Pancreatic ductal adenocarcinoma (PDAC) eludes immune control by mechanisms that are poorly understood but might be restored to improve clinical outcomes. The primary impact of our proposal is that it addresses the need for theranostic markers to assist the clinical development of IDO inhibitors, a promising new class of small molecule immunotherapy now in Phase II trials. Building upon an earlier R21 award, we will develop our hypothesis that the IDO2 gene can (1) inform the development of pancreatic ductal adenocarcinoma (PDAC) and (2) define a host biomarker to stratify individual PDAC patient responses to an IDO inhibitor, based on natural polymorphic variations in the IDO2 coding region that affect its enzyme activity. In essence, our project seeks to illuminate an immune basis for PDAC development and to identify a theranostic marker that could predict the efficacy of IDO inhibitor treatment in an individual patient. A major source of scientific significance in our proposal is how it approaches the question of cancer- associated inflammation: why does chronic inflammation lead to cancer in some individuals but not others? Inflammation and immune escape are well established as causative factors in PDAC, but it is clear that this question has broader general significance in oncology. While variations in a single pathway cannot address this question fully, our focus on IDO2 may inform IDO inhibitor therapy and help tilt some PDAC patients with a suitable IDO2 genotype into a more manageable state. It is in this sense that our project is incisive in the opportunity if offers to improve clinical treatment. Our preliminary results suggest that IDO2 programs a pathogenic process that enforces a powerful mechanism of immune escape in PDAC, thereby licensing its rapid progression and resistance to treatment. We discovered IDO2 and generated a unique conditionally genetic mutant mouse to understand how IDO2 informs the inflammatory tumor microenvironment. Among human cancers, PDAC was a chosen focus because of our discovery that this type of cancer overexpresses IDO2 in both immune cells and solid tumor cells (the latter of which is not usually the case for IDO2 in most tumors). This feature may be relevant to the particularly strong correlates of PDAC with chronic inflammation and aggressive pathology.
Aim 1 will continue a clinical study of IDO2 genetic variants in a unique subset of PDAC patients, where pilot investigations to date suggest that a select set of PDAC patients (i.e., late-onset as well as female patients) are more likely to correlate with a WT host IDO2 genotype.
Aim 2 will develop a mouse genetic study demonstrating that IDO2 deficiency limits a type of pathogenic inflammation that is critical for K-Ras-induced PDAC.
This Aim will explore molecular and cellular mechanisms to learn how IDO2 expression in immune cells and tumor cells contribute to malignant development and treatment response.
Aim 3 will compare pathogenic and mechanistic contributions of the naturally occurring human IDO2 genetic variants in the mouse, in terms of their impact on PDAC development and treatment. This project offers the opportunity to leverage an outstanding, experienced team to promote the development of IDO inhibitors for effective combination immunochemotherapy of PDAC.
This project seeks to advance work on the immunoregulatory enzyme IDO2 as a candidate theranostic target to improve the clinical management of pancreatic adenocarcinoma (PDAC). We discovered IDO2 and explored an hypothesized role in PDAC development under the auspices of an earlier R21 award. In this revised R01 proposal, we have added new findings to deepen the clinical and mouse genetic data in support of our core hypothesis that IDO2 informs a pathogenic inflammation that promotes PDAC. The overall significance and impact relates to the ability of IDO2 to inform a pathogenic state that supports PDAC development and the effect of IDO2 genetic variants on treatment outcomes with an IDO inhibitor. Accordingly, our project offers an opportunity to address core questions about the nature of 'cancer-associated' inflammation and how to best use an IDO inhibitor to improve treatment of PDAC patients who have a wild-type IDO2 genotype, when combined with experimental or standard-of-care treatments to engender an effective immunochemotherapy. The conceptual, immunological, genetic and therapeutic innovations offered in this project will be developed by an outstanding multidisciplinary team of preclinical and clinical experts in oncoimmunology, mouse genetics, drug discovery and PDAC management. The overall impact and significance offers a powerful opportunity to drive study of IDO inhibitors in PDAC patients, based on contributions of IDO2 in this setting.
| Nevler, Avinoam; Muller, Alexander J; Cozzitorto, Joseph A et al. (2018) A Sub-Type of Familial Pancreatic Cancer: Evidence and Implications of Loss-of-Function Polymorphisms in Indoleamine-2,3-Dioxygenase-2. J Am Coll Surg 226:596-603 |
| Prendergast, George C; Mondal, Arpita; Dey, Souvik et al. (2018) Inflammatory Reprogramming with IDO1 Inhibitors: Turning Immunologically Unresponsive 'Cold' Tumors 'Hot'. Trends Cancer 4:38-58 |
| 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 |
| Nevler, Avinoam; Muller, Alexander J; Sutanto-Ward, Erika et al. (2018) Host IDO2 Gene Status Influences Tumor Progression and Radiotherapy Response in KRAS-Driven Sporadic Pancreatic Cancers. Clin Cancer Res : |
| Merlo, Lauren M F; Grabler, Samantha; DuHadaway, James B et al. (2017) Therapeutic antibody targeting of indoleamine-2,3-dioxygenase (IDO2) inhibits autoimmune arthritis. Clin Immunol 179:8-16 |
| Prendergast, George C; Malachowski, William P; DuHadaway, James B et al. (2017) Discovery of IDO1 Inhibitors: From Bench to Bedside. Cancer Res 77:6795-6811 |
| Merlo, Lauren M F; DuHadaway, James B; Grabler, Samantha et al. (2016) IDO2 Modulates T Cell-Dependent Autoimmune Responses through a B Cell-Intrinsic Mechanism. J Immunol 196:4487-97 |
