Official websites use .gov

A .gov website belongs to an official government organization in the United States.

Secure .gov websites use HTTPS

A lock ( 🔒 ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

Need Help

Mechanisms of natural killer cell resistance of treatment-persistent residual tumor cells in hematologic malignancies

Award Number: R01CA276156
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2023
PERIOD OF PERFORMANCE END DATE: 12/31/2027

Group Awards By:

View Award Description

Mechanisms of natural killer cell resistance of treatment-persistent residual tumor cells in hematologic malignancies - PROJECT SUMMARY Significance: Currently available pharmacological therapies for hematologic malignancies, including multiple myeloma (MM) and myeloid leukemias often fail, despite ongoing treatment, to eradicate all malignant cells, resulting in establishment of treatment-persistent residual disease TPRD (often referred to as “minimal” residual disease, MRD), which serves as a reservoir for eventual patient relapses. Despite the critical role of TPRD/MRD tumor cells as a barrier to cure, their biology and therapeutic vulnerabilities, including immune responsiveness, has remained understudied. Preliminary data: Our recent studies and preliminary data indicate that treatment- persistent cancer cells in acute myeloid leukemia (AML), MM, and solid tumors persist through cytotoxic drug treatments via a non-genetic (and reversible upon drug withdrawal) low-Myc tumor cell state with transcriptional changes resembling embryonic diapause, a stress-induced dormant stage of suspended development in many species. In parallel to these studies, our collaborating labs characterized, through CRISPR and pooled pheno- typic studies, the molecular determinants of response vs. resistance of treatment-naïve solid tumor or blood cancer cells to natural killer (NK) cells; and how NK cell-induced adaptive transcriptional changes in tumor cells may contribute to their persistence against NK cells. These studies identified several previously underappreci- ated regulators of NK cell responses in chemo-naïve tumor cells; and observed that molecular signatures of clinical resistance to immune checkpoint inhibitors overlap with signatures of NK cell response in treatment- naïve tumor cells, suggesting orthogonal mechanisms regulating NK vs. cytotoxic T lymphocyte responses. No- tably, TPRD/MRD tumor cells with embryonic diapause-like (EDL) chemopersistence exhibit complex and het- erogeneous dysregulation of transcripts associated with NK cell resistance in treatment-naïve tumor cells. We hypothesize that cytotoxic drug-persistent residual MM or leukemic cells may often exhibit, compared to treatment-naïve cells, distinct patterns of responses to the cytotoxic activity of NK cells, as well as both shared and distinct mechanisms regulating those responses. Approach: Building on our experience with studies on NK cell resistance of treatment-naïve tumor cells and with experimental models of residual dis- ease, we will (1) identify genomic factors that define responsiveness vs. resistance to NK cells using myeloma and myeloid leukemia cells persistent to cytotoxic pharmacological therapies. We will also (2) define adaptive molecular changes induced during TPRD tumor cell - NK cell interactions and charac- terize their functional impact. Novelty-Impact: By focusing on the understudied biology of TPRD/MRD, this project will provide new insights on how to develop individualized NK cell-based therapies for MM or AML with persistence to cytotoxic drugs.


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 = $400,243 )
2026	2026	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Biology Research	001	4	1/23/2026	NON-COMPETING CONTINUATION	$350,562
2026	2026	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Biology Research	004	4	4/17/2026	SUPPLEMENT FOR EXPANSION	$999
2026	2026	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Biology Research	003	4	4/16/2026	NON-COMPETING CONTINUATION	$39,691
2026	2026	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Biology Research	002	4	1/30/2026	SUPPLEMENT FOR EXPANSION	$8,991
2026	2025	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Biology Research	000	3	1/8/2026	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $400,243

Issue Date FY: 2025 ( Subtotal = $403,103 )
2025	2025	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Biology Research	001	3	9/19/2025	NON-COMPETING CONTINUATION	$31,060
2025	2025	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Biology Research	000	3	11/22/2024	NON-COMPETING CONTINUATION	$362,793
2025	2025	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Biology Research	002	3	9/23/2025	SUPPLEMENT FOR EXPANSION	$9,250
														Subtotal = $403,103

Issue Date FY: 2024 ( Subtotal = $385,609 )
2024	2024	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Biology Research	001	2	4/16/2024	NON-COMPETING CONTINUATION	$20,295
2024	2024	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Biology Research	000	2	12/21/2023	NON-COMPETING CONTINUATION	$365,314
														Subtotal = $385,609

Issue Date FY: 2023 ( Subtotal = $406,038 )
2023	2023	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	000	1	12/29/2022	NEW	$406,038
														Subtotal = $406,038

Grand Total All Awards = $1,594,993

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Mechanisms of natural killer cell resistance of treatment-persistent residual tumor cells in hematologic malignancies

Award Number: R01CA276156

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/2023

PERIOD OF PERFORMANCE END DATE: 12/31/2027

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer