Uncovering treatment targets for peripheral nerve sheath tumor progression in NF1

发现 NF1 周围神经鞘瘤进展的治疗靶点

• 批准号: 10653687
• 负责人: DAVID ANDREW LARGAESPADA
• 金额: $ 57.18万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10653687
• 关键词: Address; Alleles; Allografting; Benign; C57BL/6 Mouse; CDKN2A gene; Cell Line; Cells; Chemicals; Clustered Regularly Interspaced Short Palindromic Repeats; DNA sequencing; Detection; Development; Drug Screening; Drug Targeting; Environment; Epigenetic Process; Erinaceidae; Evolution; Genes; Genetic; Genetic Diseases; Genetic Screening; Genetically Engineered Mouse; Genotype; Goals; Heritability; Heterozygote; Human; Image Analysis; Immune; Immune system; Immunocompromised Host; In Vitro; Lesion; Lethal Genes; Life; Loss of Heterozygosity; Malignant - descriptor; Malignant Neoplasms; Methods; Modeling; Modification; Molecular Target; Morbidity - disease rate; Mus; Mutation; NF1 gene; Neoplasms; Nerve; Nerve Sheath Tumors; Neurofibromatoses; Neurofibromatosis 1; Neurofibrosarcoma; Operative Surgical Procedures; Pain; Patients; Perinatal; Peripheral Nerve Sheath Neoplasm; Peripheral Nerves; Persons; Pharmaceutical Preparations; Plexiform Neurofibroma; Population; Pre-Clinical Model; Preclinical Testing; Premalignant Cell; Prevention; Process; Prognosis; Protein Phosphatase 2A Regulatory Subunit PR53; Role; Schwann Cells; Soft tissue sarcoma; Source; Surgical complication; Syndrome; System; Testing; Therapeutic Uses; Tissues; Wild Type Mouse; autosome; cancer predisposition; cell transformation; chemotherapy; dermal neurofibroma; drug candidate; exome; gene product; genetically modified cells; human data; immunoregulation; in vitro Model; in vitro testing; in vivo; in vivo Model; indexing; induced pluripotent stem cell; loss of function mutation; molecular targeted therapies; mortality; mouse model; mutant; neurofibroma; new therapeutic target; novel therapeutics; prevent; recruit; sciatic nerve; subcutaneous; transcriptome; transcriptome sequencing; transplant model; tumor; tumor progression; tumor-immune system interactions

Project Summary/Abstract Neurofibromatosis type 1 (NF1) syndrome is an autosomal dominant cancer-predisposing syndrome afflicting ~1 in every 3,500 persons worldwide with the majority of patients developing benign plexiform and/or dermal neurofibromas. Plexiform neurofibromas constitute a lifelong source of disfigurement, morbidity and mortality, and have the potential to transform to a malignant peripheral nerve sheath tumor (MPNST), an aggressive soft tissue sarcoma. In fact, approximately 15% of NF1 patients develop poor prognosis MPNSTs, often in the second or third decade of life. Treatment options for MPNSTs are limited to complicated surgical procedures and classical chemotherapy and, so far, molecular targeted therapies have demonstrated limited efficacy. We desperately need new treatment options for the MPNSTs and methods to prevent them from development. It was recently found that plexiform neurofibromas progress to MPNST via an intermediate, “atypical” neurofibroma (ANF) that in 70% of tumors shows heterozygous or homozygous loss of CDKN2A the gene encoding p16INK4a and p14ARF (Beert et al., 2011; Pemov et al., 2018). Our proposal will address critical unmet needs in this field, including better in vitro and in vivo models of ANF and identification of critical vulnerabilities of these cells. To provide a model for preclinical testing and prevention of ANF to MPNST development, we combined Desert hedgehog (Dhh)-Cre driven biallelic deletion of Nf1 with heterozygous loss of Cdkn2a, creating a unique model of transplantable ANF developing within pre-existing neurofibroma (Chaney et al., submitted). We also combined Dhh-Cre driven biallelic deletion of Nf1 and Pten, generating rapidly developing perinatal ANF-like lesions (Keng et al., 2012). ANF from Dhh-Cre;Nf1fl/fl;Cdkn2a+/- mice grafted subcutaneously into immunocompromised hosts grew, after a delay, providing a more rapid, tractable, transformation system. We plan a complete transcriptome and exome analysis in these models (Aim 1a), and further investigate the model by identifying and validating cell populations and markers altered in mouse and human PNF, ANF, and MPNST in unperturbed tissue sections using a new image analysis method called CO-Detection by IndEXing (Aim 1b). Modulation of the immune environment is increasing used therapeutically. We will therefore define the influence of the nerve microenvironment and immune system on progression from ANF to MPNST (Aim 1c). To identify ANF vulnerabilities, we have completed drug and CRISPR-based genetic synthetic lethality screens in isogenic immortalized human Schwann cells that are NF1 wildtype or were made homozygous for NF1 loss of function mutations using gene editing. Candidate drugs that inhibit PP2A, and other novel targets from the drug screening effort, will be tested for their effects in ANF- like cells in vitro (Aim 2a) and, when successful, in our unique GEMMs (Aim 2b). Similarly, our genetic screening effort will be used to define additional vulnerabilities tested in vitro (Aim 2c) and in vivo (Aim 2d).

项目总结/文摘

项目成果

Modeling human cancer predisposition syndromes using CRISPR/Cas9 in human cell line models.

• DOI: 10.1002/gcc.23140
• 发表时间: 2023-09
• 期刊: GENES CHROMOSOMES & CANCER
• 影响因子: 3.7
• 作者: Draper, Garrett M.;Panken, Daniel J.;Largaespada, David A.
• 通讯作者: Largaespada, David A.

Selumetinib normalizes Ras/MAPK signaling in clinically relevant neurofibromatosis type 1 minipig tissues in vivo.

• DOI: 10.1093/noajnl/vdab020
• 发表时间: 2021-01
• 期刊: Neuro-oncology advances
• 作者: Osum SH;Coutts AW;Duerre DJ;Tschida BR;Kirstein MN;Fisher J;Bell WR;Delpuech O;Smith PD;Widemann BC;Moertel CL;Largaespada DA;Watson AL
• 通讯作者: Watson AL