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Developing high-throughput genetic perturbation strategies for single cells in cancer organoids

Award Number: U01CA250554
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/08/2020
PERIOD OF PERFORMANCE END DATE: 06/30/2025

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Developing high-throughput genetic perturbation strategies for single cells in cancer organoids - PROJECT SUMMARY To address the complexity of heterogeneous cancers that are resistant to chemotherapy and frequently recur or metastasize, we propose to develop a set of tools based on multidisciplinary innovations combining Synthetic Biology, Cancer Organoid Technology, and Bioinformatics. These Synthetic Tools to Annotate Reporter Organoids for Cancer Heterogeneity and Recurrence Development (StarOrchard) include: Synthetic Promoter Activated Recombination of Kaleidoscopic Organoids (SPARKO), Combinatorial Genetics En Masse (CombiGEM), and single-cell RNA sequencing panorama (Scanorama). SPARKO can annotate heterogeneous cancer populations in living cells via fluorescent protein expression libraries to make multi- colored tumor organoids. CombiGEM can rapidly identify potential therapeutic targets via large-scale, massively parallel, and unbiased combinatorial genetic screens. Scanorama can integrate the analysis of large datasets of single-cell transcriptomics via sophisticated bioinformatics algorithms. These tools focus on barcoding strategies to enable accurate tracking and analysis of individual tumor cells that harbor distinct genetic aberrations, and substantially expand the utility of the Next Generation Cancer Models (NGCMs) for cancer mechanistic investigations or therapeutic discovery. The StarOrchard tools enable targeted genetic perturbations in annotated heterogeneous tumor phenotypes without destroying cells for sequencing. These tools will be applied to a large number and variety of NGCMs to optimize experimental protocol. To ensure success, we have convened an outstanding team: PI Timothy K. Lu, MD, PhD, has made strikingly original contributions to Synthetic Biology tools that enable high-throughput genetic interrogation of cancer cell drug dependency; PI Ömer Yilmaz, MD, PhD, has extensive expertise in cancers of the gastrointestinal tract and has developed novel technologies to maintain patient-derived colon cancer organoids for in vivo modeling; and PI Bonnie Berger, PhD, will use her expertise in bioinformatics and her Scanorama algorithm to integrate data across all tumor types based on dynamic single cell RNA sequencing (scRNAseq). We are also supported by leading experts in cancer biology and various cancer types at both the basic science and clinical oncology frontiers of cancer research. The collective commitment and multidisciplinary contributions of the entire team ensure the establishment of an openly distributed investigative tool set that accelerates advancements in cancer biology and therapeutic 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: 2026 ( Subtotal = -$118 )
2026	2022	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	000	3	11/24/2025	NON-COMPETING CONTINUATION	-$118
														Subtotal = -$118

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2022	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	000	3	1/3/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2022	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	000	3	10/13/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $922,170 )
2022	2022	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	000	3	8/3/2022	NON-COMPETING CONTINUATION	$922,170
														Subtotal = $922,170

Issue Date FY: 2021 ( Subtotal = $922,170 )
2021	2021	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	000	2	7/22/2021	NON-COMPETING CONTINUATION	$922,170
														Subtotal = $922,170

Issue Date FY: 2020 ( Subtotal = $922,170 )
2020	2020	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	000	1	7/8/2020	NEW	$922,170
														Subtotal = $922,170

Grand Total All Awards = $2,766,392

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Developing high-throughput genetic perturbation strategies for single cells in cancer organoids

Award Number: U01CA250554

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 07/08/2020

PERIOD OF PERFORMANCE END DATE: 06/30/2025

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