Background. There is a great need for improved strategies to eliminate systemic cancer. Immune interventions may be useful given that immune evasion occurs universally in cancer. One mechanism cancers use to evade immunity is mediated by activation of the immunosuppressive enzyme, IDO (indoleamine 2, 3-dioxygenase), which limits activation of cytotoxic T cells. We identified IDO through its genetic control by Bin 1, a tumor suppressor commonly attenuated in breast cancers and other cancers. Mouse knockout studies link Bin 1 loss to increased malignant capacity, in part via IDO-mediated immune evasion. If lesions in Bin 1 or other tumor suppressors promote immune evasion by elevating IDO, then small molecule inhibitors of IDO activity would be predicted to promote immune rejection of tumor cells. Guiding Hypothesis and Specific Aims: Preliminary studies show that the combination of a bioactive IDO inhibitor with a cytotoxic chemotherapeutic drug triggers massive tumor cell deaths and regression in a transgenic mouse model of breast cancer (MMTVneu mice), where single agents are ineffective. IDO inhibitors are not cytotoxic in vitro, so their antitumor activity would not be revealed by traditional in vitro drug screens.
In Aim 1, we will vary dosing and scheduling of an IDO inhibitor to optimize efficacy.
In Aims 2 and 3, we will synthesize and assay the enzyme inhibitory activity of compounds in four series of IDO inhibitors that have been identified. Lastly, in Aims 4 and 5, the pharmacology and efficacy of lead compounds will be examined. Our long-term goal is to build a foundation for clinical development of this new therapeutic strategy. Innovation and Significance: Several innovations are offered. The most general innovation is the unexplored concept that cancer treatment might be enhanced by combining immunotherapy and cytotoxic chemotherapy. The biochemistry of IDO is well developed, but its pathophysiological role in cancer is virtually unexplored: Small molecule inhibitors of IDO provide a new modality for cancer therapy, and they offer a tool for chemical genetics to establish the significance of IDO to tumor immunity and survival. IDO has attractive features as a cancer drug target, including its pharmacological tractability, its lack of genomic relatives, and its facile pharmacodynamic measurement. This application offers a unique opportunity to gain an innovative perspective on cancer pathophysiology and treatment.
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| Prendergast, George C; Malachowski, William J; Mondal, Arpita et al. (2018) Indoleamine 2,3-Dioxygenase and Its Therapeutic Inhibition in Cancer. Int Rev Cell Mol Biol 336:175-203 |
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| Bessede, Alban; Gargaro, Marco; Pallotta, Maria T et al. (2014) Aryl hydrocarbon receptor control of a disease tolerance defence pathway. Nature 511:184-90 |
| Thomas, Sunil; DuHadaway, James; Prendergast, George C et al. (2014) Specific in situ detection of murine indoleamine 2, 3-dioxygenase. J Cell Biochem 115:391-6 |
| Pigott, Elizabeth; DuHadaway, James B; Muller, Alexander J et al. (2014) 1-Methyl-tryptophan synergizes with methotrexate to alleviate arthritis in a mouse model of arthritis. Autoimmunity 47:409-18 |
| Galluzzi, Lorenzo; Vacchelli, Erika; Bravo-San Pedro, José-Manuel et al. (2014) Classification of current anticancer immunotherapies. Oncotarget 5:12472-508 |
| Merlo, Lauren M F; Pigott, Elizabeth; DuHadaway, James B et al. (2014) IDO2 is a critical mediator of autoantibody production and inflammatory pathogenesis in a mouse model of autoimmune arthritis. J Immunol 192:2082-2090 |
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