If everything goes as planned, researchers from the University of Oxford will emerge from a collaboration with GE Healthcare with pharmacogenomic methods to guide colorectal cancer therapy.
"The genomic pathology [portion of the study] is multi-stranded," John Bell, a principal investigator of the study and a professor of clinical medicine at Oxford, told Pharmacogenomics Reporter this week. "It ranges all the way from trying to evaluate the range of drugs that are in current use for colorectal cancer, to identifying genetic variants that could contribute to toxicity or response to therapy," he said.
Both collaborating organizations have been guarded about the study's details, but Pharmacogenomics Reporter has learned that it is divided into five main projects: Improvements to Colon Cancer Magnetic Resonance Imaging; Data Integration; RNA Transcript Profiling; Pharmacogenomics for Chemotherapy Selection and Prediction of Toxicity; and DNA Sequencing Applied to Genomic Pathology.
While the studies will certainly involve copious molecular technologies, the Oxford investigators and GE Healthcare have been tight-lipped about which of GE's platforms will be involved and which are under consideration. But in the end, Oxford and GE hope to end up with lots of intellectual property to pour into diagnostics.
"The combination of the two groups looks pretty good on paper."
The two-year collaboration will be funded with approximately $1.5 million per year from GE, and it will include 30 to 40 GE Healthcare researchers and as many as 2,000 to 3,000 patients, according to David Kerr, a professor of clinical pharmacology and cancer therapeutics at Oxford. The University of Oxford will contribute about 25 to 30 researchers, said Bell.
Oxford has considerable expertise in clinical cancer and molecular diagnostics, while GE has "great strengths in imaging, and also great strengths in molecular diagnostics platforms, so the combination of the two groups look pretty good on paper," said Bell. "We might emerge with a set of useful tools that will predict response or adverse events" to chemotherapy, and "a set of genetic determinants that predict overall prognosis … based on somatic genetic variation or messenger RNA expression," he said. For these purposes, the research groups will examine samples using comparative genome hybridization techniques and by characterizing individual genes, he added.
The project will also attempt to correlate mRNA expression patterns with colorectal cancer disease states and prognoses, said Bell.
Asked whether one goal of the project was to develop a diagnostic gene chip, Kerr said, "Exactly."
Details of the collaboration are murky, partly because a key GE Healthcare scientist was unavailable immediately after the announcement. Pharmacogenomics Reporter and its sister publication Biocommerce Week were later granted answers to e-mailed questions.
Asked whether GE's CodeLink platform would be involved in the study, Jonathan Allis, vice president of Technology, Medical Diagnostics for GE Healthcare in Amersham, UK, said in a written response to e-mailed questions that, "There are a number of GE Healthcare platorms that will be pertinent to this project."
When asked whether the project might result in a diagnostic chip, Allis wrote, "One of the aims of the project is to study genomic pathology as a more specific prognostic for tumour type; however, its too early a stage to speculate on how this would then manifest itself into clinical practice."
According to Oxford's Bell, the drugs under investigation will "almost invariably" include common treatments 5-fluorouracil, Pfizer's Camptosar, and Roche Pharmaceuticals' Xeloda. In addition, he said, "Increasingly people will be using Avastin and those sorts of drugs for angiogenesis inhibition, because they've shown survival benefits, so we'll probably get a chance to look at those as well." However, the group had not yet drawn up a list of specific drugs to investigate, he added.
Pharmacogenomic Details of Colorectal Cancer Drugs
"The analysis will be conducted using two new chemotherapeutic agents recently introduced onto the market," Allis said. These efficacy and toxicity studies may involve some of the following drugs.
Camptosar in particular is known as a treatment benefiting from pharmacogenomics. Also known by its generic name irinotecan, the drug is metabolized by the enzyme product of the gene UGT1A1, a variation of which confers a five-fold greater risk of adverse events, according research conducted by the US Food and Drug Administration. Adverse events can include neutropenia, an immune-system disorder, according to the drug's label. Other events include severe diarrhea.
The FDA changed Camptosar's label in June to encourage companies to develop and submit their own UGT1A1 assays, but the only FDA-cleared diagnostic for detecting UGT1A1 genotype so far is an Invader test made by Third Wave Technologies. The newer label recommends a lower starting dose of the drug in patients homozygous for the UGT1A1*28 allele.
Roche's Xeloda is a prodrug that metabolizes to 5-fluorouracil, a common chemotherapeutic used in colorectal cancer. Thymidine phosphorylase converts the prodrug, and dihydropyrimidine dehydrogenase breaks down 5-FU to inactive metabolites. A transporter protein called hCNT-1 transports the drug into tumor cells, and its protein target is thymidylate synthase, which it inhibits, slowing cell proliferation and DNA repair.
The expression levels of these enzymes vary, making them suitable for use as biomarkers of response, according to information from Roche, however no diagnostics are currently in use to support the drug's prescription. High gene and protein expression of TP, DPD, and TS above a certain cut-off level are claimed to predict resistance to 5-FU and a poor prognosis, the company said. Roche sells LightCycler RT-PCR kits for determining mRNA expression of TP, DPD and TS, and ELISA and immunohistochemical tests for the enzymes are marketed by several companies. None has been validated, and none is yet FDA cleared.
Genentech and Roche Pharmaceuticals' Avastin is a VEGF inhibitor, and overexpression of that gene may predict some drug response, but the data are incomplete. Several tests are available for measuring serum VEGF levels, such as assays offered by LabCorp.
The expression of VEGF is also important as a possible prognostic indicator. Tumor expression of proangiogenic factors, including VEGF, has been associated with advanced tumor progression in a number of human cancers, and increased expression of VEGF has been associated with poorer prognosis in patients with cancer of the colon, according to LabCorp.
Chris Womack ([email protected])