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Clonal analysis of cancer by mitochondrial DNA barcoding

Award Number: R33CA278393
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/11/2023
PERIOD OF PERFORMANCE END DATE: 04/30/2026

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Clonal analysis of cancer by mitochondrial DNA barcoding - Project Summary/Abstract All tumors contain a mixture of different cell types. Within the malignant cell population, clonal evolution leads to the emergence of clones with different genetic lesions, and various biological processes shape the co-occurrence of different cell states that are characterized by specific transcriptional/epigenetic landscapes. This heterogeneity underlies the persistence of small populations of tumor cells through treatment, leading to disease recurrence, which is a major clinical challenge. To better understand clonal structures and transcriptional/epigenetic states in primary human tumors, there is an unmet need for technologies that comprehensively profile these modalities at single-cell resolution. The PI/PDs Peter van Galen and Vijay Sankaran have pioneered the use of mitochondrial DNA (mtDNA) variants as naturally occurring cell barcodes to reconstruct clonal relationships between cells, and demonstrate simultaneous profiling of transcriptional (scRNA-seq) and epigenetic (scATAC-seq) cell states. As such, they are uniquely positioned to realize the potential of these technologies to illuminate the complex tumor ecosystem and identify vulnerabilities of different malignant cell types. The long-term goal of this research is to guide new therapeutic approaches that can effectively eradicate heterogeneous tumor cells. The overall objective is to establish enabling technologies that can be used across a wide range of tumors to transform our understanding of cancer biology. Drs. Van Galen and Sankaran, supported by a strong network of collaborators, will jointly work towards this objective through two specific aims: 1) Advance and validate experimental methods to simultaneously dissect the transcriptome, epigenome, and clonal structures in cancer and 2) Proof-of-principle profiling of acute myeloid leukemia clones at diagnosis that subsequently drive recurrence. In the first Aim, the investigators will build on their recent accomplishments to establish optimized and validated procedures for multi-omic analysis of primary human cancer cells with clear performance measures. In the second Aim, paired diagnosis-relapse samples from a well-defined cohort of acute myeloid leukemia patients will be analyzed to demonstrate the simultaneous dissection of longitudinal patterns of clonal evolution with transcriptional/epigenetic cell states - a key proof-of-principle for this technology. The approach is innovative by leveraging naturally occurring mtDNA variants to layer clonal relationships onto current state-of-the-art assays for single-cell analysis. The proposed research is significant because the successful completion of the project would equip the scientific community with new tools for the comprehensive molecular/cellular characterization of cancer. The expected output is a repeatable, reliable approach for single-cell analysis of primary human cancer cells at three core modalities, yielding transcriptional, epigenetic, and clonal resolution. This will be enabling for NCI-funded projects in a range of tumor systems.


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: 2025 ( Subtotal = $443,222 )
2025	2025	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Cancer Detection and Diagnosis Research	000	3	4/9/2025	NON-COMPETING CONTINUATION	$398,899
2025	2025	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Cancer Detection and Diagnosis Research	001	3	5/22/2025	NON-COMPETING CONTINUATION	$44,323
														Subtotal = $443,222

Issue Date FY: 2024 ( Subtotal = $421,062 )
2024	2024	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Cancer Detection and Diagnosis Research	000	2	4/15/2024	NON-COMPETING CONTINUATION	$421,062
														Subtotal = $421,062

Issue Date FY: 2023 ( Subtotal = $462,970 )
2023	2023	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Cancer Detection and Diagnosis Research	000	1	5/11/2023	NEW	$462,970
														Subtotal = $462,970

Grand Total All Awards = $1,327,254

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Clonal analysis of cancer by mitochondrial DNA barcoding

Award Number: R33CA278393

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/11/2023

PERIOD OF PERFORMANCE END DATE: 04/30/2026

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