Development of a Novel Therapeutic Paradigm Utilizing a Mammary Gland- Targeted, Bin-1 Knockout Mouse Model; Annual rept. 14 Mar 2007-13 Mar 2008

摘要

Evidence of loss or attenuation of the Bin-1 gene in human breast cancers has implicated Bin-1 as a tumor suppressor or negative modifier gene in mammary gland epithelial cells. We have discovered that Bin-1 loss can promote tumorigenesis through an immune escape mechanism and that this correlated with the negative regulatory impact that we showed Bin-1 can exert on the important immunomodulatory enzyme indoleamine 2,3-dioxygenase (IDO). Previously we have demonstrated that, in combination with certain chemotherapeutic agents, inhibitors of IDO can be employed in a non-obvious therapeutic regimen to successfully treat pre-established, autochthonous breast tumors in MMTV-Neu transgenic mice. During this reporting period, we have obtained direct evidence in the MMTV-Neu model that, in the context of breast cancer, IDO activity in plasmacytoid dendritic cells from the tumor draining lymph nodes may be more relevant than in the tumor cells themselves. Furthermore, we have found that 1- methyl-D-tryptophan (D-1MT), the presumptive IDO inhibitor which is in early phase clinical trials may instead be directly targeting IDO2, a related enzyme that we discovered. Our data argue that genetic evaluation of patients for known IDO2 polymorphisms may be critically important to interpreting trial outcomes with D-1MT.