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Experimental-Computational Synthesis of Altered Immune Signaling in Breast Cancer

Award Number: U01CA232216
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/16/2019
PERIOD OF PERFORMANCE END DATE: 08/31/2024

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Experimental-Computational Synthesis of Altered Immune Signaling in Breast Cancer - PROJECT SUMMARY/ABSTRACT This integrated experimental–computational proposal seeks to unravel the complexity of immune signaling networks in healthy individuals and patients with estrogen receptor-positive breast cancer (ER+ BC). Our goal is to identify and characterize, at a systems level, the dynamical flow of information through immune signaling networks in healthy individuals and ER+ BC patients and to understand how immune signaling defects at diagnosis reflect patients' immune responses, leading to different clinical outcomes. This work and its approach are motivated by our experience in immune signaling in cancer and our existing collaborations with oncologists and computational biologists at the City of Hope Cancer Center. We have shown that approximately 40% of ER+ BC patients harbor defects in their immune signaling network, specifically in signaling molecules called cytokines. Importantly, our preliminary data revealed major cytokine signaling abnormalities within immune cells from the peripheral blood of ER+ BC patients, which reflect immune activity within tumors and can predict cancer relapse years later. We believe that understanding how these cytokines interact with each other and other critical elements of the immune signaling network can ultimately lead to improved cancer treatments. Because the individual components of signaling networks interact in complicated and difficult-to-predict ways, we propose to apply a systems biology computational modeling approach. First, we propose to experimentally capture a rich data set of biological variables (molecular, genetic, and cellular data) using state-of-the-art technologies in peripheral blood collected from healthy people (Aim 1) and patients with ER+ BC (Aim 2). We will integrate these data into Bayesian networks, a way of modeling the data that will allow us to mathematically and statistically describe the relationships between cancer and measured variables. We will also perform high-dimensional histology and spatial image analysis of human ER+ breast tumors (Aim 3), then apply Bayesian networks and dynamical mathematical models to identify common immune features between tumor tissue (Aim 3) and peripheral blood (Aims 1 and 2), which we will also correlate with outcome. Impact and deliverables. This proposal will begin unraveling the complexity of the immune signaling network from a systems biology perspective. Significant outcomes of the proposed studies will include i) identification, at the systems biology level, of a prognostic and clinically relevant immune phenotype that is characterized by defects in signaling networks in ER+ BC, and ii) development of a data-driven, computational framework for the study of immune signaling and its defects as a dynamical system in cancer patients with such signaling defects. Our approach should be broadly applicable to other types of cancers and immunological diseases. Therefore, an important deliverable will be a computational systems biology data analysis toolkit to construct, interrogate, and dissect immune signaling networks that can be shared with other groups and applied to other diseases.


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: 2025 ( Subtotal = -$12,522 )
2025	2023	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Biology Research	000	5	4/7/2025	NON-COMPETING CONTINUATION	-$12,522
														Subtotal = -$12,522

Issue Date FY: 2023 ( Subtotal = $183,872 )
2023	2023	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Biology Research	000	5	8/16/2023	NON-COMPETING CONTINUATION	$183,872
														Subtotal = $183,872

Issue Date FY: 2022 ( Subtotal = $612,300 )
2022	2022	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Biology Research	000	4	8/11/2022	NON-COMPETING CONTINUATION	$612,300
														Subtotal = $612,300

Issue Date FY: 2021 ( Subtotal = $921,294 )
2021	2021	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Biology Research	001	3	8/24/2021	NON-COMPETING CONTINUATION	$921,294
2021	2020	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Biology Research	000	2	8/18/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $921,294

Issue Date FY: 2020 ( Subtotal = $624,796 )
2020	2020	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Biology Research	000	2	8/24/2020	NON-COMPETING CONTINUATION	$624,796
														Subtotal = $624,796

Issue Date FY: 2019 ( Subtotal = $624,796 )
2019	2019	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Biology Research	000	1	9/16/2019	NEW	$624,796
														Subtotal = $624,796

Grand Total All Awards = $2,954,536

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Experimental-Computational Synthesis of Altered Immune Signaling in Breast Cancer

Award Number: U01CA232216

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 09/16/2019

PERIOD OF PERFORMANCE END DATE: 08/31/2024

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