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TJU, CHOP Team Pioneers Neuroblastoma Chip, Larger Study and Commercial Partnership Planned

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A paper published in this month's issue of Genome Research describes a microarray-based method of attack for treating neuroblastoma, a cancer of the chest or abdomen that normally strikes infants' peripheral nervous systems.

The research suggests that determining the degree of loss of heterozygosity could eventually help physicians treat neuroblastoma patients and determine what kinds of therapies would best suit them.

The authors, two of whom previously worked at Orchid Bioscience, have also said that they are seeking a commercial partnership.

Entitled "Region-specific detection of neuroblastoma loss of heterozygosity at multiple loci simultaneously using a SNP-based tag-array platform," the paper describes a method that was developed by collaborators from the Children's Hospital of Philadelphia and Thomas Jefferson University's Jefferson Medical College.

"We are moving towards using tumor genetics and biology to guide treatment recommendations rather than clinical correlates that are likely only rough surrogates for the underlying biology," John Maris, a principal investigator at CHOP who co-authored the paper, wrote in an e-mail to BioArray News last week.

Maris, along with TJU's Paolo Fortina and Saul Surrey, worked to develop an assay that could assess loss of heterozygosity in neuroblastoma patients.

The work builds upon research previously performed at John Maris' lab at CHOP where it was determined that a loss of heterozygosity in regions of chromosome 11 can be correlated to an aggressive case of neuroblastoma.

In their Genome Research paper, Maris, Fortina, Surrey and others have shown that if they can determine the degree of loss of heterozygosity, or LOH, at chromosome 11, as well as other chromosomes, they can make a prognosis on how a neuroblastoma patient may progress in their disease, and what kinds of therapies would best suit them.

"Our array allows simultaneous detection of 9 [chromosomal] regions which previously have been shown to be prone to LOH," Paolo Fortina wrote in an e-mail to BioArray News last week.

According to Saul Surrey, current methods of determining LOH are "pretty laborious." "This approach sort of shortens that and is very flexible," he said.

Surrey said that the chip they have developed "involves a commercial and/or homemade array [with] 2,000 oligonucleotides attached to the array. None of them are repeating in the human genome so the whole purpose is to capture oligonucleotide sequences. So that is the capture part of the assay."

CHOP and TJU's method also uses a way of labeling the probes so that researchers can tell whether a patient has undergone LOH, Surrey said.

"What you do is eventually have 20 or 30 SNPs in a row. You'll find that they're heterozygous, heterozygous, heterozygous — and then all of a sudden you hit a region where they've undergone loss of heterozygosity. They'll switch to being homozygous or one signal. So in that way you can very quickly assess regions that have undergone LOH," he said.

Such knowledge can then be used to give a prognosis on how a neuroblastoma patient's cancer is progressing and which therapies are likely to work. "Hopefully [the user will] be able to target different therapies based on what the indication is," he said.

"If the outcome is obviously dire then you'd want to be very aggressive in your chemotherapy, and if it's mild, then obviously you would not want to be very aggressive," he said.

According to John Maris, who provided the researchers with samples from a dozen neuroblastoma patients to develop the chip, one of the reasons that a microarray was chosen as a tool was because of the high number of variables it could process in a single experiment.

"We expect the number of variables that we will want to assay to grow, so a microarray solution is desired," Maris said.

Paolo Fortina told BioArray News last week that not only is the method applicable for neuroblastoma, but it may have ramifications in how other cancers are treated.

"Additional tumors such as colon, ovarian, lung and other cancers in which LOH regions have been characterized could be investigated with this technology," Fortina said.

Fortina also said that because they felt their method — which is expected to be refined by studies involving larger samples studies — was promising, they were seeking commercial partners to make the chip available to other clinicians.

The CHOP and TJU team did have some former commercial contacts in their study — two former Orchid Biosciences scientists were listed as co-authors in the Genome Research paper, although Orchid sold off its SNP genotyping unit to Beckman Coulter in 2002.

Still, Fortina said that the Beckman Coulter connection could be a vehicle to getting a neuroblastoma chip on the market. He mentioned that he was currently "working in collaboration with Beckman Coulter to test the [firm's new] SNPstream Genotyping platform."

In the meantime the group plans larger studies and a refinement of its methodology.

"This was a pilot/proof of concept study in only a dozen subjects. The next phase will involve hundreds of subjects," Maris said.

"We are working with Drs. Fortina and Surrey to make this even better by removing the requirement for PCR amplification of the test DNA. This is inherent in any SNP-based detection strategy," he said.

— Justin Petrone ([email protected])