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A novel lncRNA-responsive and xenobiotic receptor-mediated regulation of drug metabolism and disposition

Award Number: R01CA255196
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/01/2020
PERIOD OF PERFORMANCE END DATE: 11/30/2025

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A novel lncRNA-responsive and xenobiotic receptor-mediated regulation of drug metabolism and disposition - A novel lncRNA-responsive and xenobiotic receptor-mediated regulation of drug metabolism and disposition Abstract Drug metabolism and disposition are essential xenobiotic responses. The long non-coding RNAs (lncRNAs) are non-coding RNAs larger than 200 nucleotides (nt) in length and do not have protein-coding potentials. Although many of the biological functions of lncRNAs have been recognized, it is unclear whether and how lncRNAs can regulate the expression of drug-metabolizing enzymes and transporters and if so, whether the regulations are implicated in cancer chemo-resistance. Through integrative analysis of cancer non-coding genomic and high-through drug screening data of 505 cancer cell lines, our preliminary study have discovered and functionally characterized a group of ADME(drug absorption, distribution, metabolism, and excretion) chemo-resistance lncRNAs, including LINC00992, whose up-regulation is associated with resistance to more than 100 chemotherapy compounds and may regulate drug-metabolizing enzymes and transporters through interacting with xenobiotic nuclear receptor. We hypothesize that dysregulation of ADME chemo-resistance lncRNAs is an important contributor for the development of cancer chemo-resistance. Mechanistically, ADME chemo-resistance lncRNAs affect chemo-resistance through their regulation of drug-metabolizing enzymes and transporters that are responsible for the metabolism and disposition of chemotherapy drugs. We propose three specific aims to test our hypotheses: In Aim 1, we will perform bioinformatic analysis and molecularly clone of lncRNAs associated with cancer chemo-resistance and clinical prognosis. In Aim 2: we will functional characterize of ADME chemo-resistance lncRNAs, including LINC00992, using in vivo and in vitro cancer chemotherapy models. In Aim 3: we will determine the mechanism by which ADME chemo-resistance lncRNAs, including LINC00992, regulate the expression of drug-metabolizing enzymes and transporters. Chemotherapy remains a mainstay in the clinical management of cancer patients, but chemo-resistance is a major challenge to overcome. Understanding the novel lncRNA responsive and xenobiotic nuclear receptor- mediated chemo-resistance will help provide novel strategies to enhance therapeutic efficacy and avoid the development of chemo-resistance.


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 = $376,250 )
2025	2025	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Cancer Treatment Research	002	5	6/12/2025	NON-COMPETING CONTINUATION	$37,625
2025	2025	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Cancer Treatment Research	000	5	11/26/2024	NON-COMPETING CONTINUATION	$338,625
2025	2025	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Cancer Treatment Research	001	5	2/14/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $376,250

Issue Date FY: 2024 ( Subtotal = $357,438 )
2024	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Cancer Treatment Research	000	4	12/14/2023	NON-COMPETING CONTINUATION	$338,625
2024	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Cancer Treatment Research	001	4	4/16/2024	NON-COMPETING CONTINUATION	$18,813
														Subtotal = $357,438

Issue Date FY: 2023 ( Subtotal = $368,725 )
2023	2023	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Cancer Treatment Research	001	3	3/16/2023	NON-COMPETING CONTINUATION	$30,100
2023	2023	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Cancer Treatment Research	000	3	12/2/2022	NON-COMPETING CONTINUATION	$338,625
														Subtotal = $368,725

Issue Date FY: 2022 ( Subtotal = $353,169 )
2022	2022	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Cancer Treatment Research	001	2	5/10/2022	NON-COMPETING CONTINUATION	$28,831
2022	2022	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Cancer Treatment Research	000	2	11/30/2021	NON-COMPETING CONTINUATION	$324,338
														Subtotal = $353,169

Issue Date FY: 2021 ( Subtotal = $357,994 )
2021	2021	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Cancer Treatment Research	000	1	11/25/2020	NEW	$357,994
														Subtotal = $357,994

Grand Total All Awards = $1,813,576

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A novel lncRNA-responsive and xenobiotic receptor-mediated regulation of drug metabolism and disposition

Award Number: R01CA255196

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/01/2020

PERIOD OF PERFORMANCE END DATE: 11/30/2025

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