Development of a Novel Therapeutic Paradigm Utilizing a Mammary Gland-Targeted, Bin1-Knockout Mouse Model
Final rept. 14 Feb 2005-30 Jun 2008
LANKENAU INST OF MEDICAL RESEARCH WYNNEWOOD PA
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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 discovered that Bin 1 loss can promote tumorigenesis through an immune escape mechanism and that this correlated with the negative regulatory impact that Bin 1 can exert on the important immunomodulatory enzyme indoleamine 2,3- dioxygenase IDO. We had also 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. As a result of our work on this project, we have obtained direct evidence that in the MMTV-Neu model IDO activity in plasmacytoid dendritic cells from the tumor draining lymph nodes may be more relevant than in the tumor cells themselves, a finding that appears to be of general relevance to breast cancer. 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, an IDO-related enzyme that we recently discovered. Our data argue that genetic evaluation of patients for known IDO2 polymorphisms may be critically important to interpreting trial outcomes with D-1MT.
- Anatomy and Physiology
- Medicine and Medical Research