Saturday, March 14, 2026 3/14/2026

Targeting the Microenvironment/Oncogene Cooperation to treat poor prognosis T-ALL

Award Number: R01CA269740
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/09/2023
PERIOD OF PERFORMANCE END DATE: 02/29/2028

Group Awards By:

View Award Description

Targeting the Microenvironment/Oncogene Cooperation to treat poor prognosis T-ALL - Background. Despite the significant success of recent therapies, Acute Lymphoblastic Leukemia (ALL) remains the second leading cause of childhood death. The discordance between therapeutic improvements and poor outcomes is partially caused by the difficulty of salvaging relapsed disease. While outcomes have improved in de novo treatment, dismal rates of overall survival (less than 25%) were observed in relapsed subtypes of ALL. The clinical armamentarium for treating relapsed or refractory T-ALL must be supported with new options. Strategy. While most of T-ALL cases exhibit gain-of-function mutations in Notch signaling, therapies against Notch have not fulfilled their clinical promise. To identify alternative targets for new therapies, we propose to define how cell-intrinsic oncogenic events integrate with external signals from the microenvironment. Recent studies point to the functional impact of “stromal” signals in leukemia biology. However, one significant gap in this knowledgebase is how microenvironmental factors become essential for leukemogenesis and maintenance. Preliminary results. According to our results in primary T-ALL cells, activating mutations in Notch failed to saturate Notch signaling: Notch signal strength increased when T-ALL cells encounter Notch ligands within the microenvironment – e.g. interleukin 7 (IL-7). The increased strength of Notch signaling correlated with increased surface expression of IL-7Rα by direct transcriptional activation of the IL-7Rα promoter, resulting in T-ALL hyper- responsiveness to IL-7. IL-7 also induced the cell cycle regulator SKP2, activated STAT5, and (surprisingly) STAT3. Primary T-ALL cells showed persistent STAT3 activation and our results suggest STAT3 deletion impairs T-ALL leukemogenesis. Hypothesis. These data support significant interplay between oncogenic factors and the microenvironment. According to our hypothesis, interplay between microenvironmental signals (IL-7), Notch signaling, SKP2, and STAT3 form a reciprocal positive feedback loop that is essential for T-cell leukemogenesis; this axis also compensates for the action of standard therapies in relapsed and refractory disease. Approach. To test this, we propose: 1) To determine the temporal requirement for STAT3 deletion in initiation, progression, and relapse in T-ALL by using a model of inducible genetic deletion of STAT3 in combination with a model of Notch-induced T-ALL. 2) To map how T-ALL development is affected by Notch/IL-7/STAT3/SKP2 signaling circuitry by using overexpression and gene silencing approaches to define the reciprocal regulation of Notch, STAT3, and SKP2. 3) To identify the impact of inhibiting Notch/STAT/SKP2 circuitry in relapsed T-ALL by testing both pre-clinical and clinical inhibitors of STAT signaling and SKP2 inhibitors in pre-clinical PDX models of T-ALL. Impact. Successful completion of this proposed work will: 1) define how cooperation between oncogenic signaling and the microenvironment affects therapy of relapsed and refractory T-ALL; 2) build a foundation for validating new molecular targets in relapsed and refractory T-ALL; 3) provide a proof-of-principle for an alternative strategy in which entire molecular circuits are considered during the development of therapies.


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 = $467,705 )
2026	2026	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Biology Research	000	4	2/18/2026	NON-COMPETING CONTINUATION	$467,705
														Subtotal = $467,705

Issue Date FY: 2025 ( Subtotal = $519,672 )
2025	2025	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Biology Research	000	3	2/19/2025	NON-COMPETING CONTINUATION	$467,705
2025	2025	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Biology Research	001	3	5/23/2025	NON-COMPETING CONTINUATION	$51,967
														Subtotal = $519,672

Issue Date FY: 2024 ( Subtotal = $488,414 )
2024	2024	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Biology Research	002	2	4/18/2024	NON-COMPETING CONTINUATION	$25,705
2024	2024	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Biology Research	001	2	2/15/2024	NON-COMPETING CONTINUATION	$462,709
2024	2023	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Biology Research	000	1	12/27/2023	NEW	$0
														Subtotal = $488,414

Issue Date FY: 2023 ( Subtotal = $512,292 )
2023	2023	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Biology Research	000	1	3/9/2023	NEW	$512,292
														Subtotal = $512,292

Grand Total All Awards = $1,988,083

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Targeting the Microenvironment/Oncogene Cooperation to treat poor prognosis T-ALL

Award Number: R01CA269740

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/09/2023

PERIOD OF PERFORMANCE END DATE: 02/29/2028

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer