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Can Walter Reed and a Penn Team Turn SNPs, Proteins Into Cancer Vacc Tools?

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What do the US Army, a small research facility in Pennsylvania, and a quartet of African nations have in common? They may each play a role in bringing SNP-genotyping and protein-expression technologies into the cancer-vaccine spotlight.

Researchers from the Pennsylvania-based Windber Research Institute, the Walter Reed Army Medical Center, an immunology center affiliated with the US Army, and the nations of Ghana, Kenya, Nigeria, and South Africa will contribute these pharmacogenomcis technologies together with scores of tissue samples in hopes of developing the vaccine.

If the researchers validate their findings — an experimental version of the vaccine is currently being tested on Walter Reed patients — they may lead drug makers to believe that genotyping and proteomic tools can help them uncover biomarkers in this poorly understood and under-used corner of oncology.

“We want to set up some of the baseline information that should have been done earlier that no one has done,” said Richard Somiari, COO and CSO of Windber Research Institute. “If we collect the tissue in the best possible way … and we have the same platform to analyze these tissues without having to subcontract to different laboratories, then lab-to-lab variation is eliminated.

“Our main goal is to elucidate the underlying molecular mechanisms and find cures for breast cancer,” he said. But whose isn’t these days? Biopharma companies with cancer programs are desperate to bolster their pipelines and have been turning their eyes increasingly to pharmacogenomics methodologies such as genotyping and protein expression. Those who haven’t eventually will.

Yet the cancer vaccine option presents pharmas with novel challenges: Results from recent trials, especially the recent question of whether the measles-mumps-rubella vaccine causes autism, have soured many drug makers on the idea of creating or commercializing a vaccine based on genetic or proteomic data. Plus, pharmas generally are more interested in developing small-molecule drugs, which are comparatively less difficult to develop, and have a proven track record.

The breast cancer vaccine research being performed at Windber, Walter Reed, and the Immunology Research Center at the Uniformed Services University of the Health Sciences, in Baltimore, may have an edge: The groups plan to collect more than 240,000 tissue samples over the next few years and simultaneously perform high-throughput genetic- and proteomic-expression studies.

“The key here is isolating DNA, RNA, and protein from the same sample,” Somiari told SNPtech Reporter recently. “There is still very little information available based on the transfer of hereditary information from DNA [and] RNA, to proteins.”

Somiari said Windber has collected around 6,000 tissue samples for the breast-cancer project since the facility became operational in October 2001, and intends to control more than 20,000 samples by this time next year. The tissue bank, which also includes demographic data, histopathology reports, and medical histories, can handle 240,000 samples, he added.

So far, the samples originate at the Reed Center — which has been responsible for delivering some 5,000 samples — and from other smaller centers in Pennsylvania, such as the Windber Institute’s parent group, the Windber Medical Center. (Both Windber facilities share a president.)

The Windber Research Institute has also penned a collaboration with the Nigerian Army Medical Corps, and will begin collecting samples from the nation’s military hospitals in October. Somiari, who is Nigerian, said this project will begin next month, and is expected to generate approximately 3,000 tissue samples each year. Somiari added that Windber also brought on board Kenya, Ghana, and South Africa, each of which has pledged to contribute 3,000 samples annually.

Once Windber obtains the samples, its researchers study them using a variety of genotyping and proteomic technologies. Windber employs Affymetrix’s HuSNP technology together with Amersham’s SNuPe platform, which it uses with Amersham’s 96-capillary and 384-capillary MegaBase sequencers. The SNuPe platform enables Windber to perform 450,000 genotypes per day, said Somiari.

At the same time, the 50-researcher group uses an Amersham 2D gel-electrophoresis platform for in silico analysis of differentially expressed proteins. Somiari said Windber researchers can generate a pick list and instruct robots to digest the gels and spot the targets for MALDI-TOF analysis. Somiari said Windber’s MALDI-TOF unit can run 288 samples per day. A subset of proteins not identified on the MALDI-TOF are sent to an ESI-profile time-of-flight mass-spec platform — in this case a triple-quadrupole Q-TOF made by MicroMass, he said.

Somiari said that Windber’s organizational structure performs the high-throughput discovery upfront, and has the PhDs analyzing the relationships between the protein and DNA markers and the phenotypes.

Windber spent around $30 million between 2000 and 2003 to outfit the center, according to Somiari. The US Department of Defense and the state of Pennsylvania paid for most of the equipment. He said it costs between $3 million and $5 million to operate the center each year.

Somiari said Windber currently has multiple markers for the vaccine, which would target the Her-2 pathway. “The next phase is to develop vaccines for each stage and each clinical phenotype for breast cancer,” he said.

He added that the facility next year will begin researching all female reproductive cancers.

Somiari said that biopharma companies have not approached Windber for R&D collaboration, but stressed this is because his group has not yet published results of its vaccine research.

Drug makers that currently have a vaccine program include Wyeth and Merck. “We are new, and we are only working prospectively,” he said. The outcome of the research that Windber is doing today “will only be known in about five years’ time, when some [patients] will have recurrences, or some may have died.”

Yet some say the breast cancer vaccine project has its work cut out for it if it wishes to parlay its discoveries into biophama alliances. “Not all [pharma companies] are into vaccines,” said Michael Liebman, director of the Abramson Cancer Center of the University of Pennsylvania. Liebman is a member of Walter Reed’s scientific advisory board and traveled to Nigeria last year for research into sickle cell anemia. “

Only a few have maintained that because of specificity issues; most pharmas are really looking for small molecules.” On the other hand, he said, if a directed target exists, then “it is a way that you can produce the response you want.”

— KL

 

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