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Role of PTEN and PI-3 Kinase in Medulloblastomagenesis

Award Number: R01CA172513
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/03/2017
PERIOD OF PERFORMANCE END DATE: 02/28/2025

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Role of PTEN and PI-3 Kinase in Medulloblastomagenesis - Medulloblastoma (MB) is a cancer arising within the cerebellum, and is the most common malignant brain tumor in children. Current care which relies on radiotherapy and chemotherapy, only cures 60% of patients, and has serious long-term neurocognitive sequelae in survivors, hence the unmet medical need to develop more efficacious, less toxic therapies for this disease. Malignant brain tumors including the sonic hedgehog (SHH) subgroup of MB are driven by tumor propagating cells (cancer stem cells; CSCs) expressing the cell surface glycoprotein CD15. A knowledge gap exist in that the molecular mechanisms controlling CSC and non CSC phenotypes are poorly delineated. The central hypothesis for this proposal is that the PI3K/PTEN signaling axis exerts control over the CSC phenotype in SHH MB and hence represents a target for therapeutic exploitation with PI3K inhibitors. Importantly, work from our laboratory has demonstrated that PTEN expression is suppressed in the CSC compartment of the Smo transgenic (SHH pathway) mouse model of MB. The clinical relevance of the PTEN deficient Smo transgene mouse model is highlighted by our finding that PTEN expression is lost in human MB, and the observation that PTEN loss correlates with poor survival in MB patients. Our grant proposal, guided by our preliminary data proposes 3 specific aims: 1) Determine if genetic alterations in PTEN or specific isoforms of PI3K are necessary and/or sufficient for SHH driven CSC phenotype and tumorigenesis 2) Utilize high throughput kinome library screens and genomic profiling of mouse and human MB CSCs and non CSCs to identify a molecular signature and synthetic lethality effects which will predict sensitivity or resistance to a PI-3K inhibitor. 3) Elucidate the epigenetic mechanism by which PTEN is regulated in the CSC compartment in human SHH PDX models and the SmoTg GEMM model; Focused on PTEN specific miRNA regulatory networks. We will use the Math1creER recombinase to generate the conditional deletion of PTEN, p110 and/or p110 in normal cerebellar granule neuronal precursor cells (GNPs) or in the CSC compartment and determine the effects on the development of MB and CSC phenotype. In Aim 2, we will expand upon our recent report demonstrating the activity of the PI3K inhibitor, BKM120 against CSCs to include synthetic lethality screens with other targeted agents and conventional chemotherapeutics. An innovative component of our application is the recent discovery of a novel miRNA network which epigenetically regulates PTEN in the CSC compartment which is associated with the CSC phenotype. This observation will be explored in our GEMMs , MB PDX models and in human MB tumor samples to determine the role of these miRNAs in the regulation of PTEN, PI3K and the CSC phenotypes including tumor initiating activity. The proposed work is significant in that it will: 1) establish a role for PTEN, p110 and p110 in CSC biology in MB 2) identify novel synthetic lethalities in combination with PI3K inhibition in MB CSCs and 3) elucidate a role for miRNA networks in the control of PTEN and CSC phenotypes.


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 = -$2,178 )
2025	2023	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Cancer Biology Research	000	6	5/19/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$2,178
														Subtotal = -$2,178

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2023	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Cancer Biology Research	001	6	1/17/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$47,543
2024	2022	THE CHARLOTTE-MECKLENBURG HOSPITAL AUTHORITY	1000 BLYTHE BLVD	CHARLOTTE	NC	28203	MECKLENBURG	USA	Cancer Biology Research	000	5	1/17/2024	NON-COMPETING CONTINUATION	-$47,543
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $309,307 )
2023	2023	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Cancer Biology Research	003	6	5/15/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$309,307
2023	2022	CHARLOTTE-MECKLENBURG HOSPITAL AUTHORITY, THE	1000 BLYTHE BOULEVARD	CHARLOTTE	NC	28203	MECKLENBURG	USA	Cancer Biology Research	002	5	5/15/2023	NON-COMPETING CONTINUATION	$0
2023	2022	CHARLOTTE-MECKLENBURG HOSPITAL AUTHORITY, THE	1000 BLYTHE BOULEVARD	CHARLOTTE	NC	28203	MECKLENBURG	USA	Cancer Biology Research	001	5	3/10/2023	NON-COMPETING CONTINUATION	$0
2023	2019	CHARLOTTE-MECKLENBURG HOSPITAL AUTHORITY, THE	1000 BLYTHE BOULEVARD	CHARLOTTE	NC	28203	MECKLENBURG	USA	Cancer Biology Research	000	4	3/10/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $309,307

Issue Date FY: 2022 ( Subtotal = $309,307 )
2022	2022	CHARLOTTE-MECKLENBURG HOSPITAL AUTHORITY, THE	1000 BLYTHE BOULEVARD	CHARLOTTE	NC	28203	MECKLENBURG	USA	Cancer Biology Research	001	5	8/10/2022	NON-COMPETING CONTINUATION	$309,307
2022	2019	CHARLOTTE-MECKLENBURG HOSPITAL AUTHORITY, THE	1000 BLYTHE BOULEVARD	CHARLOTTE	NC	28203	MECKLENBURG	USA	Cancer Biology Research	000	4	1/3/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $309,307

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2019	CHARLOTTE-MECKLENBURG HOSPITAL AUTHORITY, THE	1000 BLYTHE BOULEVARD	CHARLOTTE	NC	28203	MECKLENBURG	USA	Cancer Biology Research	000	4	8/26/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $0 )
2020	2019	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Cancer Biology Research	000	3	8/6/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$301,211
2020	2019	CHARLOTTE-MECKLENBURG HOSPITAL AUTHORITY, THE	1000 BLYTHE BOULEVARD	CHARLOTTE	NC	28203	MECKLENBURG	USA	Cancer Biology Research	001	4	8/6/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$301,211
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $301,211 )
2019	2019	UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Cancer Biology Research	001	3	7/15/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$301,211
2019	2018	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Biology Research	002	2	7/24/2019	NON-COMPETING CONTINUATION	$0
2019	2018	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Biology Research	000	2	7/15/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $301,211

Issue Date FY: 2018 ( Subtotal = $315,619 )
2018	2018	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Biology Research	000	2	5/8/2018	NON-COMPETING CONTINUATION	$315,619
														Subtotal = $315,619

Issue Date FY: 2017 ( Subtotal = $315,619 )
2017	2017	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Biology Research	000	1	7/3/2017	NEW	$315,619
														Subtotal = $315,619

Grand Total All Awards = $1,548,885

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Role of PTEN and PI-3 Kinase in Medulloblastomagenesis

Award Number: R01CA172513

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/03/2017

PERIOD OF PERFORMANCE END DATE: 02/28/2025

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