Tuesday, July 1, 2025 7/1/2025

Therapeutic potential of antitumorigenic soluble MET variants induced by splicing interference

Award Number: R01CA219689
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/08/2017
PERIOD OF PERFORMANCE END DATE: 11/30/2024

Group Awards By:

View Award Description

Therapeutic potential of antitumorigenic soluble MET variants induced by splicing interference - Gastric cancer (GC) is the third leading cause of cancer-related death worldwide, with a median overall survival limited to 1 year for advanced disease. A significant fraction of GC is due to aberrant HGF/MET axis signaling, most commonly due to MET receptor gene amplification. However, no effective MET-targeted therapies are currently available, with resistance frequently emerging rapidly, following an initial response. The development of additional, alternative approaches to effectively inhibit MET and other RTKs is therefore a necessity for a cure to be found. We recently identified a number of novel soluble decoy RTKs isoforms (sdRTKs), generated by an alternative splicing/intronic polyadenylation (IPA) mechanism, which can act as potent natural inhibitors of RTK signaling. We developed an antisense-based method to specifically and effectively induce IPA usage and sdRTKs expression in vitro and in vivo. These compounds identify a new class of drugs that carry the advantage of simultaneously knocking down the pathological targets while introducing natural dominant-negative isoforms, thus greatly increasing their efficacy. We will apply this antisense-based approach to promote IPA and stimulate the expression of dominant-negative, endogenous soluble decoy MET inhibitory variants (sdMET), normally expressed at low levels. sdMETs encode the extracellular ligand-binding and dimerization domains, but lack the transmembrane and the intracellular kinase domains. We hypothesize that sdMET-inducing compounds suppress HGF/MET signaling by a three fold-mechanism: A) direct removal of full-length MET receptor mRNAs, B) binding and sequestration of MET ligand (HGF), and C) non- productive hetero-dimerization with residual MET receptors. We further posit that, as the resulting products are secreted from targeted cells, they affect signaling in both targeted and neighboring cells alike and interfere with paracrine and autocrine loops, thus wielding an amplified effect. Since the mechanism of action is different from that of current therapies, this strategy should be effective in all tumors that rely on HGF/MET signaling, including relapsing ones. To this end, we will pursue the following specific aims: 1) Identification and characterization of effective inhibitory sdMET splicing variants. 2) Reprogramming of MET splicing/polyadenylation in gastric cancer cells by antisense-based splicing redirection compounds that induce IPA. 3) Assessment of the therapeutic potential of sdMET-inducing antisense oligonucleotides in multiple gastric cancer models, in vitro and in vivo. These results will be important for the development of powerful novel investigative tools and therapeutic approaches in any cancer type where the HGF/MET signaling axis plays a determinant role. The findings emerging from this study will be broadly translatable to disease dependent on other RTKs and oncogenes, in gastric cancer and other tumors. Analogous compounds can in fact be similarly designed to directly target other RTKs or other targets responsible for drug-resistance and pathological signaling, or to overcome various mechanisms of 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 = $0 )
2025	2023	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Cancer Treatment Research	000	6	3/28/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2023	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Cancer Treatment Research	001	6	2/8/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$112,713
2024	2022	RUTGERS, THE STATE UNIVERSITY	3 RUTGERS PLZ	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Cancer Treatment Research	000	5	2/8/2024	NON-COMPETING CONTINUATION	-$112,713
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $352,564 )
2023	2023	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Cancer Treatment Research	001	6	1/30/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$352,564
2023	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Cancer Treatment Research	000	5	1/30/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $352,564

Issue Date FY: 2022 ( Subtotal = $352,564 )
2022	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Cancer Treatment Research	001	5	5/19/2022	NON-COMPETING CONTINUATION	$28,781
2022	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Cancer Treatment Research	000	5	11/19/2021	NON-COMPETING CONTINUATION	$323,783
														Subtotal = $352,564

Issue Date FY: 2021 ( Subtotal = $1 )
2021	2021	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Cancer Treatment Research	000	4	1/28/2021	NON-COMPETING CONTINUATION	$1
														Subtotal = $1

Issue Date FY: 2020 ( Subtotal = $359,759 )
2020	2020	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Cancer Treatment Research	001	3	1/13/2020	NON-COMPETING CONTINUATION	$35,977
2020	2020	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Cancer Treatment Research	000	3	11/26/2019	NON-COMPETING CONTINUATION	$323,782
														Subtotal = $359,759

Issue Date FY: 2019 ( Subtotal = $348,965 )
2019	2019	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Cancer Treatment Research	000	2	12/19/2018	NON-COMPETING CONTINUATION	$348,965
														Subtotal = $348,965

Issue Date FY: 2018 ( Subtotal = $372,340 )
2018	2018	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Cancer Treatment Research	002	1	2/14/2018	NEW	$372,340
2018	2018	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	83 SOMERSET ST	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Cancer Treatment Research	000	1	12/8/2017	NEW	$372,340
2018	2018	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Cancer Treatment Research	001	1	2/9/2018	NEW	-$372,340
														Subtotal = $372,340

Grand Total All Awards = $1,786,193

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Therapeutic potential of antitumorigenic soluble MET variants induced by splicing interference

Award Number: R01CA219689

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/08/2017

PERIOD OF PERFORMANCE END DATE: 11/30/2024

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer