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Single mutant gene might explain many common cancers
Newsdesk Viral vector helps prodrug improve chemotherapy VDEPT, there should be few overlapping side-effects, which commonly limit the use of conventional chemotherapy combinations”, he explains. The researchers are unsure why CB1954 works so well with fluorouracil, and not with other drugs. Palmer
Rights were not granted to include this image in electronic media. Please refer to the printed journal.
VDEPT uses a modified adenovirus vector.
believes fluorouracil might enable CB1954 to form DNA cross-links more easily, and therefore help initiate the cell-death process. “Fluorouracil may also inhibit DNA repair pathways that would otherwise counteract CB1954induced damage”, he adds. Early clinical trials into VDEPT and CB1954 have now begun. Nick
© Richard J Green/Science Photo Library
Virus-directed enzyme prodrug therapy (VDEPT) could make chemotherapy more effective, according to researchers from the University of Birmingham, UK. The team found that VDEPT caused cell death in ovarian cancer cells and worked in synergy with the cytotoxic drug fluorouracil (Br J Cancer 2003; 89: 944–50). VDEPT uses a genetically modified virus to infect cancer cells, where the virus expresses an enzyme to activate a prodrug. In these studies, the virus expressed an enzyme called nitroreductase which converts the harmless drug CB1954 into its short-lived, toxic form which induces cell death in the infected cells. Daniel Palmer, lead author of the study, believes the drug could cause extensive tumour-cell death with only limited side-effects. Preclinical trials showed “significant antitumour effects” when only 5% of cells expressed the enzyme. He also thinks VDEPT is suited to combination treatments. “An advantage of such a combination is that, given the lack of toxicity expected with
James, University of Birmingham, UK, is the principal investigator of these phase I studies, which involve patients with cancers of the prostate, liver, and head and neck. “On the basis of the results to date, we’re looking to extend the prostate cancer studies into early phase II trials”, James says. “The treatments have proven safe in all of the trials, but it looks likely that efficacy is best in patients with prostate cancer.” Future clinical trials will include patients receiving fluorouracil treatment for colorectal, gastrointestinal, and ovarian cancers. “The next logical step is to design clinical trials using this approach in combination with traditional fluorouracil-based chemotherapy regimens”, Palmer comments. Similar cancer treatments use other vehicles, such as antibodies, to target tumours. But Palmer thinks VDEPT looks the most promising. “At present, viruses remain by far the most efficient gene therapy vectors”, he says. Rachel Liddle
Single mutant gene might explain many common cancers A US study has revealed that a relatively common mutation in a single gene, TGFBR1, predisposes people who carry it to develop breast, colon, and ovarian cancers (J Clin Oncol 2003; 21: 3236–43). All previously discovered “cancer risk alleles” have been rare mutations where the cancer risk is greatly increased in carriers, but carriers only constitute a small proportion of the population. By contrast, although the risk of any individual carrying the cancer-associated TGFBR1 variant developing the disease is fairly low, the variant is so frequent that this mutation may be associated with up to 16% of cases of some common tumours. TGFBR1 is a receptor for transforming growth factor  (TGF). Lead author Boris Pasche (Northwestern University, Chicago, IL, USA) explains: “TGF is the most potent cell-growth inhibitor known, and most tumour cell lines do not respond to it. Also, cells expressing one variant, TGFBR1*6A, respond to TGF less effectively than those expressing the more common TGFBR1*9A.” Pasche and colleagues found that cancer risk was high in individuals heterozygous or homozygous for this allele (Cancer Res 1999; 59: 5678–82), but some smaller studies found no effect.
THE LANCET Oncology Vol 4 October 2003
The researchers did a meta-analysis of all case-control studies of this allele in papers published during the past 4 years. The results were dramatic. Individuals heterozygous for the TGFBR1*6A allele—about 16% of the population—were found to be around 25% more likely to develop cancers of the breast, ovaries, or colon. Homozygous individuals—about one in 167—were twice as likely to develop these cancers as normal people. However, no effect was observed with one tumour type: bladder cancer. The reason for this is not known. Pasche speculates: “It may be because the long arm of chromosome 9, where TGFBR1 is located, is deleted in most bladder tumours. An alternative explanation could be that bladder tumours arise from transitional cells, which may not be as susceptible to this signalling pathway as epithelial cells.” Pasche is now studying the prevalence of this gene in families at risk for colon and breast cancer. “Rare, high penetrance genes are only found in a small proportion of these families. TGFBR1 is an attractive candidate cancercausing gene in familial cancers. In a couple of years we hope to know exactly how important it is.” Clare Sansom
http://oncology.thelancet.com
For personal use. Only reproduce with permission from The Lancet.
589
Rights were not granted to include this image in electronic media. Please refer to the printed journal.
VDEPT uses a modified adenovirus vector.
believes fluorouracil might enable CB1954 to form DNA cross-links more easily, and therefore help initiate the cell-death process. “Fluorouracil may also inhibit DNA repair pathways that would otherwise counteract CB1954induced damage”, he adds. Early clinical trials into VDEPT and CB1954 have now begun. Nick
© Richard J Green/Science Photo Library
Virus-directed enzyme prodrug therapy (VDEPT) could make chemotherapy more effective, according to researchers from the University of Birmingham, UK. The team found that VDEPT caused cell death in ovarian cancer cells and worked in synergy with the cytotoxic drug fluorouracil (Br J Cancer 2003; 89: 944–50). VDEPT uses a genetically modified virus to infect cancer cells, where the virus expresses an enzyme to activate a prodrug. In these studies, the virus expressed an enzyme called nitroreductase which converts the harmless drug CB1954 into its short-lived, toxic form which induces cell death in the infected cells. Daniel Palmer, lead author of the study, believes the drug could cause extensive tumour-cell death with only limited side-effects. Preclinical trials showed “significant antitumour effects” when only 5% of cells expressed the enzyme. He also thinks VDEPT is suited to combination treatments. “An advantage of such a combination is that, given the lack of toxicity expected with
James, University of Birmingham, UK, is the principal investigator of these phase I studies, which involve patients with cancers of the prostate, liver, and head and neck. “On the basis of the results to date, we’re looking to extend the prostate cancer studies into early phase II trials”, James says. “The treatments have proven safe in all of the trials, but it looks likely that efficacy is best in patients with prostate cancer.” Future clinical trials will include patients receiving fluorouracil treatment for colorectal, gastrointestinal, and ovarian cancers. “The next logical step is to design clinical trials using this approach in combination with traditional fluorouracil-based chemotherapy regimens”, Palmer comments. Similar cancer treatments use other vehicles, such as antibodies, to target tumours. But Palmer thinks VDEPT looks the most promising. “At present, viruses remain by far the most efficient gene therapy vectors”, he says. Rachel Liddle
Single mutant gene might explain many common cancers A US study has revealed that a relatively common mutation in a single gene, TGFBR1, predisposes people who carry it to develop breast, colon, and ovarian cancers (J Clin Oncol 2003; 21: 3236–43). All previously discovered “cancer risk alleles” have been rare mutations where the cancer risk is greatly increased in carriers, but carriers only constitute a small proportion of the population. By contrast, although the risk of any individual carrying the cancer-associated TGFBR1 variant developing the disease is fairly low, the variant is so frequent that this mutation may be associated with up to 16% of cases of some common tumours. TGFBR1 is a receptor for transforming growth factor  (TGF). Lead author Boris Pasche (Northwestern University, Chicago, IL, USA) explains: “TGF is the most potent cell-growth inhibitor known, and most tumour cell lines do not respond to it. Also, cells expressing one variant, TGFBR1*6A, respond to TGF less effectively than those expressing the more common TGFBR1*9A.” Pasche and colleagues found that cancer risk was high in individuals heterozygous or homozygous for this allele (Cancer Res 1999; 59: 5678–82), but some smaller studies found no effect.
THE LANCET Oncology Vol 4 October 2003
The researchers did a meta-analysis of all case-control studies of this allele in papers published during the past 4 years. The results were dramatic. Individuals heterozygous for the TGFBR1*6A allele—about 16% of the population—were found to be around 25% more likely to develop cancers of the breast, ovaries, or colon. Homozygous individuals—about one in 167—were twice as likely to develop these cancers as normal people. However, no effect was observed with one tumour type: bladder cancer. The reason for this is not known. Pasche speculates: “It may be because the long arm of chromosome 9, where TGFBR1 is located, is deleted in most bladder tumours. An alternative explanation could be that bladder tumours arise from transitional cells, which may not be as susceptible to this signalling pathway as epithelial cells.” Pasche is now studying the prevalence of this gene in families at risk for colon and breast cancer. “Rare, high penetrance genes are only found in a small proportion of these families. TGFBR1 is an attractive candidate cancercausing gene in familial cancers. In a couple of years we hope to know exactly how important it is.” Clare Sansom
http://oncology.thelancet.com
For personal use. Only reproduce with permission from The Lancet.
589