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Preclinical Testing of PI3K Inhibitors for Vestibular Schwannomas

PI3K 抑制剂治疗前庭神经鞘瘤的临床前测试

基本信息

批准号：
10238743
负责人：
CRISTINA Maria FERNANDEZ-VALLE
金额：
$ 63.87万
依托单位：
UNIVERSITY OF CENTRAL FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10238743
关键词：
Acoustic Nerve Acoustic Neuroma Address Adult Allografting Animal Model Antineoplastic Agents Apoptosis Auditory Brainstem Responses Autophagocytosis Benchmarking Benign Benign Schwannoma Biological Assay Brain Stem Cell Cycle Arrest Cell Line Cell Proliferation Cells Child Clinical Data Clinical Trials Consequentialism Cytostatics Development Disease Drug Combinations Drug Kinetics Drug Screening Drug Targeting Epidermal Growth Factor Receptor Equilibrium Evaluation Excision FDA approved FRAP1 gene Facial paralysis Family Follow-Up Studies Future Genes Global Change Goals Growth Hearing Hematopoietic Neoplasms Histone Deacetylase Inhibitor Human Immunohistochemistry In Vitro Individual Label Lead Libraries Life Measures Modeling Molecular Molecular Analysis Molecular Profiling Mus Mutation Necrosis Nerve Neurilemmoma Neurofibromatosis 2 Neurofibromin 2 Operative Surgical Procedures Outcome Study Pathway interactions Patient observation Patients Pharmaceutical Preparations Pharmacotherapy Phenotype Phosphatidylinositols Phosphotransferases Play Preclinical Testing Preparation Radiation Radiation therapy Rattus Reporting Robotics Rodent Role Schwann Cells Signal Pathway Solid Neoplasm Testing Therapeutic Translations Tumor Expansion Tumor Suppressor Genes Tumor Suppressor Proteins Work Xenograft Model Xenograft procedure bevacizumab bilateral vestibular Schwannoma cancer clinical trial comparative efficacy cytotoxic deafness drug candidate drug development drug efficacy drug mechanism druggable target efficacy evaluation efficacy testing hearing impairment hearing loss risk hearing preservation high throughput screening in vivo inhibitor/antagonist kinase inhibitor lapatinib leukemia loss of function nanomolar novel off-label use pre-clinical preclinical evaluation preservation prevent progressive hearing loss research clinical testing response sciatic nerve screening standard care transcriptome transcriptome sequencing tumor

项目摘要

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.

摘要