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Targeting the mutant promoter of Telomerase Reverse Transcriptase (TERT)

Award Number: R01CA275078
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2025
PERIOD OF PERFORMANCE END DATE: 07/31/2027

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Targeting the mutant promoter of Telomerase Reverse Transcriptase (TERT) - PROJECT SUMMARY TElomerase Reverse Transcriptase (TERT) is rate limiting in maintenance of telomere length by telomerase and also has telomere independent functions such as regulating cell growth. We showed TERT promoter mutations (mutTERT) occur in ~70% of Bladder Cancers (BC), most commonly at -146bp and −124bp which generate an identical 11 bp sequence that is recognized by a common upstream signaling mechanism. These mutations drive TERT overexpression, maintain BC growth and are associated with poor BC patient prognosis. These data led us to develop a panel of innovative assays specifically designed to identify, through a chemical library screening approach, small molecules that reduce TERT expression from mutTERT but not wtTERT. Discovery of such compounds is a first step in attaining our overall goal of developing a drug that is selectively toxic for BC cells, while having minimal toxicity on normal stem cells, which require TERT for self-renewal. Preliminary Data: Using CRISPR, we constructed BC cells expressing HiBiT or EGFP reporters downstream of mutant or wt TERT promoters. We validated these assays by showing that siRNA-mediated depletion of GABPA, a regulator of mutant promoter expression, selectively reduced mutTERT as monitored by HiBiT or EGFP. We deployed our mutTERT-HiBiT assay in an High-Throughput Screen (HTS) pilot screen of 605 kinase inhibitors and found 23 hits that reduced mutTERT-HiBiT. Among these were inhibitors to known drivers of TERT expression such as Aurora Kinase A, as well as inhibitors that were mutTERT selective, all of which targeted mTOR. This data leads us to the Hypothesis that small molecules that specifically suppress TERT expression driven by a mutant promoter can be identified by a phenotypic screen. Three Specific Aims test this hypothesis. In Aim 1, an HTS screen of a 350K chemical library will be conducted using a mutTERT-HiBiT reporter assay to identify compounds that decrease TERT expression driven off the mutant promoter at 16hrs. Hits will then be confirmed, and counter screened to remove those with unwanted activities. In Aim 2, priority hits will be purchased, reconfirmed in the primary assay and their selectivity to effect mutant over wt TERT evaluated head to head deploying EGFP reporter assays in BC cells and by allele-specific qPCR. An iterative analog-by-catalog (ABC) approach will be used to establish nascent structure-activity relationship of hit scaffolds and improve potency and selectivity. In Aim 3, the best hit from each scaffold that meet a set of rigorous potency and selectivity criteria will be selected as a probe and characterized in multiple assays to map their activity on downstream effects of TERT. These assays use a panel of BC and non-BC cell lines with and w/o TERT promoter mutations to determine the probes’ effects on: 1) downstream TERT-related gene transcription via evaluation of our TERT Expression Signature (TES); 2) telomere length quantitation; 3) Telomerase-dependent and independent TERT functions including cell growth. Future Directions: We set the stage for novel drugs targeting cancer specific, mutTERT driven, telomerase activity in patients with BC or other TERT-driven malignancies.


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 = $631,711 )
2025	2025	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Cancer Treatment Research	001	3	8/28/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$631,711
2025	2024	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Cancer Treatment Research	000	2	8/28/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $631,711

Issue Date FY: 2024 ( Subtotal = $563,904 )
2024	2024	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Cancer Treatment Research	000	2	7/1/2024	NON-COMPETING CONTINUATION	$563,904
														Subtotal = $563,904

Issue Date FY: 2023 ( Subtotal = $772,180 )
2023	2023	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Cancer Treatment Research	000	1	9/18/2023	NEW	$772,180
														Subtotal = $772,180

Grand Total All Awards = $1,967,795

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Targeting the mutant promoter of Telomerase Reverse Transcriptase (TERT)

Award Number: R01CA275078

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2025

PERIOD OF PERFORMANCE END DATE: 07/31/2027

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