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Development of microfluidic enabled CRISPR-Cas9 functional genetic screening technologies for target discovery in cancer immunotherapy

Award Number: R01CA260170
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary: Genome-scale genetic screens performed using CRISPR-Cas9 editing can interrogate determinants of cell viability and are powerful tools for the identification of genetic regulators. Using this technology, hundreds of millions of cells - each targeted with a specific genetic alteration - can be surveyed, typically based on a live/dead survival profiling. Phenotype-based genetic screens - where protein expression alterations are detected - represent a next-generation approach and can facilitate the identification of regulators of therapeutically-relevant proteoforms. Due to challenges related to implementation, phenotype-based screens are less commonly used compared to proliferation-based screens. Thus, rapid and robust selection approaches for targeted capture of live cells are required to realize the potential of phenotypic genome-scale screens for functional discovery, further annotation of the human genome, and discovery of novel targets for the development of therapeutics. Recently, through the use of a newly developed high-throughput approach for phenotypic CRISPR- Cas9 screening (Microfluidic Immunomagnetic Cell Sorting (MICS)) we processed an entire genome- wide screen containing more than 108 cells in under one hour to study factors that modulate the display of CD47 on the cell surface. This highly scalable cell sorting technology maintained high levels of cell viability throughout the screening process. CD47 is a widely expressed cell surface protein that acts as a “don’t eat me” signal through inhibitory interactions with SIRPa, a protein expressed on macrophages and other myeloid cells that negatively regulates phagocytosis. CD47 is highly expressed on various tumour types and blocking the CD47-SIRPa interaction has been explored as a novel cancer immunotherapy strategy that has shown promising results for some cancer types. We robustly identified modulators of CD47 function including QPCTL, an enzyme required for formation of the pyroglutamyl modification at the N-terminus of CD47 and interaction with SIRPa. The proposed study will expand the utility of the platform, develop new classes of microfluidic chips for cytometric analysis, and produce a comprehensive database of geno/phenotypic relationships. This new high-performance phenotypic assessment system will greatly accelerate target discovery for cancer therapeutics. In this project we will specifically interrogate VISTA (V-domain immunoglobulin (Ig)-containing suppressor of T-cell activation) and cGAS/STING signaling pathways using a series of related cell lines to identify novel targets for immunotherapies. Importantly, these data will demonstrate the utility of the technology for rapid assessment of regulatory networks for drug discovery.


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: 2023 ( Subtotal = $259,550 )
2023	2023	NORTHWESTERN UNIVERSITY	633 CLARK STREET	EVANSTON	IL	60208	COOK	USA	Cancer Detection and Diagnosis Research	000	3	3/31/2023	NON-COMPETING CONTINUATION	$259,550
2023	2021	GOVERNING COUNCIL OF THE UNIVERSITY OF TORONTO	27 KING'S COLLEGE CIR	TORONTO	ON			CAN	Cancer Detection and Diagnosis Research	001	1	5/12/2023	NEW	$0
														Subtotal = $259,550

Issue Date FY: 2022 ( Subtotal = $268,031 )
2022	2022	NORTHWESTERN UNIVERSITY	633 CLARK	EVANSTON	IL	60208	COOK	USA	Cancer Detection and Diagnosis Research	003	2	9/21/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$88,235
2022	2022	NORTHWESTERN UNIVERSITY	633 CLARK	EVANSTON	IL	60208	COOK	USA	Cancer Detection and Diagnosis Research	001	2	7/28/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$268,031
2022	2021	GOVERNING COUNCIL OF THE UNIVERSITY OF TORONTO	27 KING'S COLLEGE CIR	TORONTO	ON			CAN	Cancer Detection and Diagnosis Research	000	1	7/28/2022	NEW	$0
2022	2021	GOVERNING COUNCIL OF THE UNIVERSITY OF TORONTO	27 KING'S COLLEGE CIR	TORONTO	ON			CAN	Cancer Detection and Diagnosis Research	002	1	9/21/2022	NEW	-$88,235
														Subtotal = $268,031

Issue Date FY: 2021 ( Subtotal = $212,579 )
2021	2021	GOVERNING COUNCIL OF THE UNIVERSITY OF TORONTO	27 KING'S COLLEGE CIR	TORONTO	ON			CAN	Cancer Detection and Diagnosis Research	000	1	3/10/2021	NEW	$212,579
														Subtotal = $212,579

Grand Total All Awards = $740,160

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Development of microfluidic enabled CRISPR-Cas9 functional genetic screening technologies for target discovery in cancer immunotherapy

Award Number: R01CA260170

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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