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A High Throughput Human Tumor Modeling Technology for Cancer Drug Discovery

Award Number: R33CA225549
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2019
PERIOD OF PERFORMANCE END DATE: 05/31/2025

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A High Throughput Human Tumor Modeling Technology for Cancer Drug Discovery - Project Summary Tumor stroma, encompassing both extracellular matrix (ECM) and cells, regulates essentially all aspects of tumor growth and metastasis. Signaling among cancer cells, stromal cells, and ECM in tumors promotes proliferation of cancer cells and drug resistance among other key outcomes. Therefore, disrupting stroma- cancer cells signaling is essential to restoring drug sensitivity of cancer cells and improving outcomes for patients. Despite this recognition, the lack of physiologic, high throughput human tumors models significantly impedes drug development and discovery efforts targeting tumor-stromal interactions. We will address this need by developing a high throughput tumor microtissue technology to recreate the complexity of native tumors and enable drug testing against tumor-stromal signaling. This facile technology is based on two-step robotic micropatterning of user-defined cancer cells, stromal cells, and ECM using a polymeric aqueous two-phase system in 1536 microwell plates. A 3D mass of cancer cells is formed in an aqueous nanodrop settled at the bottom of a microwell and immiscible from the immersion aqueous phase. A second aqueous drop containing the stromal components is then dispensed to merge with the nanodrop and surround the cancer cell mass to spontaneously generate a microtissue upon incubation. This approach uniquely offers the flexibility of incorporating tissue-specific matrix proteins and different stromal cells to reproduce physicochemical properties of tumors in vivo. We will validate this technology using triple negative breast cancer (TNBC) as a disease model, demonstrating effects of carcinoma-associated fibroblasts (CAFs) and ECM on proliferation and drug responses of cancer cells. With this technology, we will test effects of disrupting tumor-stromal signaling on treatment efficacy against TNBC cells. These studies will use engineered tumor models of both TNBC cell lines and conditionally reprogrammed cells generated from cancer cells of patients with metastatic TNBC to establish the feasibility of using our TMT model system for precision oncology. We will perform combinatorial drug screening using standard chemotherapeutics and molecular inhibitors against signaling pathways active in cells of specific TNBC patients to inhibit stroma- mediated proliferation and drug resistance of cancer cells, and validate the most effective treatments in mouse xenograft models of human TNBC. Through this research, we expect to establish our TMT technology as a transformative advance that will be implemented broadly for drug discovery, mechanistic studies of breast cancer and other malignancies, and precision medicine.


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: 2024 ( Subtotal = $0 )
2024	2021	THE UNIVERSITY OF AKRON	302 BUCHTEL COMMON	AKRON	OH	44325	SUMMIT	USA	Cancer Detection and Diagnosis Research	000	3	4/30/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2021	THE UNIVERSITY OF AKRON	302 BUCHTEL COMMON	AKRON	OH	44325	SUMMIT	USA	Cancer Detection and Diagnosis Research	001	3	5/11/2023	SUPPLEMENT FOR EXPANSION	$0
2023	2021	THE UNIVERSITY OF AKRON	302 BUCHTEL COMMON	AKRON	OH	44325	SUMMIT	USA	Cancer Detection and Diagnosis Research	000	3	5/11/2023	NON-COMPETING CONTINUATION	$0
2023	2021	THE UNIVERSITY OF AKRON	302 BUCHTEL COMMON	AKRON	OH	44325	SUMMIT	USA	Cancer Detection and Diagnosis Research	002	3	5/11/2023	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $590,632 )
2021	2021	THE UNIVERSITY OF AKRON	302 BUCHTEL COMMON	AKRON	OH	44325	SUMMIT	USA	Cancer Detection and Diagnosis Research	002	3	6/17/2021	SUPPLEMENT FOR EXPANSION	$166,399
2021	2021	THE UNIVERSITY OF AKRON	302 BUCHTEL COMMON	AKRON	OH	44325	SUMMIT	USA	Cancer Detection and Diagnosis Research	001	3	6/10/2021	SUPPLEMENT FOR EXPANSION	$59,188
2021	2021	THE UNIVERSITY OF AKRON	302 BUCHTEL COMMON	AKRON	OH	44325	SUMMIT	USA	Cancer Detection and Diagnosis Research	000	3	6/3/2021	NON-COMPETING CONTINUATION	$365,045
														Subtotal = $590,632

Issue Date FY: 2020 ( Subtotal = $370,110 )
2020	2020	THE UNIVERSITY OF AKRON	302 BUCHTEL COMMON	AKRON	OH	44325	SUMMIT	USA	Cancer Detection and Diagnosis Research	000	2	5/8/2020	NON-COMPETING CONTINUATION	$370,110
														Subtotal = $370,110

Issue Date FY: 2019 ( Subtotal = $476,844 )
2019	2019	THE UNIVERSITY OF AKRON	302 BUCHTEL COMMON	AKRON	OH	44325	SUMMIT	USA	Cancer Detection and Diagnosis Research	002	1	9/9/2019	NEW	$76,000
2019	2019	THE UNIVERSITY OF AKRON	302 BUCHTEL COMMON	AKRON	OH	44325	SUMMIT	USA	Cancer Detection and Diagnosis Research	001	1	2/26/2019	NEW	$0
2019	2019	THE UNIVERSITY OF AKRON	302 BUCHTEL COMMON	AKRON	OH	44325	SUMMIT	USA	Cancer Detection and Diagnosis Research	000	1	2/20/2019	NEW	$400,844
														Subtotal = $476,844

Grand Total All Awards = $1,437,586

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A High Throughput Human Tumor Modeling Technology for Cancer Drug Discovery

Award Number: R33CA225549

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/01/2019

PERIOD OF PERFORMANCE END DATE: 05/31/2025

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