TAM receptor inhibition in NF1-associated peripheral nerve sheath tumors

点击翻译按钮获取中文摘要

PROJECT SUMMARY / ABSTRACT – no changes from the parent award for this document 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.