Sunday, July 6, 2025 7/6/2025

Preclinical Testing of PI3K Inhibitors for Vestibular Schwannomas

Award Number: R01DC017264
ORGANIZATION: NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2018
PERIOD OF PERFORMANCE END DATE: 06/30/2025

Group Awards By:

View Award Description

Preclinical Testing of PI3K Inhibitors for Vestibular Schwannomas - ABSTRACT Mutations in the merlin (NF2) tumor suppressor gene cause the benign tumor disorder, Neurofibromatosis type 2 (NF2). This disorder predisposes individuals to develop bilateral vestibular schwannomas (VS) that cause progressive hearing loss and can cause life-threatening brainstem compression. Because surgical removal of a VS often causes deafness, facial paralysis, and imbalance, there is a need to develop drug therapies to slow or prevent VS growth and preserve nerve function. We have worked to establish an in vitro and in vivo drug screening platform to identify novel compounds as well as FDA-approved drugs that can be developed/repurposed for VS therapies. Toward this goal, we have created mouse and human merlin-deficient Schwann cell lines and optimized their use in 384-well high-throughput and high-content assays in order to screen large compound/drug libraries using robotic platforms. This approach identified several phosphoinositide- 3 kinase (PI3K) inhibitors that selectively reduce viability of mouse merlin-deficient compared to wild-type Schwann cells with nanomolar IG50. This initial finding was confirmed in human merlin-deficient Schwann cell lines for multiple PI3K, dual PI3K/mTOR and PI3K/HDAC inhibitors. Because PI3K plays a critical role in cell proliferation, survival, and invasion, there are currently 15 different PI3K inhibitors in clinical trials for various blood cancers and solid tumors. The first in class PI3K inhibitor (idelalisib) was approved in 2014 for leukemia. In this proposal, we advance our findings by conducting a systematic screen of PI3K pathway inhibitors in vitro and in vivo. The aims of this proposal are to: 1) profile a library of PI3K pathway inhibitors for efficacy in reducing viability of human merlin-deficient Schwann cell lines and primary human VS cells; 2) test efficacy of the advanced PI3K inhibitors to slow graft expansion and preserve hearing and balance in a novel rat xenograft model, and 3) conduct phenotypic, kinome, and transcriptome analysis to reveal the molecular signatures and adaptive changes of the cells and grafts to the inhibitors. We expect to obtain the necessary pre-clinical data to support the potential use of PI3K inhibitors in patients with NF2-associated VS.


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: 2024 ( Subtotal = $0 )
2024	2022	THE UNIVERSITY OF CENTRAL FLORIDA BOARD OF TRUSTEES	4000 CENTRAL FLORIDA BLVD	ORLANDO	FL	32816	ORANGE	USA	Research Related to Deafness and Communication Disorders	000	5	4/19/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $556,980 )
2022	2022	UNIVERSITY OF CENTRAL FLORIDA BOARD OF TRUSTEES, THE	4000 CENTRAL FLORIDA BLVD	ORLANDO	FL	32816	ORANGE	USA	Research Related to Deafness and Communication Disorders	000	5	6/22/2022	NON-COMPETING CONTINUATION	$556,980
														Subtotal = $556,980

Issue Date FY: 2021 ( Subtotal = $638,661 )
2021	2021	UNIVERSITY OF CENTRAL FLORIDA BOARD OF TRUSTEES, THE	4000 CENTRAL FLORIDA BLVD	ORLANDO	FL	32816	ORANGE	USA	Research Related to Deafness and Communication Disorders	000	4	7/8/2021	NON-COMPETING CONTINUATION	$638,661
														Subtotal = $638,661

Issue Date FY: 2020 ( Subtotal = $640,803 )
2020	2020	UNIVERSITY OF CENTRAL FLORIDA BOARD OF TRUSTEES, THE	4000 CENTRAL FLORIDA BLVD	ORLANDO	FL	32816	ORANGE	USA	Research Related to Deafness and Communication Disorders	000	3	8/13/2020	NON-COMPETING CONTINUATION	$640,803
														Subtotal = $640,803

Issue Date FY: 2019 ( Subtotal = $622,304 )
2019	2019	UNIVERSITY OF CENTRAL FLORIDA BOARD OF TRUSTEES, THE	4000 CNTRL FLORIDA BLVD	ORLANDO	FL	32816	ORANGE	USA	Research Related to Deafness and Communication Disorders	000	2	6/20/2019	NON-COMPETING CONTINUATION	$622,304
														Subtotal = $622,304

Issue Date FY: 2018 ( Subtotal = $637,684 )
2018	2018	UNIVERSITY OF CENTRAL FLORIDA BOARD OF TRUSTEES, THE	4000 CNTRL FLORIDA BLVD	ORLANDO	FL	32816	ORANGE	USA	Research Related to Deafness and Communication Disorders	000	1	6/25/2018	NEW	$637,684
														Subtotal = $637,684

Grand Total All Awards = $3,096,432

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Preclinical Testing of PI3K Inhibitors for Vestibular Schwannomas

Award Number: R01DC017264

ORGANIZATION: NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2018

PERIOD OF PERFORMANCE END DATE: 06/30/2025

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer