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IDO2 Targeting in Pancreatic Cancer

Award Number: R01CA191191
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/16/2015
PERIOD OF PERFORMANCE END DATE: 06/30/2020

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IDO2 Targeting in Pancreatic Cancer - ¿ DESCRIPTION (provided by applicant): 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2019	LANKENAU INSTITUTE FOR MEDICAL RESEARCH	100 E LANCASTER AVE	WYNNEWOOD	PA	19096	MONTGOMERY	USA	Cancer Biology Research	000	5	1/8/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $379,675 )
2019	2019	LANKENAU INSTITUTE FOR MEDICAL RESEARCH	100 E LANCASTER AVE	WYNNEWOOD	PA	19096	MONTGOMERY	USA	Cancer Biology Research	000	5	6/17/2019	NON-COMPETING CONTINUATION	$379,675
														Subtotal = $379,675

Issue Date FY: 2018 ( Subtotal = $391,418 )
2018	2018	LANKENAU INSTITUTE FOR MEDICAL RESEARCH	100 E LANCASTER AVE	WYNNEWOOD	PA	19096	MONTGOMERY	USA	Cancer Biology Research	000	4	7/19/2018	NON-COMPETING CONTINUATION	$391,418
														Subtotal = $391,418

Issue Date FY: 2017 ( Subtotal = $391,418 )
2017	2017	LANKENAU INSTITUTE FOR MEDICAL RESEARCH	100 E LANCASTER AVE	WYNNEWOOD	PA	19096	MONTGOMERY	USA	Cancer Biology Research	000	3	6/22/2017	NON-COMPETING CONTINUATION	$391,418
														Subtotal = $391,418

Issue Date FY: 2016 ( Subtotal = $391,418 )
2016	2016	LANKENAU INSTITUTE FOR MEDICAL RESEARCH	100 LANCASTER AVENUE	WYNNEWOOD	PA	19096	MONTGOMERY	USA	Cancer Biology Research	000	2	6/15/2016	NON-COMPETING CONTINUATION	$391,418
														Subtotal = $391,418

Issue Date FY: 2015 ( Subtotal = $407,668 )
2015	2015	LANKENAU INSTITUTE FOR MEDICAL RESEARCH	100 LANCASTER AVENUE	WYNNEWOOD	PA	19096	MONTGOMERY	USA	Cancer Biology Research	000	1	7/16/2015	NEW	$407,668
														Subtotal = $407,668

Grand Total All Awards = $1,961,597

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IDO2 Targeting in Pancreatic Cancer

Award Number: R01CA191191

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/16/2015

PERIOD OF PERFORMANCE END DATE: 06/30/2020

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