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NCI Center for Cancer Research Taps Director of New Gene Silencing Group

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More than a year after it began putting together a plan to establish a new RNAi research group, the NCI’s Center for Cancer Research has named Natasha Caplen as director of the program, RNAi News has learned.

The group, according to the CCR, is designed to promote collaboration on RNAi cancer research among investigators both inside and outside the National Institutes of Health, as well as facilitate translational and clinical cancer research. In July, the agency began advertising the director position, and while Caplen had essentially been given the job late last year, the formal hiring process has only just now concluded. (See RNAi News, 10/17/2003).

Caplen, who holds a BS from the University of Liverpool and a PhD from the University of London, joins the CCR as head of the gene silencing section — which is technically a part of the Office of Science and Technology Partnerships — after working for the National Human Genome Research Institute for the past seven years.

With a background in gene therapy, Caplen came to the US in the mid-1990’s to conduct post-doctoral work with adeno-retroviral chimeric viruses, she told RNAi News. But soon she became interested in alternative methods of modulating gene expression, primarily those that down-regulate gene expression, which ultimately led her to begin studying RNAi around 1999.

Caplen and colleagues published data in July 2001 in the Proceedings of the National Academy of Sciences data that demonstrated that the use of short double-stranded RNAs were able to silence genes in human and mouse cell lines. The PNAS paper came out just a few weeks after Thomas Tuschl et al. published their landmark paper in Nature describing how 21-nucleotide long RNA duplexes can trigger RNAi in cultured mammalian cells. While Caplen’s group was disappointed, her research in the field didn’t slow.

“At that point, I then embarked on a series of studies looking at the potential for gene therapy applications [of RNAi],” Caplen said. “I did some work with the NINDS trying to down-regulate CAG-specific transcripts … and we also completed a study [with the FDA] looking at the feasibility of using RNAi in invertebrate systems as an antiviral agent.”

Then in the spring of 2003, Caplen said, she began looking for new opportunities in the RNAi field. “After discussions with various people at NCI, it seemed that [the RNAi program] was a very obvious fit [given] that I had a strong background in doing nucleic acid transfer and RNAi.”

Rubber Meets the Road

In her new position, Caplen has her work cut out for her as she implements a five-pronged program that includes both technology development and basic research initiatives that will help CCR researchers use RNAi to advance cancer research.

“The first part is to work as a central resource and information exchange in relation to RNAi technologies,” she said. This involves providing investigators with “information about RNAi [such as] appropriate resources and protocols.” The gene silencing section also hopes to “standardize systems within different cell lines that may be appropriate for [researchers],” and, some time down the road, provide a place where postodocs can learn about RNAi, Caplen said.

The gene silencing group is also currently putting together an internal website where such information can be accessed, she noted.

“The second [part focuses] on developing high-throughput RNAi analysis for mammalian cells,” Caplen said. “This is taking some of the paradigms from the C. elegans and Drosophila studies and trying to apply those to mammalian cells grown in culture using automated robot systems for doing large-scale transfections of synthetic siRNAs,” as well as short hairpin RNAs.

Caplen said that the key to this part of the effort is that the RNAi work is being done on a large scale. “Most PIs are interested in one gene or a very specific aspect of a pathway. We [want to] do this on a slightly larger scale,” she said, which would allow the group to “do much more extensive delineation of pathways using general RNAi screens.”

This stage of the program, according to Caplen, has links to the CCR’s Molecular Targets Development Program, which is “trying to develop new pipelines for potential drugs within [CCR]. We can help them, potentially, with doing validation of their targets, suggesting new targets that our chemists may want to look at, and looking at drug sensitivity assays” to see if the knockdown of a particular gene can boost the sensitivity of cancer cells to a particular drug, she said.

Caplen noted that most of the target genes that the gene silencing section will look at will be ones in areas “where we have principal investigators in established labs in CCR that will be able to conduct all the appropriate downstream assays and have existing expertise. We’ve really focused on the strengths within [CCR] in terms of what priority we’re giving to the genes that we’re going to be analyzing,” she said. As such, “there’s a lot of emphasis on the multiple drug resistance genes, on metastasis-related genes, on various DNA and histone modifiers, and those [genes] that are putative targets for drugs within our molecular targeting pipeline.”

The third portion of the program involves establishing an infrastructure “that will allow PIs to be able to utilize the short hairpin RNA libraries that are being developed by other academics, in particular those ones that are being developed within the extramural program of NCI … [for example] the library that’s been developed by Cold Spring Harbor and also the library that’s been developed by the Netherlands Cancer Institute by Rene Bernards,” Caplen said.

The fourth aspect of the program will focus on the development of new cell and animal models for RNAi. According to Caplen, “there is still a paucity of models both at the cell level and in animals for a lot of different aspects of the cancer process. And so, I’m working with a number of principal investigators in CCR that have existing model systems, or model systems they want to alter, using RNAi to see if we can improve these.”

She said that particular emphasis is being placed on working on models for metastases and for preclinical drug screening.

“There, we’ll be looking at using probably short hairpin versions of RNAi triggers to obtain stable systems, fully characterizing those, [and] seeing how we can adapt new vector systems so we can use these very effectively in different cell and animal models,” she said.

Under the final portion of the program, the gene silencing section will continue to support basic research looking into the role of RNAi as an endogenous epigenetic silencing mechanism, specifically RNAi-associated changes in cancer, Caplen said. “There are many suggestions within the cancer literature that not all the changes that are seen within a cancer cell, versus a normal cell, are due to direct genetic lesions, but … to epigenetic changes.”

Given that RNAi is a naturally occurring epigenetic silencing mechanism, Caplen said, it is obvious to continue researching the role of RNAi and RNAi-regulated genes in cancer cells.

Another goal of the OSTP’s gene silencing section, said Caplen, is to promote collaboration between public and private RNAi researchers.

“There’s a great deal of RNAi technology development in the private sector, so we want to build partnerships,” she said. “As part of that, we already put out one search for our first [cooperative research and development agreement partner].”

This CRADA partnership, according to a posting on the NCI’s website, will be focused on developing and validating molecules that mediate RNAi in order to generate sequence-specific inhibition of the expression of between 350 to 400 target genes involved in cancer, as well as between 20 to 50 control genes. The partnership will also work to assess the potential application of RNAi to other CCR programs, including those in which researchers are working on new animal models of cancer and the Molecular Targets Development Program, said the posting.

Caplen said that late-stage negotiations are ongoing with one RNAi company, but she declined to name it. She added that a final deal is expected to be struck within the first quarter of this year.

For the foreseeable future, Caplen said that the gene silencing section’s activities will mostly be focused on RNAi as it applies to the development of small molecule treatments for cancer. “We are seeing [RNAi] as a new therapeutic approach, but our focus is to see if we can use it to increase the efficiency of our pipeline using existing small drug-type approaches,” she said.

“We have one small research project which could give us a handle on the feasibility in a particular cancer of [RNAi] as a therapeutic approach,” Caplen added. “But in fairness, having spent nearly 10 years in [the] gene therapy [field], I am a little more pessimistic than perhaps some of my colleagues about how RNAi can be used as a therapeutic.”

Caplen said that as it stands now, the gene silencing section still has not been formally established, but that all loose ends, including a finalized 2004 budget for the group, as well as staff and equipment, will be tied up by the spring.

—DM

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