Gallbladder and Bile Duct Cancer

2005 News Archive

Potential New Target for Therapy in Biliary Cancer Discovered at Johns Hopkins

The goal of cancer research is to develop treatments that are specifically toxic to tumor cells but not harmful to the host. It is hoped that our knowledge of the molecular genetics of cancer will guide the selection of such specific treatments. One such potential avenue of treatment has recently been discovered at Johns Hopkins. This avenue involves the methylthioadenosine phosphorylase (MTAP) gene.

The principle of this work is as follows: Normal cells synthesize the purines of DNA by two mechanisms: a salvage pathway, which involves and requires the MTAP gene, and a de novo synthesis pathway. Hence, cells have two mechanisms, or a back-up, to perform this very vital function. A number of cancers have been shown to have inactivation of the MTAP gene, which maps to chromosome 9p21, and these cancers should be strictly dependent upon the de novo synthesis pathway. Treatment of such tumors with inhibitors of the de novo pathway should be selectively toxic to the cancer, but not to normal cells, since normal cells should have the back-up salvage pathway intact. Until recently, it was difficult to assay tumors for loss of the MTAP gene, since it would require direct sequencing of the DNA. However, an immunohistochemical assay has become available which mirrors MTAP genetic status. This assay can be applied to all sorts of tumor types to determine which ones have inactivation of MTAP. Using this assay, Hustinx et al. have recently shown that a subset of biliary cancers (12%) demonstrates complete absence of MTAP protein expression. Importantly, these tumors also demonstrated loss of the adjacent p16 gene, indicating that this likely results from homozygous deletion of these genes in tandem. While this number is relatively small, one would predict that such tumors might be more sensitive to blockers of the de novo synthesis pathway, such as L-alanosine. One could therefore envision testing a tumor for MTAP status before determining whether a patient should receive this drug.

While the percentage of biliary tract tumors that demonstrate MTAP loss is, again, fairly small, this study illustrates the important principle that analysis of the genetics of cancer can allow us to design treatments that are specifically toxic to the tumor and not to the patient. It is hoped that further genetic analysis of biliary tract cancers will allow other such targets to be determined.

Reference:
Cancer Biol Ther. 2005 Jan 15;4(1)

~March 2005