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AND-gated Synthetic Biomarkers for Early Detection of Liver Metastasis

Award Number: U01CA265711
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/23/2021
PERIOD OF PERFORMANCE END DATE: 08/31/2026

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AND-gated Synthetic Biomarkers for Early Detection of Liver Metastasis - PROJECT SUMMARY Advances in synthetic biology will play a fundamental role in shaping the future of cancer diagnostics toward earlier and more specific detection of disease. For example, whole-cell biosensors such as bacteria have been genetically engineered to perform complex functions such as signal amplification to detect clinically relevant biomarkers in human urine and serum. In mammalian cells, sense-and-respond components that employ Boolean logic have been demonstrated for multiplexed control of engineered T cell therapies, thereby increasing the specificity of tumor sensing and reducing systemic toxicity. These advances highlight the promise of synthetic biology when applied to cancer, yet the vast majority of these strategies rely on genetic circuits and make use of non-mammalian protein components. Such circuits are complex and raise safety and immunogenicity concerns for regulatory approval, especially in the context of in vivo early cancer detection where repeated administrations of biosensors are likely needed to monitor for nascent disease. This proposal seeks to develop a new class of diagnostics called AND-gated synthetic biomarkers for early detection of cancer metastasis. Synthetic biomarkers are an emerging class of activatable biological sensors that are designed to be administered systemically, query sites of early disease, and harness tumor-dependent activation mechanisms, such as dysregulated protease activity, to drive production of a reporter. These reporters can then be detected noninvasively from blood, urine, or other bodily fluid samples. Proteases play key biological roles across the major hallmarks of metastasis and are particularly potent molecular amplifiers by catalyzing the irreversible hydrolysis of peptide bonds, allowing a single protease to turnover thousands of substrates. AND-gated synthetic biomarkers will be applied for early detection of colorectal cancer (CRC) liver metastasis. Although the liver is a common site for metastatic spread from primary CRC, regional resection of liver-isolated metastases can lead to potentially curative results. Yet early detection of CRC liver metastases at a size when they are most responsive to therapy (1–2 mm) remains challenging by radiographic imaging such as CT and FDA-approved blood test such as the carcinoembryonic antigen (CEA) test. To design AND-gated synthetic biomarkers for CRC liver metastasis, pairwise combinations of proteases will be selected based on differential RNA expression in CRC liver metastases compared to healthy liver tissue. Multivariate mathematical models will be developed to understand how design parameters enhance specificity and cooperativity compared to experimental results. Syngeneic and xenograft models of CRC liver metastasis will be used for preclinical validation studies to allow benchmarking against CT and CEA. This proposal will lay the groundwork for earlier detection of cancer metastasis by programmable synthetic biomarkers.


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 = $574,650 )
2024	2024	GEORGIA TECH RESEARCH CORP	926 DALNEY ST NW	ATLANTA	GA	30318	FULTON	USA	Cancer Detection and Diagnosis Research	000	4	8/13/2024	NON-COMPETING CONTINUATION	$574,650
														Subtotal = $574,650

Issue Date FY: 2023 ( Subtotal = $592,796 )
2023	2023	GEORGIA TECH RESEARCH CORPORATION	926 DALNEY ST NW	ATLANTA	GA	30332	FULTON	USA	Cancer Detection and Diagnosis Research	000	3	8/28/2023	NON-COMPETING CONTINUATION	$592,796
														Subtotal = $592,796

Issue Date FY: 2022 ( Subtotal = $591,551 )
2022	2022	GEORGIA TECH RESEARCH CORPORATION	926 DALNEY ST NW	ATLANTA	GA	30332	FULTON	USA	Cancer Detection and Diagnosis Research	001	2	8/17/2022	NON-COMPETING CONTINUATION	$591,551
2022	2021	GEORGIA TECH RESEARCH CORPORATION	926 DALNEY ST NW	ATLANTA	GA	30332	FULTON	USA	Cancer Detection and Diagnosis Research	000	1	7/19/2022	NEW	$0
														Subtotal = $591,551

Issue Date FY: 2021 ( Subtotal = $599,590 )
2021	2021	GEORGIA TECH RESEARCH CORPORATION	926 DALNEY ST NW	ATLANTA	GA	30332	FULTON	USA	Cancer Detection and Diagnosis Research	000	1	9/23/2021	NEW	$599,590
2021	2021	GEORGIA TECH RESEARCH CORPORATION	926 DALNEY ST NW	ATLANTA	GA	30332	FULTON	USA	Cancer Detection and Diagnosis Research	001	1	9/23/2021	NEW	$0
2021	2021	GEORGIA TECH RESEARCH CORPORATION	926 DALNEY ST NW	ATLANTA	GA	30332	FULTON	USA	Cancer Detection and Diagnosis Research	002	1	9/24/2021	NEW	$0
														Subtotal = $599,590

Grand Total All Awards = $2,358,587

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AND-gated Synthetic Biomarkers for Early Detection of Liver Metastasis

Award Number: U01CA265711

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 09/23/2021

PERIOD OF PERFORMANCE END DATE: 08/31/2026

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