TAM receptor inhibition in NF1-associated peripheral nerve sheath tumors

项目概要/摘要 NF 1肿瘤抑制基因的突变导致1型神经纤维瘤病（NF 1），这是人类最常见的 遗传性癌症易感综合征患有NF 1的个体患有广泛的恶性肿瘤， 非恶性临床表现包括丛状神经纤维瘤（PNF），复杂的癌前病变 其影响25-40%的NF 1患者并导致主要的终身发病率和死亡率。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恶性外周肉瘤 神经鞘瘤，这是NF 1患者过早死亡的主要原因。在最近的工作中， 我们利用了新的临床前基因工程小鼠模型（GEMM）， PNF的发展及其向ANF和MPNST的进展。在这里，我们提供了多条证据线， 使用多受体酪氨酸激酶（RTK）的机制相关临床前和II期临床试验 抑制剂卡博替尼，将TAM家族激酶（AXL和MERTK）鉴定为可能的关键激酶靶点 与PNF的治疗反应相关。使用这些GEMM，我们证明，AXL，特别是 在PNF、ANF和MPNST谱中高度表达。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中的PNF/ANF子集的恶性转化。我们 也有初步的临床数据，其中NF 1患者，谁开发了MPNST，实现了持续的抗- 在我们的儿科癌症精准基因组学诊所接受基因组分析后的肿瘤反应 发现肿瘤过度表达AXL 虽然我们已经表明卡博替尼调节TAM家族激酶，包括AXL和MERTK，并且在体外对细胞增殖有影响。 在治疗成人NF 1患者PNF的临床有效性，其广泛的靶点确实导致了一些低级别的 导致大量受试者停止治疗的AE。为了克服这一障碍，我们将 确定（目的1和2）新的TAM受体信号传导的第一类抑制剂（bavituximab及其 鼠类似物mch 1 N11）或AXL特异性小分子抑制剂（bemcentinib）单独或组合 与MEK抑制剂、司美替尼或CDK 4/6抑制剂（abemaciclib）联合使用可有效治疗现有PNF， 或甚至阻止PNF/ANF在GEMM和患者来源的移植瘤模型中进展为MPNST， NF 1相关MPNST。将探索可溶性AXL（sAXL）的循环水平作为以下疾病的推定生物标志物： 治疗反应，可以在人类受试者中进行非侵入性监测，以进一步验证 在最近的PNF和其他人类癌症的2期试验中发现了预后价值。总的来说，这些研究 提供TAM受体信号传导在调节孤儿癌肿瘤生物学中的作用的基本见解 易感综合征，并有助于催化新的治疗策略的临床转化，其中当前 选择仍然极为有限。

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.