Recurrent Tumor-Specific Alternately Processed Transcripts as a Source of Neoantigens for NF1-associated Malignant Peripheral Nerve Sheath Tumor Immunoprevention

复发性肿瘤特异性交替加工转录本作为 NF1 相关恶性周围神经鞘肿瘤免疫预防的新抗原来源

• 批准号: 10023258
• 负责人: DAVID ANDREW LARGAESPADA
• 金额: $ 76.16万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-25 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10023258
• 关键词: Alleles; Amino Acid Sequence; Benign; CDKN2A gene; Cause of Death; Cell Line; Chimera organism; Code; Codon Nucleotides; Dangerousness; Data; Development; Drug usage; Excision; Exons; Frameshift Mutation; Genes; Genetic Transcription; Grant; Human; Immune Targeting; Immune response; Immune system; Immunization; Immunoprecipitation; Introns; Knowledge; Lead; Malignant - descriptor; Malignant Neoplasms; Mass Spectrum Analysis; Modeling; Mus; Mutation; NF1 gene; Neoplasm Metastasis; Nerve; Neurofibromatosis 1; Neurofibrosarcoma; Operative Surgical Procedures; Patients; Peptide Vaccines; Peptides; Peripheral Nerve Sheath Neoplasm; Pharmaceutical Preparations; Pharmacotherapy; Phase; Plexiform Neurofibroma; Predisposition; Prevention; Preventive vaccine; Process; Production; Public Health; RNA Splicing; Radiation therapy; Recurrence; Recurrent tumor; Resistance; Reverse Transcriptase Polymerase Chain Reaction; Ribosomes; Schwann Cells; Site; Soft tissue sarcoma; Source; Surgical margins; Survival Rate; Syndrome; Terminator Codon; Transcript; Translating; Tumor Cell Line; Tumor Tissue; Vaccinated; Vaccination; Vaccines; Variant; chemoradiation; chemotherapy; dermal neurofibroma; design; lifetime risk; loss of function mutation; mouse model; neoantigens; neurofibroma; novel; premalignant; premature; prevent; prophylactic; transcriptome; transcriptome sequencing; tumor

Abstract/Summary Neurofibromatosis type 1 (NF1) syndrome is an autosomal dominant tumor predisposition syndrome that is caused by loss-of-function mutations of NF1 gene encoding neurofibromin. Among patients with NF1, loss of the non-mutant allele of NF1 in a rare Schwann cell or precursor, along with other ill-defined factors, leads to benign dermal or plexiform neurofibromas. The main cause of death among NF1 patients is the malignant peripheral nerve sheath tumor (MPNST), a highly aggressive soft tissue sarcoma that most likely develops from plexiform neurofibroma, in particular the so-called “atypical” plexiform neurofibroma. Approximately half of MPNSTs are NF1-associated, and NF1 patients have 10-15% lifetime risk of developing this terrible cancer. MPNSTs metastasize early and are often resistant to radiotherapy and chemotherapy. The main treatment for MPNSTs is surgical resection but, despite radical excision with wide surgical margins, followed by chemoradiation, 5-year survival rates are poor due to metastases as well as local recurrence. NF1 patients could greatly benefit from prophylactic vaccination that would prevent the malignant transformation of benign plexiform neurofibromas into “atypical” plexiform neurofibromas and to MPNSTs. We aim to determine if the mutations that govern the development of “atypical” plexiform neurofibroma (NF1 loss followed by CDKN2A loss) and MPSNT (NF1, CDKN2A, and SUZ12 loss) lead to the expression of recurrent alternately processed transcripts, such as transcriptionally-induced chimeras, that could express neoantigens and be used as targets for prophylactic vaccines. Such transcripts can be translated to produce novel peptides downstream of frameshift mutations caused by coding exon read-through into introns, mis-splicing from a coding exon to a non-canonical splice acceptors or splice acceptors in other genes. In most cases, a premature termination codon (PTC) will be rapidly encountered by the ribosome translating such transcripts. Therefore, we furthermore hypothesize that these alternately processed transcripts can express what we call “cryptic” neoantigens when treated with drugs that suppress utilization of premature codons such as Ataluren or gentamycin. In such a way, we could administer a prophylactic vaccine and induce conditionally active immune response that would eliminate nascent tumors only when drug treatment is used.

摘要/摘要 神经纤维瘤病1型（NF1）综合征是一种常染色体显性肿瘤易感综合征 由编码神经纤维蛋白的NF1基因的功能丧失突变引起。在NF1患者中，损失 NF1的非突变等位基因在稀有的Schwann细胞或前体中以及其他不确定的因素，导致 良性皮肤或丛状神经纤维瘤。 NF1患者死亡的主要原因是恶性肿瘤 周围神经鞘肿瘤（MPNST），一种高度侵略性的软组织肉瘤，最有可能发展 来自丛状神经纤维瘤，特别是所谓的“非典型”神经纤维瘤。大约一半 MPNST与NF1相关，NF1患者的终生风险为10-15％，患这种可怕的癌症。 MPNST早日转移，通常对放射疗法和化学疗法具有抵抗力。主要治疗 MPNST是手术切除术，但目的地自由基切除术具有宽外科缘，其次是 由于转移和局部复发，化学放疗，5年生存率较差。 NF1患者 预防性疫苗接种可能会大大受益，这将防止良性的恶性转化 丛状神经纤维瘤进入“非典型”丛状神经纤维瘤和MPNST。我们旨在确定是否 控制“非典型”丛状神经纤维瘤发展的突变（NF1损失，然后是CDKN2A 损失）和MPSNT（NF1，CDKN2A和SUZ12损失）导致经常处理的表达 笔录，例如转录诱导的嵌合体，可以表达新抗原并用作目标 用于预防性疫苗。这些成绩单可以翻译成在下游的新型肽 通过编码外显子读入介绍引起的移码突变，从编码外显子到一个错误的插图 其他基因中的非典型剪接受体或剪接受体。在大多数情况下，过早终止 翻译此类成绩单的核糖体将迅速遇到密码子（PTC）。因此，我们 此外，假设这些经过处理的成绩单可以表达我们所谓的“隐秘” 新抗原用抑制过早密码子（例如ataluren或 庆大霉素。以这种方式，我们可以给予预防性疫苗并诱导有条件活跃的免疫 只有在使用药物治疗时才能消除新生肿瘤的反应。