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Dysregulation of the Core Binding Factor Complex Inhibits Differentiation and Drives Group 4 Medulloblastoma

Award Number: R01CA159859
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/04/2011
PERIOD OF PERFORMANCE END DATE: 08/31/2027

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Dysregulation of the Core Binding Factor Complex Inhibits Differentiation and Drives Group 4 Medulloblastoma - PROJECT SUMMARY Medulloblastoma (MB) is the most common malignant brain tumor in children. Although aggressive treatments have improved outcomes, many MB patients still die of their disease, and survivors suffer severe long-term side effects from therapy. MB comprises four subgroups—WNT, Sonic hedgehog (SHH), Group 3 and Group 4—that differ in terms of molecular alterations, clinical characteristics and outcomes. We have some understanding of the molecular mechanisms underlying WNT, SHH and Group 3 tumors, but the pathways that drive Group 4 medulloblastoma (G4MB), the most prevalent form of the disease, remain a mystery. The lack of progress on G4MB has been due to a poor understanding of the genes, cells and processes leading to the disease. Recently, we identified a putative cell of origin for G4MB and a polyprotein complex whose members are mutated in the majority of G4 tumors. Our preliminary studies suggest that G4MB arises from a population of bipotential progenitor cells in the rhombic lip that gives rise to glutamatergic neurons, including unipolar brush cells (UBCs) and granule neurons (GNs). The fate of these progenitors is controlled by the Core Binding Factor (CBFA) complex, which contains transcriptional co-repressors, transcription factors, histone demethylases and histone methyltransferases. During early development, this complex maintains cells in a progenitor state. Later, when the complex is inactivated, cells undergo differentiation into GNs and UBCs. Alterations that prevent inactivation of this complex are predicted to prevent differentiation and maintain cells in a progenitor state. Importantly, we found that genetic alterations in members of this complex are among the most common driver events in G4MB. We hypothesize that mutations in the CBFA complex derail normal differentiation and constitute the core mutational route to G4MB, and that targeting this complex will improve outcomes for G4MB patients. To test this hypothesis, we will determine how the CBFA complex regulates differentiation and tumorigenesis, test whether alteration of the complex can drive G4MB tumorigenesis, and determine whether targeting the CBFA complex promotes differentiation and inhibits G4MB. Collectively, these studies will address fundamental questions regarding the origin and underlying mechanisms driving G4MB tumorigenesis, and probe newly revealed vulnerabilities to develop novel approaches to therapy for this devastating disease.


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 = $706,017 )
2025	2025	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Cancer Cause and Prevention Research	001	15	9/24/2025	NON-COMPETING CONTINUATION	$706,017
2025	2022	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Cause and Prevention Research	000	11	1/13/2025	COMPETING CONTINUATION	$0
														Subtotal = $706,017

Issue Date FY: 2024 ( Subtotal = $670,714 )
2024	2024	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Cancer Cause and Prevention Research	000	14	9/4/2024	NON-COMPETING CONTINUATION	$670,714
														Subtotal = $670,714

Issue Date FY: 2023 ( Subtotal = $706,017 )
2023	2023	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Cancer Cause and Prevention Research	003	13	9/15/2023	NON-COMPETING CONTINUATION	$14,121
2023	2023	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Cancer Cause and Prevention Research	002	13	9/1/2023	NON-COMPETING CONTINUATION	$691,896
2023	2022	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Cause and Prevention Research	000	11	5/17/2023	COMPETING CONTINUATION	-$643,914
2023	2022	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Cancer Cause and Prevention Research	001	12	5/17/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$643,914
														Subtotal = $706,017

Issue Date FY: 2022 ( Subtotal = $803,132 )
2022	2022	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Cause and Prevention Research	001	11	9/1/2022	COMPETING CONTINUATION	$803,132
2022	2021	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Cause and Prevention Research	000	10	6/7/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $803,132

Issue Date FY: 2021 ( Subtotal = $746,845 )
2021	2021	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Cause and Prevention Research	000	10	1/26/2021	NON-COMPETING CONTINUATION	$746,845
														Subtotal = $746,845

Issue Date FY: 2020 ( Subtotal = $746,845 )
2020	2020	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Cause and Prevention Research	000	9	1/16/2020	NON-COMPETING CONTINUATION	$746,845
														Subtotal = $746,845

Issue Date FY: 2019 ( Subtotal = $724,440 )
2019	2019	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Cause and Prevention Research	000	8	2/4/2019	NON-COMPETING CONTINUATION	$724,440
														Subtotal = $724,440

Issue Date FY: 2018 ( Subtotal = $746,845 )
2018	2018	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Cause and Prevention Research	000	7	1/16/2018	NON-COMPETING CONTINUATION	$672,161
2018	2018	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Cause and Prevention Research	001	7	5/23/2018	NON-COMPETING CONTINUATION	$74,684
														Subtotal = $746,845

Issue Date FY: 2017 ( Subtotal = $794,344 )
2017	2017	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Cause and Prevention Research	001	6	3/2/2017	COMPETING CONTINUATION	$153,750
2017	2017	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Cause and Prevention Research	000	6	1/30/2017	COMPETING CONTINUATION	$640,594
														Subtotal = $794,344

Issue Date FY: 2015 ( Subtotal = $617,747 )
2015	2015	SANFORD-BURNHAM MEDICAL RESEARCH INSTITUTE	10901 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Cause and Prevention Research	000	5	3/11/2015	NON-COMPETING CONTINUATION	$617,747
														Subtotal = $617,747

Issue Date FY: 2014 ( Subtotal = $599,474 )
2014	2014	SANFORD-BURNHAM MEDICAL RESEARCH INSTITUTE	10901 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Cause and Prevention Research	000	4	5/6/2014	NON-COMPETING CONTINUATION	$599,474
														Subtotal = $599,474

Issue Date FY: 2013 ( Subtotal = $581,217 )
2013	2013	SANFORD-BURNHAM MEDICAL RESEARCH INSTITUTE	10901 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Cause and Prevention Research	000	3	3/12/2013	NON-COMPETING CONTINUATION	$278,242
2013	2013	SANFORD-BURNHAM MEDICAL RESEARCH INSTITUTE	10901 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Cause and Prevention Research	001	3	7/3/2013	NON-COMPETING CONTINUATION	$302,975
														Subtotal = $581,217

Issue Date FY: 2012 ( Subtotal = $618,678 )
2012	2012	SANFORD-BURNHAM MEDICAL RESEARCH INSTITUTE	10901 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Cause and Prevention Research	000	2	4/4/2012	NON-COMPETING CONTINUATION	$618,678
														Subtotal = $618,678

Issue Date FY: 2011 ( Subtotal = $640,572 )
2011	2011	SANFORD-BURNHAM MEDICAL RESEARCH INSTITUTE	10901 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Cause and Prevention Research	000	1	4/4/2011	NEW	$640,572
														Subtotal = $640,572

Grand Total All Awards = $9,702,887

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Dysregulation of the Core Binding Factor Complex Inhibits Differentiation and Drives Group 4 Medulloblastoma

Award Number: R01CA159859

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/04/2011

PERIOD OF PERFORMANCE END DATE: 08/31/2027

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