U01CA265711

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. However, the 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 tests 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.

Georgia Tech Research

TO IMPROVE SCREENING AND EARLY DETECTION STRATEGIES AND TO DEVELOP ACCURATE DIAGNOSTIC TECHNIQUES AND METHODS FOR PREDICTING THE COURSE OF DISEASE IN CANCER PATIENTS. SCREENING AND EARLY DETECTION RESEARCH INCLUDES DEVELOPMENT OF STRATEGIES TO DECREASE CANCER MORTALITY BY FINDING TUMORS EARLY WHEN THEY ARE MORE AMENABLE TO TREATMENT. DIAGNOSIS RESEARCH FOCUSES ON METHODS TO DETERMINE THE PRESENCE OF A SPECIFIC TYPE OF CANCER, TO PREDICT ITS COURSE AND RESPONSE TO THERAPY, BOTH A PARTICULAR THERAPY OR A CLASS OF AGENTS, AND TO MONITOR THE EFFECT OF THE THERAPY AND THE APPEARANCE OF DISEASE RECURRENCE. THESE METHODS INCLUDE DIAGNOSTIC IMAGING AND DIRECT ANALYSES OF SPECIMENS FROM TUMOR OR OTHER TISSUES. SUPPORT IS ALSO PROVIDED FOR ESTABLISHING AND MAINTAINING RESOURCES OF HUMAN TISSUE TO FACILITATE RESEARCH. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.286 - Discovery and Applied Research for Technological Innovations to Improve Human Health

National Cancer Institute (NCI) [HHS - NIH]

National Institute of Biomedical Imaging and Bioengineering (NIBIB) [HHS - NIH]

Georgia United States

State-Wide

Collaborative Approaches to Engineer Biology for Cancer Applications (U01 Clinical Trial Not Allowed) (RFA-CA-20-054)

Amendment Since initial award the total obligations have increased 1448% from $-175,000 to $2,358,587.