Cancer cells from the human colon

© Eye of Science / photoresearchers.com

Not all colorectal cancers are the same, says Patrick Johnston. "Some respond well to one drug, some need three," explains the professor of oncology at Queen's University Belfast (QUB). "With more information about each type, we could do so much more for patients." Molecular approaches are the best way to get that information, Johnston says, but for clinicians steeped in more traditional methods, "it takes guts to use molecular technology."

Johnston, who discovered the first biomarker for colorectal cancer (J Clin Oncol,12:2640-7, 1994), is taking that next step, harnessing the kind of molecular technologies already used to personalize breast cancer therapy, and applying them to tumors of the colon. Howard L. McLeod, director of the Institute for Pharmacogenomics and Individualized Therapy at the University of North Carolina, Chapel Hill, says QUB's cancer center demonstrates "great leadership in truly translational research."

The 17 researchers at the cancer research group at Queen's, where Johnston is also dean of the School of Medicine and Dentistry, takes a pharmacogenomic approach, looking, for example, at the genetic predictors of response to the drug 5-fluorouracil in cancer cells. Working in a new 5,000-m² building, their mix of clinicians and basic scientists has garnered funding from charities and government agencies, including Cancer Research UK.

Johnston's team is developing tests based on transcriptome mapping to identify the best drugs for patients with colorectal cancer. The approach has led to the formation of a new company, Almac Diagnostics, where Johnston is a director. Next year, the company expects to launch a recurrence test for stage-two colorectal cancer. In stage two, the tumor has advanced from the mucosa of the bowel wall into the muscular layer.

"The active partnership with commercial enterprise, such as Almac Diagnostics, has allowed QUB investigators to rapidly move their research into the clinic," says McLeod. Johnston (and Almac) now have libraries of transcriptome maps for various cancers, from laboratory cell lines and most significantly from biopsy material taken from patients at various stages of disease. Johnston says Almac's technology can cope with the kind of degraded RNA found in clinical samples preserved in formalin, which makes it especially useful in characterizing late-stage disease.

Johnston's research group is also studying how some cancer cells develop resistance to chemotherapeutic drugs. The group's focus is on cFLIP, a protein that blocks death-receptor apoptosis in cancer cells (Cancer Res, 67:5754-62, 2007). He says the group found that knocking out cFLIP with RNA interference kills colorectal cancer cells, but the real surprise, he says, is that this also makes chemotherapy drugs more effective. "It augments the chemotherapy, which means there is some unique biology going on." Such a finding also raises the possibility of reducing chemotherapy doses for patients, and provides a new target for potential drugs. Johnston says they have now successfully used small peptides to inhibit cFLIP, research that is yet to be published.