomics and the benefits that it has for the patient—that it will make the patient feel better. We already have some data indicating that certain genetic properties will influence the amount of the drug [the patient receives] or increase their risk for adverse reactions. This area is very important, and apparently ... patients are beginning to acquire an interest in [pharmacogenomics] and are expecting our results.
Are there barriers to advancing the field?
YN: I think pharmaceutical companies in Japan are not so interested. They are concerned about losing their commercial market. But I think the important thing is to provide better [disease] management to the patient. As long as the patients want to go in this direction, no one can stop [the advancement of the field]. And many patients are encouraging our activities.
Where is the funding coming from?
MR: The funding is coming ... from the NIH's grant to the PGRN. Although, some of these studies are partially supported by other funding sources, such as the NCI's Cooperative Group Program.
YN: The funding for the genotyping comes from a grant from the Ministry of Education, Culture, Sports, Science, and Technology in Japan.  
MR: There's no new funding being allocated to this. This is basically leveraging existing funding. That's what everyone is so excited about, that the PGRN is already funded, the clinical trial structure is already funded, Dr. Nakamura's laboratory is already funded, and it's really about wisely utilizing the funding in a leveraged way to create this international synergy.

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