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NTP Hosts RFI Meeting to Develop ‘Rigorous, Comprehensive’ HTS Toxicity-Screen Battery

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Research Triangle Park, NC The National Toxicology Program, seeking information on how to identify and select critical cellular toxicity pathways to be interrogated by cell-based high-throughput screens, this week held a Request for Information meeting at its facility here, and said it will use the responses to develop what it terms a “rigorous and comprehensive” battery of high-throughput assays, an NTP official told CBA News.
 
The NTP also solicited recommendations on particular molecular targets within these cell-tox pathways that are most informative for profiling the pathways in both cell-based and biochemical assays, and on technologies and assay systems that may enable a comprehensive approach to high-throughput toxicological screening.
 
“The simplest reason for [the meeting] is that we are interested in identifying both critical pathways and assays that inform on those pathways, that provide information relevant to those pathways,” Raymond Tice, acting chief of the National Toxicology Program biomolecular screening branch, told CBA News in an interview following the first day of the meeting.
 
Researchers are evaluating chemicals and their relationship to toxicity through their own experiences and their methodologies, Tice said. He explained that companies employ people with experience in a particular arena, who then start thinking about how to apply their experience and expertise from drug-discovery and toxicology perspectives.
 
“So, by having a meeting, we start bringing together a critical mass of people,” and all of those people who are in the NTP Toxicology in the 21st Century focus group on pathways and assays get all this information, see the presentations, think about it, and then go back to those companies that they feel have the most interesting approaches and do a follow-up, Tice explained.
 
“I think that not only was this meeting of benefit to those of us in the government as we develop these screening approaches as alternatives to investigating toxicology, but I think it also was of benefit to the participants” because it brought people together from all over the country who may have similar interests but who may not have communicated with each other before, said Kristine Witt, a toxicologist at the NTP biomolecular screening branch.
 
Witt told CBA News that "one of the things that I was pleased to see was how much discussion occurred among the attendees during the breaks and during lunch." Because many pharmaceutical companies are currently reorganizing their businesses and laying off research staffers, this is a good time for cell-based assay tool and technology companies to consider diversifying beyond drug discovery into areas such as toxicology, said John Westwick, president and CEO of Odyssey Thera and a presenter at the meeting. Westwick told CBA News that the meeting could be a prelude to something bigger, such as an RFA.
 
“It is also nice to have some external validation for what you are doing,” he said.
Toxicology strategies are likely to be similar to drug discovery, which Westwick said seems to spark the question, “’Is the line being blurred between environmental and pharmacological toxicology, allowing companies to expand into both spheres?’”
 
Interagency Collaboration
 
In February, the National Human Genome Research Institute and the National Institute of Environmental Sciences signed an agreement with the US Environmental Protection Agency to use the NHGRI’S National Chemical Genomics Center high-speed automated screening robots to test suspected toxic compounds using cells and isolated molecular targets (see CBA News, 2/15/08).
 
Witt said this week that the NTP is looking for assays that are ready to be installed as soon as possible, or could be installed shortly following modification, at the NCGC screening program.
 

“[H]earing about the options at this meeting will allow us to think about how we might develop that full, comprehensive screening program.”

In addition, “As our program grows, it is going to expand, and we have to look at other options that go beyond the capabilities of NCGC, because they are exploiting a particular technology, and there are limits to that technology,” Witt said.
 
As the NTP examines the significance of the biological responses that it comes across in the NCGC’s high-throughput screens, “we will have to move into different kinds of systems, so hearing about the options at this meeting will allow us to think about how we might develop that full, comprehensive screening program,” Witt said.
 
The NCGC will ultimately have a library of about 8,000 to 10,000 compounds, comprising “every single chemical that we can find that is of environmental concern or in commerce, or is of interest to organizations such as the EPA, NIEHS, or the US Centers for Disease Control,” said Tice.
 
These compounds generally have to be those about whose structure something is known. They should also purchasable and should be soluble in DMSO because that is the vehicle in which the center tests its compounds. “There are certain limits to the kinds of compounds in the library, but there will be a library that gets tested,” said Tice.
 
The NCGC also has limits in terms of the assays it runs in that they have to be a compatible with a 1,536-well format and be add-on assays. Within that context, however, the NCGS has the ability to test large numbers of compounds.
 
The EPA’s ToxCast program, another part of the memorandum of understanding signed between the EPA, NHGRI, and the NIEHS, focuses on contracts with small companies, each of which has a spectrum of assays.
 
“What we are trying to do is take the data from the NCGC, which involves screening lots of compounds, but fewer assays, with that from ToxCast, which involves many assays but fewer compounds, and integrate it with the data that we already have from animals, and human data that we are trying to get from the FDA — whatever we can find,” said Tice.
 
There is probably built-in redundancy in those assays. For example, different companies measure estrogen receptor activation in different ways. “By looking at the redundancy, we will be able to look at the total package and determine if the data is consistent for a particular compound and across different assays measuring different or related endpoints,” Tice said.
 
Companies, organizations, or individuals in the scientific community are joining ToxCast who are not being paid by contract, but who are testing ToxCast’s 320 phase 1 compounds anyway in their own assay systems, to leverage what they are trying to do.
 
“We are trying to … bring these companies and individuals in who may test the same compounds on their own dime to further their own efforts,” Tice said.
 
In terms of follow-ups to the RFI meeting, “one of the questions that we are still trying to resolve is, “’How do you prioritize pathways?’” said Tice. That may be a practical issue, in terms of there may be an assay for that pathway that already can be put into high throughput. 
 
However, another pathway may exist that is more valuable from the standpoint of disease, but for which an assay has not been developed. “What we will do is put out RFPs that say we are interested in having someone develop assays using an SBIR grant in that particular pathway or arena,” said Tice.
 
In addition to Odyssey Thera, shops that play in the cell-based assay market that participated in the RFI meeting included Invitrogen, PerkinElmer, Promega, BioSeek, DiscoveRx, and Cellumen.
 

“We did not have any criteria” for inviting companies to participate,” Tice said. “These are companies that actually submitted something to us and said that they were interested in attending. To the best of my knowledge, we did not turn anyone down.”

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