The National Institute of Environmental Health Sciences has awarded Oxford Biomedical Research a $729,939 Phase 2 Small Business Innovation Research contract to develop an assay to measure the levels of the NAG-1 protein in blood, which may help clinicians gauge the efficacy of chemopreventative agents and lead to the development of new anti-cancer drugs.
It was a team of NIEHS researchers that first made the link between cancer prevention and the expression of NAG-1, or non-steroidal anti-inflammatory drug-activated gene, which is upregulated in the presence of certain COX-2-inhibitor NSAIDs.
These researchers, led by Thomas Eling, “discovered that treatment of animals with low doses of NSAIDs, such as aspirin and ibuprofen, which significantly reduce the incidence of certain cancers in humans, increases the production of NAG-1,” Michigan-based Oxford Biomedical said in a statement.
“Although it is now well known that … regular use of NSAIDs reduces the risk of cancer (especially colorectal cancer), and that certain nutritional supplements can also reduce cancer incidence, there is presently no way to assess the impact of these agents in humans,” the company said.
Similar results have been observed from resveratrol, a component in certain red wines, and genistein, contained in soy products, and studies have reported that these compounds may help prevent cancer.
NAG-1 is a member of the transforming growth factor family. In addition to having proapoptotic and antitumorigenic properties, NAG-1 is a macrophage inhibitory cytokine-1, a growth/differentiation factor-15, a prostate-derived factor, and a placental TGF-beta.
Other studies have linked NAG-1 to three tumor-suppressor genes: p53, the early growth response gene-1, and the phosphatidylinositol 3-kinase/protein kinase B/glycogen synthase kinase-3 pathway.
With the type of blood test being developed by Oxford Biomedical, clinicians can gauge the effectiveness of novel or potential cancer prevention drugs by measuring their ability to elevate levels of NAG-1 in a cell culture, in animal models with high incidence of cancer, and ultimately, in human subjects.
Additionally, such a test “may be useful” for screening for new chemopreventative agents, the company noted.
“The availability of a NAG-1 blood test may permit clinicians to monitor the effectiveness of known anti-cancer agents. It may also be useful for screening for new anti-cancer agents.”
Oxford Biomedical President Denis Callewaert identified several agents that are known up-regulate NAG-1 expression in the presence of cancer, particularly in colorectal cancer. In addition to NSAIDs like ibuprofen and aspirin, phytochemicals such as resveratrol, genistein, diallyl disulfide, and indole-3-carbinol, which have shown anti-cancer activity, increase NAG-1 expression.
According to Callewaert, however, the most potent pharmacological inducer of NAG-1 is the anti-cancer agent 5F-203, which is not an NSAID. 5F-203 has been shown in studies to induce NAG-1 in HCT116 colon cancer cells at nM levels and in the MCF-7 breast cancer cell line.
In a May 2006 article published by NIEHS’ Eling and colleagues in the Journal of Pharmacology and Experimental Therapeutics, researchers found that in animal studies, the prodrug of 5F-203, Phortress, increased in vivo expression of NAG-1 in RNA as measured by RT-PCR, which resulted in increased expression correlated with tumor volume reduction. Pharminox is developing Phortress, a water soluble pro-drug of the active moiety 5F-203.
“These results confirm that NAG-1 suppresses tumor growth, and its in vivo expression can be controlled by treating mice with anticancer drugs, such as Phortress,” the researchers wrote in the article. “Drugs that target NAG-1 could lead to a unique strategy for the development of chemotherapeutic and chemopreventive agents.”
According to Eling and his colleagues, NAG-1-targeting chemopreventative agents like Phortress may be a good alternative to NSAIDs since “recently revealed cardiotoxicity of COX-2 inhibitors detected in chemoprevention clinical trials seems to exclude their long-term use as chemopreventive drugs.”
Ideally, a blood test developed by Oxford Biomedical would allow clinicians to gauge the effectiveness of such chemopreventative agents and lead to the development of similar new products.
Oxford Biomedical said it will use the SBIR contract to initially develop a blood test on an ELISA-based platform. “We may also be able to adapt it to a point-of-care semi-quantitative ‘dip stick’ lateral flow immunoassay, but that is not the focus of initial efforts,” Callewaert told Pharmacogenomics Reporter this week.
According to Callewaert, the company has already developed a prototype of the test. However, a commercial test will be launched within the next year and a half to two years, following assay refinement and validation.
Although it is too early to discuss commercialization plans, Callewaert noted that the company will most likely seek a marketing partner for the test.
He noted that the company is looking into launching the test as both a laboratory test under CLIA and as an FDA-cleared product.
“In addition to assays provided by CLIA-certified labs, with no specific diagnostic claims, we have received mixed advice regarding path through FDA,” Callewaert said. “The test is envisioned to reflect wellness, not disease, and may initially be marketed with appropriate labeling to reflect restricted claims.”