权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

TAM receptor inhibition in NF1-associated peripheral nerve sheath tumors

NF1 相关周围神经鞘肿瘤中的 TAM 受体抑制

基本信息

批准号：
10616770
负责人：
David W Clapp
金额：
$ 26.39万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10616770
关键词：
Adult Affect Antitumor Response Benign Binding Biological Markers CDK4 gene Cells Cessation of life Child Clinic Clinical Clinical Data Clustered Regularly Interspaced Short Palindromic Repeats Collagen Complex Development FDA approved Family Genetically Engineered Mouse Genomics Germ-Line Mutation Growth Human Human Genetics Immune Immunologics Immunotherapeutic agent Individual Laboratories Lesion Link LoxP-flanked allele MEK inhibition MEKs MERTK gene Malignant - descriptor Malignant Childhood Neoplasm Malignant Neoplasms Measures Modeling Molecular Monoclonal Antibodies Morbidity - disease rate Mus Mutant Strains Mice Mutation NF1 gene Neural Crest Neurofibromatosis 1 Neurofibrosarcoma Non-Malignant Orphan Orphan Drugs Participant Patients Peripheral Nerve Sheath Neoplasm Persons Pharmaceutical Preparations Phase II Clinical Trials Phenotype Phosphotransferases Plasma Plexiform Neurofibroma Probability Prognostic Marker Proteins Receptor Inhibition Receptor Protein-Tyrosine Kinases Receptor Signaling Role Series Serine Syndrome Testing Toxic effect Tumor Biology Tumor Suppressor Genes Tyrosine Kinase Inhibitor Tyrosine Kinase Receptor Inhibition Work Xenograft Model analog angiogenesis cancer predisposition cancer stem cell clinical translation effective therapy efficacy evaluation genome analysis human subject implantation inhibitor insight man mortality mouse model mutant neurofibroma new therapeutic target non-invasive monitor novel novel therapeutic intervention overexpression patient derived xenograft model pharmacodynamic biomarker pharmacokinetics and pharmacodynamics pharmacologic phase II trial pre-clinical premalignant premature prevent prognostic value receptor response sarcoma small molecule small molecule inhibitor stem cells synergism targeted treatment treatment response tumor tumor growth tumor microenvironment tumor progression tumorigenic

项目摘要

PROJECT SUMMARY / ABSTRACT Mutations in the NF1 tumor suppressor gene cause neurofibromatosis type 1 (NF1), the most common human genetic cancer predisposition syndrome. Individuals with NF1 suffer from a wide range of malignant and nonmalignant clinical manifestations including plexiform neurofibromas (PNF), complex precancerous lesions which affect 25-40% of NF1 patients and cause major lifelong morbidity and mortality. A subset of these tumors will progress to atypical neurofibroma (ANF) and a highly aggressive form of sarcoma called malignant peripheral nerve sheath tumor, which represents the leading cause of premature death in persons with NF1. In recent work, we utilized novel preclinical genetically engineered murine models (GEMMs) that accurately recapitulate the development of PNF and their progression to ANF and MPNST. Here we provide multiple lines of evidence in a mechanistically linked preclinical and phase 2 clinical trial utilizing the multi-receptor tyrosine kinase (RTK) inhibitor cabozantinib, identifying TAM family kinases (AXL and MERTK) as a probable key kinase target associated with treatment responses in PNF. Using these GEMMs, we demonstrate that AXL, in particular is highly expressed across a spectrum of PNF, ANF, and MPNST. In further preliminary studies, we found that cabozantinib can delay or prevent the malignant transformation of a subset of PNF/ANF in these GEMMs. We also have preliminary clinical data where a NF1 patient, who developed a MPNST, achieved a sustained anti- tumor response upon being treated at our Pediatric Cancer Precision Genomics Clinic after genome analysis found the tumor overexpressed AXL. While we have shown that cabozantinib modulates TAM family kinases including AXL and MERTK, and is effective clinically in treating PNF in adult NF1 patients, its broad target profile did result in a number of low grade AEs that led a significant number of participants to discontinue therapy. To overcome this barrier, we will determine (Aims 1 and 2) whether a novel, first in class inhibitor of TAM receptor signaling (bavituximab and its murine analogue mch1N11) or an AXL specific small molecule inhibitor, (bemcentinib) alone or in combination with a MEK inhibitor, selumetinib, or a CDK4/6 inhibitor (abemaciclib) can effectively treat existing PNF and delay or even prevent the progression of PNF/ANF to MPNST in GEMMs and patient derived xenograft models of NF1-associated MPNST. Circulating levels of soluble AXL (sAXL) will be explored as a putative biomarker of treatment response which could be monitored non-invasively in human subjects to further validate the potential prognostic value found in recent phase 2 trials in PNF and other human cancers. Collectively, these studies provide basic insights into the role of TAM receptor signaling in modulating tumor biology in an orphan cancer predisposition syndrome, and serve to catalyze clinical translation of new therapeutic strategies where current options remain exceedingly limited.

项目摘要/摘要