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：
10501263
负责人：
David W Clapp
金额：
$ 41.52万
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/10501263
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 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 Pharmacology Phase II Clinical Trials Phenotype Phosphotransferases Plasma Plexiform Neurofibroma 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 Work analog cancer predisposition cancer stem cell clinical translation effective therapy 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 phase II trial pre-clinical premalignant premature prevent prognostic value receptor response sarcoma small molecule small molecule inhibitor stem cells 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.

项目概要/摘要 NF1 抑癌基因突变会导致 1 型神经纤维瘤病 (NF1)，这是人类最常见的疾病遗传性癌症易感综合症。患有 NF1 的个体患有多种恶性和非恶性临床表现，包括丛状神经纤维瘤 (PNF)、复杂的癌前病变它影响 25-40% 的 NF1 患者，并导致重大的终生发病率和死亡率。这些肿瘤的一个子集将进展为非典型神经纤维瘤 (ANF) 和一种高度侵袭性的肉瘤，称为恶性外周肉瘤神经鞘瘤，它是 NF1 患者过早死亡的主要原因。在最近的工作中，我们利用新型临床前基因工程小鼠模型 (GEMM) 准确地概括了 PNF 的发展及其进展为 ANF 和 MPNST。在这里，我们提供了多方面的证据利用多受体酪氨酸激酶 (RTK) 进行机械关联的临床前和 2 期临床试验抑制剂卡博替尼，将 TAM 家族激酶（AXL 和 MERTK）确定为可能的关键激酶靶标与 PNF 的治疗反应相关。使用这些 GEMM，我们证明了 AXL 特别是在 PNF、ANF 和 MPNST 谱系中高度表达。在进一步的初步研究中，我们发现卡博替尼可以延迟或预防这些 GEMM 中 PNF/ANF 子集的恶性转化。我们也有初步临床数据显示，患有 MPNST 的 NF1 患者取得了持续的抗- 经过基因组分析后，在我们的儿科癌症精密基因组学诊所接受治疗后的肿瘤反应发现肿瘤过度表达AXL。虽然我们已经证明卡博替尼可以调节 TAM 家族激酶，包括 AXL 和 MERTK，并且在临床上有效治疗成年 NF1 患者的 PNF，其广泛的靶点概况确实导致了许多低级别的导致大量参与者停止治疗的不良事件。为了克服这个障碍，我们将确定（目标 1 和 2）是否是一种新型、首创的 TAM 受体信号抑制剂（bavituximab 及其鼠类似物 mch1N11) 或 AXL 特异性小分子抑制剂 (bemcentinib) 单独或组合联合 MEK 抑制剂、selumetinib 或 CDK4/6 抑制剂 (abemaciclib) 可以有效治疗现有 PNF 并延缓病情甚至阻止 GEMM 和患者来源的异种移植模型中 PNF/ANF 进展为 MPNST NF1 相关的 MPNST。可溶性 AXL (sAXL) 的循环水平将作为假定的生物标志物进行探索可以在人类受试者中进行非侵入性监测的治疗反应，以进一步验证潜力最近在 PNF 和其他人类癌症的 2 期试验中发现了其预后价值。总的来说，这些研究提供关于 TAM 受体信号传导在调节孤儿癌症肿瘤生物学中的作用的基本见解易感综合症，并有助于催化当前新治疗策略的临床转化选择仍然极其有限。