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University of Washington Research May Lead to Metabolomic Dx for Certain Aggressive Cancers

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In a study of metastatic neuroendocrine tumors in the lungs, thyroids, and prostates of transgenic mice, researchers at the Washington University School of Medicine in St. Louis have linked a high level of the neurotransmitter GABA with a poor prognosis for human patients with neuroendocrine cancers, a finding that may lead to diagnostics to guide treatment.

The study will appear in the July 12 issue of the Proceedings of the National Academy of Sciences, and it is currently available in the online version of the journal.

"One possible way [to turn the study results into a diagnostic] would be to sample GABA and use metabolites in the serum of patients, but as we also note at the end of the paper, one might be able to use an MR spectroscopy approach to look at the concentration of GABA metabolite in the tumor itself," Joe Ippolito, lead author of the paper and a graduate student in the university's Medical Scientist Training Program, told Pharmacogenomics Reporter.

A diagnostic capable of identifying neuroendocrine cancer from serum could potentially guide therapy by giving doctors an idea of which metabolic pathways cancer cells are using, and which might be vulnerable to drugs targeting them, said Ippolito. He singled out drugs that are already known to affect GABA-related pathways, but which may not have been tested for their activity against cancer.

A serum-based test also has the potential to identify the beginnings of aggressive cancer. "Usually these tumors are diagnosed only after they have spread to other parts of the body, but now we have the potential to recognize them before they metastasize," Jeff Gordon, director of the Center for Genome Sciences at Washington University, said in a statement. Among other findings, the researchers identified higher levels of serum GABA in mice with neuroendocrine cancers.

Beginning with neuroendocrine cancer cell lines, as well as mice engineered to have abnormally proliferating prostate, lymph node, and liver tumors, the investigators identified 446 genes having a higher expression level in neuroendocrine cancers than in normal tissue. The researchers transferred this signature onto metabolic maps from the Kyoto Encyclopedia of Genes and Genomes to reconstruct neuroendocrine-cancer cell metabolism.

Ippolito chose a series of enzymes for investigation and predicted their metabolic products, then followed up with a mass spectrometric verification of the metabolites' presence in the mouse tumors and cell lines. "He then took and applied it to a variety of human cancers — lung cancers, prostate cancers, cancers derived from a type of multiple endocrine neoplasia syndrome," to determine whether they also adopted a similar metabolic activities, said Gordon of Ippolito's work.

Of those tumors with poor prognoses, GABA production tended to be high. "We found that the human genes that give rise to the key enzymes required to produce these metabolites were invariably switched on in the poor-prognosis [tumors group], but not the good-prognosis tumor group," said Ippolito in a statement.

Verifying the importance of GABA to the tumor cells' metabolism, the researchers used a patch clamp procedure to determine that the cells bound the neurotransmitter. "So you have the full [compliment] of the metabolite, the ligand that binds to the receptors, the different components of the receptors being expressed — you have this model of neuroendocrine [cancers] that is, I think, applicable for a variety of additional follow up, proof-of-principle pharmacologic studies," to develop a complete metabolic model and possible drug treatments, said Ippolito.

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