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Regulation of Amino-acid Transport in Human Gliomas

Award Number: R01CA227149
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/01/2018
PERIOD OF PERFORMANCE END DATE: 11/30/2024

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Regulation of Amino-acid Transport in Human Gliomas - Project Summary/Abstract Glutamate (Glu) has emerged as an important molecule in the biology of malignant brain tumors, specifically gliomas1. Glu can reach toxic concentrations in peritumoral tissue, contributing to enhanced tumor growth and invasion, as well as peritumoral edema, excitotoxicity, and seizures2. Mediated by the cystine-glutamate exchanger, System xc- (SXC), Glu uptake supplies cystine for production of the intracellular antioxidant glutathione (GSH). GSH protects cells from endogenous and exogenous stressors3, including radiation and chemotherapy. GSH over-production confers resistance to radiation4-6 and ferroptosis7, an iron-dependent form of programmed cell death. In previous studies, we show that xCT, the catalytic subunit of SXC, is variably expressed among glioma patients8. Approximately half of tumors show elevated xCT expression and present with seizures and Glu excitotoxicity, whereas gliomas with low xCT expression do not. Similarly, in a clinical pilot study, we show that pharmacological inhibition of SXC reduces Glu release only in gliomas with elevated xCT expression8. Based on recent, data we now hypothesize that differences in the expression and function of SXC are due to its transcriptional and co-receptor regulation. We hypothesize that xCT is transcriptionally regulated by p53, with wild type p53 acting as transcriptional suppressor. As p53 is mutated or deleted in many gliomas, this alteration would result in aberrant overexpression of xCT, explaining the observed Glu release and downstream pathophysiology. We also hypothesize, based on preliminary findings, that the activity of SXC is regulated by extracellular matrix components activating the hyaluronic acid receptor CD44, which serves as a functional co-receptor for SXC. Both p53 and CD44 activity can alter glioma biology and determine peritumoral excitotoxicity, seizures, invasion, and growth. The proposed studies are significant and clinically relevant as they explore new strategies to interfere with the abnormal glutamate biology of gliomas at a transcription and expression level. This proposal provides superior strategies to currently available pharmacological inhibitors for SXC, which have poor specificity and bioavailability. Moreover, the expression of p53 and CD44 may have predictive value regarding potential personalized treatments for this subgroup of glioma in the future.


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 )
2025	2023	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cancer Biology Research	000	6	3/28/2025	NON-COMPETING CONTINUATION	-$2
														Subtotal = -$2

Issue Date FY: 2023 ( Subtotal = $362,043 )
2023	2023	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cancer Biology Research	000	6	11/17/2022	NON-COMPETING CONTINUATION	$332,488
2023	2023	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cancer Biology Research	001	6	3/15/2023	NON-COMPETING CONTINUATION	$29,555
														Subtotal = $362,043

Issue Date FY: 2022 ( Subtotal = $362,043 )
2022	2022	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cancer Biology Research	000	5	11/4/2021	NON-COMPETING CONTINUATION	$332,487
2022	2022	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cancer Biology Research	001	5	4/28/2022	NON-COMPETING CONTINUATION	$29,556
														Subtotal = $362,043

Issue Date FY: 2021 ( Subtotal = $364,184 )
2021	2021	VIRGINIA POLYTECHNIC INSTITUTE AND STATE UNIVERSITY	300 TURNER ST NW STE 4200	BLACKSBURG	VA	24061	MONTGOMERY	USA	Cancer Biology Research	001	3	1/22/2021	NON-COMPETING CONTINUATION	$18,106
2021	2021	VIRGINIA POLYTECHNIC INSTITUTE AND STATE UNIVERSITY	300 TURNER ST NW STE 4200	BLACKSBURG	VA	24061	MONTGOMERY	USA	Cancer Biology Research	004	3	8/4/2021	NON-COMPETING CONTINUATION	-$18,738
2021	2021	VIRGINIA POLYTECHNIC INSTITUTE AND STATE UNIVERSITY	300 TURNER ST NW STE 4200	BLACKSBURG	VA	24061	MONTGOMERY	USA	Cancer Biology Research	002	3	6/17/2021	NON-COMPETING CONTINUATION	-$221,926
2021	2021	VIRGINIA POLYTECHNIC INSTITUTE AND STATE UNIVERSITY	300 TURNER ST NW STE 4200	BLACKSBURG	VA	24061	MONTGOMERY	USA	Cancer Biology Research	000	3	12/24/2020	NON-COMPETING CONTINUATION	$343,997
2021	2021	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cancer Biology Research	003	4	6/18/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$224,007
2021	2021	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cancer Biology Research	005	4	8/4/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$18,738
														Subtotal = $364,184

Issue Date FY: 2020 ( Subtotal = $362,341 )
2020	2020	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW STE 4200	BLACKSBURG	VA	24061	MONTGOMERY	USA	Cancer Biology Research	001	2	1/16/2020	NON-COMPETING CONTINUATION	$36,235
2020	2020	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW STE 4200	BLACKSBURG	VA	24061	MONTGOMERY	USA	Cancer Biology Research	000	2	12/2/2019	NON-COMPETING CONTINUATION	$326,106
														Subtotal = $362,341

Issue Date FY: 2019 ( Subtotal = $362,569 )
2019	2019	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW STE 4200	BLACKSBURG	VA	24061	MONTGOMERY	USA	Cancer Biology Research	000	1	11/30/2018	NEW	$362,569
														Subtotal = $362,569

Grand Total All Awards = $1,813,178

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Regulation of Amino-acid Transport in Human Gliomas

Award Number: R01CA227149

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/01/2018

PERIOD OF PERFORMANCE END DATE: 11/30/2024

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