Dissertation
Targeting the immune modulating enzyme IDO1 using anticancer agents
Doctor of Philosophy (Ph.D.), Drexel University
Apr 2013
DOI:
https://doi.org/10.17918/00000724
Abstract
Cancers are involved in a complex and dynamic interaction with the host immune system, which can result in either elimination or promotion of tumors. The mechanisms involved in the immune response and immune regulation continue to be elucidated and are the subject of active research. The idea that the tryptophan catabolizing enzyme IDO1 (indoleamine 2,3-dioxyganse 1) can play a key role in directing the immune system towards tumor promotion has recently received important genetic validation in mouse tumor models. The expression of IDO1 in tumors or tumor draining lymph nodes has been linked to poor prognosis and disease progression in many types of cancers. Researchers are now looking to target IDO1 in cancer in order to relieve the immune suppression and promote an anti-tumor response. The primary focus of this thesis is to identify novel approaches for targeting 001 for therapeutic intervention. Combining standard cytotoxic chemotherapy with IDO1 inhibition has been identified as a promising approach for achieving synergistic combinatorial efficacy. I have characterized a clinical pharmaceutical candidate that may incorporate both of these capabilities in a single molecule. I have also found that Raf signaling, a critical pathway for both oncogenesis and inflammation, is important for regulating the expression ID01. In this context, I have found that an approved signal transduction inhibitor, originally developed to directly eliminate tumor cells, is a potent inhibitor of IDO1 expression, and that the immune-based effects may be more relevant to the anti-tumor activity of this agent than previously recognized. The new found evidence for these two anticancer agents sheds light on their potential to be used therapeutically to alter immune regulation via 001 in cancer.
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Details
- Title
- Targeting the immune modulating enzyme IDO1 using anticancer agents
- Creators
- Hollie Elizabeth Flick
- Contributors
- Alexander J. Muller (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- xi, 107 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology; College of Medicine; Drexel University
- Other Identifier
- 991014970224104721