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Elucidating Critical Dependencies Underlying Therapeutic Evasion in Philadelphia Chromosome-like Acute Lymphoblastic Leukemia

Award Number: K08CA273531
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 01/05/2024
PERIOD OF PERFORMANCE END DATE: 12/31/2027

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Elucidating Critical Dependencies Underlying Therapeutic Evasion in Philadelphia Chromosome-like Acute Lymphoblastic Leukemia - PROJECT SUMMARY/ABSTRACT This mentored career development award proposal will facilitate my career goal to become an independent translational researcher using advances in experimental genomics and bioinformatics to develop improved precision medicine therapies for children with difficult-to-cure cancers. During the 5-year training period I plan to acquire critical skills in computational biology and pursue additional didactic training in transcriptional regulation, death pathways, single cell analyses, and early-phase clinical trial design. The proposed studies and training will be completed under the co-mentorship of Dr. Kai Tan and Dr. Sarah Tasian, both internationally recognized leaders with complementary expertise in systems and single cell biology and in translational leukemia research, respectively. My multi-disciplinary Advisory Committee is composed of world-renowned scientists who have extensive mentoring experience and diverse expertise, including Drs. Chi Dang, Nancy Speck, John Maris, and Xiaolu Yang. The scientific proposal is aimed at elucidating critical dependencies that synergize with kinase pathway oncogene addiction in Philadelphia chromosome-like (Ph-like) acute lymphoblastic leukemia (ALL), a kinase-driven leukemia with dismal outcomes. Ph-like ALL comprises 15-40% of childhood and adult ALL cases and is associated with extremely high relapse rates and very poor overall survival. We observed in preclinical Ph-like ALL models that treatment with the JAK inhibitor ruxolitinib has incomplete efficacy and also resulted in global gene expression changes. Thus, combination therapy approaches that effectively target key therapeutic escape mechanisms are needed. Additionally, single-cell variability in Ph-like ALL that may drive targeted therapy resistance is unknown. I hypothesize that ruxolitinib treatment in JAK/STAT pathway-altered Ph-like ALL cells leads to rewiring of the gene regulatory network at transcriptional and epigenetic levels (likely mediated by c-MYC), resulting in cell cycle arrest and apoptotic priming amenable to co-targeting. I propose in Aim 1 to model patient leukemia reponse to kinase inhibition in vivo and to identify transcriptional regulatory network changes during chronic ruxolitinib treatment with subsequent functional validation. This represents an unbiased approach to identifying unknown oncogenic dependencies. In Aim 2, I will use single-cell techniques to examine genetic and non-genetic sub-populational changes during targeted drug perturbation over time, then to characterize and target resistant cell states. These studies will form the basis for developing rational combinations of molecularly targeted therapies to improve cure rates for patients with Ph-like ALL. In summary, I will benefit from the exceptional interdisciplinary expertise and track-record of my mentors and Advisory Committee, as well as the rich intellectual environment and scientific resources available at CHOP and Penn, which provide an ideal setting in which to conduct cutting-edge omics analyses for eventual clinical translation. These research and training efforts will help me realize my ultimate goal to translate “big data” into clinically relevant cures for children with cancer.


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 = $184,541 )
2026	2026	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cancer Research Manpower	000	4	12/22/2025	NON-COMPETING CONTINUATION	$166,087
2026	2026	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cancer Research Manpower	001	4	4/16/2026	NON-COMPETING CONTINUATION	$18,454
														Subtotal = $184,541

Issue Date FY: 2025 ( Subtotal = $184,541 )
2025	2025	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cancer Research Manpower	001	3	12/11/2024	NON-COMPETING CONTINUATION	$184,541
2025	2022	THE CHILDREN'S HOSPITAL OF PHILADELPHIA	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Research Manpower	000	1	11/21/2024	NEW	$0
														Subtotal = $184,541

Issue Date FY: 2024 ( Subtotal = $184,541 )
2024	2024	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cancer Research Manpower	001	2	1/5/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$184,541
2024	2022	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Research Manpower	000	1	1/5/2024	NEW	$0
														Subtotal = $184,541

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2022	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Research Manpower	000	1	9/8/2023	NEW	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $184,541 )
2022	2022	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Research Manpower	000	1	9/8/2022	NEW	$184,541
														Subtotal = $184,541

Grand Total All Awards = $738,164

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Elucidating Critical Dependencies Underlying Therapeutic Evasion in Philadelphia Chromosome-like Acute Lymphoblastic Leukemia

Award Number: K08CA273531

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 01/05/2024

PERIOD OF PERFORMANCE END DATE: 12/31/2027

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