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Discovering and Exploiting Mechanisms of Neuroblastoma Therapy Resistance

Award Number: P01CA217959
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/18/2017
PERIOD OF PERFORMANCE END DATE: 02/28/2029

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Discovering and Exploiting Mechanisms of Neuroblastoma Therapy Resistance - OVERALL SUMMARY/ABSTRACT This is a revised competitive renewal application for a Program focused on high-risk neuroblastoma (NB), a diverse and enigmatic malignancy arising from the developing sympathetic nervous system that remains lethal in 50% of patients despite intensive multi-modal therapy. The primary goal of this multi-institutional and multi- disciplinary Program is to achieve improved outcomes for patients with high-risk NB by 1) discovering basic mechanisms of de novo and acquired resistance to modern therapies; 2) uncovering targetable vulnerabilities driving resistance; and 3) translating these insights into evidence-based clinical trials. The Program has been productive, with important basic, translational, and clinical research achievements over the past 5.5 years. The basic structure of the Program remains the same, with four Projects focusing on interrelated fundamental problems in the broad fields of epigenomics, tumor microenvironment, and immuno-oncology. The central hypothesis is that high-risk NBs evolve to evade therapeutic interventions but that these resistance mechanisms can be targeted therapeutically. The motivation for the proposed research is the urgent need to improve survival of patients with high-risk NB, and to decrease treatment-related morbidities. The four proposed Projects will each address the three Specific Aims of the overall Program: 1) discover mechanisms of NB therapy resistance; 2) discover tumor-intrinsic and -extrinsic therapeutic vulnerabilities imparted by therapy resistance; and 3) develop readily translatable therapeutic strategies to exploit de novo and acquired resistance mechanisms and molecular vulnerabilities. The Projects will each be supported by two Cores: A) Administrative core; B) Translational, statistical, and clinical trials core. Unique to the Program is the New Approaches to NB Therapy (NANT) consortium integrated into Core B now in its 22nd year. A major goal of the NANT is to prioritize new therapies from our Projects for Phase 1 and 2 clinical trials in the high-risk NB relapse population, with the goal of moving these to Phase 3 testing in newly diagnosed patients. The Program is responsible for the two targeted investigational agents currently being tested in an ongoing Children’s Oncology Group Phase 3 trial. The NANT also provides a unique resource of therapy resistant tumors and other biospecimens for Project investigators. Importantly, all Projects have clear milestones to deliver one or more clinical trial to the NANT, with Project specific studies designed to provide the portfolio of nonclinical data required for efficient translation to the refractory NB patient population. This highly integrated Program proposes a variety of innovative experimental strategies to uncover basic mechanisms of oncogenesis and therapy resistance, but is steadfastly translational, as the investigative team is constituted of physicians who care for children with this disease. The significance of the proposed Program is the continued discovery of fundamental mechanisms of cancer therapy resistance leading to substantively improved probability of cure coupled with reduced therapy-related morbidity for children, adolescents and adults afflicted with high-risk NB.


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 = $2,202,503 )
2025	2025	THE CHILDREN'S HOSPITAL OF PHILADELPHIA	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Treatment Research	001	7	3/28/2025	NON-COMPETING CONTINUATION	$2,202,503
2025	2021	THE CHILDREN'S HOSPITAL OF PHILADELPHIA	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Treatment Research	000	5	2/20/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $2,202,503

Issue Date FY: 2024 ( Subtotal = $2,545,516 )
2024	2024	THE CHILDREN'S HOSPITAL OF PHILADELPHIA	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Treatment Research	000	6	3/5/2024	COMPETING CONTINUATION	$2,545,516
														Subtotal = $2,545,516

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2021	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Treatment Research	000	5	9/1/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $2,085,090 )
2021	2021	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Treatment Research	003	5	8/31/2021	NON-COMPETING CONTINUATION	$2,085,090
2021	2020	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Treatment Research	002	4	3/8/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$96,202
2021	2020	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Treatment Research	000	4	10/22/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2021	2019	CHILDRENS HOSPITAL LOS ANGELES	4650 SUNSET BLVD	LOS ANGELES	CA	90027	LOS ANGELES	USA	Cancer Treatment Research	001	3	3/8/2021	NON-COMPETING CONTINUATION	-$96,202
														Subtotal = $2,085,090

Issue Date FY: 2020 ( Subtotal = $2,218,284 )
2020	2020	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Treatment Research	001	4	9/16/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$2,218,284
2020	2019	CHILDRENS HOSPITAL LOS ANGELES	4650 SUNSET BLVD	LOS ANGELES	CA	90027	LOS ANGELES	USA	Cancer Treatment Research	000	3	9/16/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $2,218,284

Issue Date FY: 2019 ( Subtotal = $2,078,428 )
2019	2019	CHILDRENS HOSPITAL LOS ANGELES	4650 SUNSET BLVD	LOS ANGELES	CA	90027	LOS ANGELES	USA	Cancer Treatment Research	002	3	9/13/2019	NON-COMPETING CONTINUATION	$2,078,428
2019	2018	CHILDRENS HOSPITAL LOS ANGELES	4650 SUNSET BLVD	LOS ANGELES	CA	90027	LOS ANGELES	USA	Cancer Treatment Research	001	2	1/30/2019	NON-COMPETING CONTINUATION	$0
2019	2017	CHILDRENS HOSPITAL LOS ANGELES	4650 SUNSET BLVD	LOS ANGELES	CA	90027	LOS ANGELES	USA	Cancer Treatment Research	000	1	1/29/2019	NEW	$0
														Subtotal = $2,078,428

Issue Date FY: 2018 ( Subtotal = $2,171,238 )
2018	2018	THE CHILDRENS HOSPITAL LOS ANGELES	4650 W SUNSET BLVD	LOS ANGELES	CA	90027	LOS ANGELES	USA	Cancer Treatment Research	000	2	9/14/2018	NON-COMPETING CONTINUATION	$2,171,238
														Subtotal = $2,171,238

Issue Date FY: 2017 ( Subtotal = $2,296,936 )
2017	2017	THE CHILDRENS HOSPITAL LOS ANGELES	4650 W SUNSET BLVD	LOS ANGELES	CA	90027	LOS ANGELES	USA	Cancer Treatment Research	000	1	9/18/2017	NEW	$2,296,936
														Subtotal = $2,296,936

Grand Total All Awards = $15,597,995

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Discovering and Exploiting Mechanisms of Neuroblastoma Therapy Resistance

Award Number: P01CA217959

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/18/2017

PERIOD OF PERFORMANCE END DATE: 02/28/2029

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