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: 10662510
• 负责人: DAVID ANDREW LARGAESPADA
• 金额: $ 77万
• 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 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10662510
• 关键词: Alleles; Amino Acid Sequence; Benign; CDKN2A gene; Cause of Death; Cell Line; Chemotherapy and/or radiation; 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; Immunoprevention; 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; Persons; Pharmaceutical Preparations; Pharmacotherapy; Phase; Plexiform Neurofibroma; Predisposition; Preventative vaccination; Prevention; Preventive vaccine; Process; Production; Public Health; RNA Splicing; 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; Vaccinee; Vaccines; Variant; autosome; cancer predisposition; candidate identification; chemoradiation; 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 1型神经纤维瘤病(NF1)综合征是一种常染色体显性遗传性肿瘤易感综合征，即 由编码神经纤维蛋白的NF1基因功能丧失突变引起。在患有NF1的患者中， 罕见的雪旺细胞或前体细胞中NF1的非突变等位基因，以及其他定义不清的因素，导致 良性真皮或丛状神经纤维瘤。NF1患者的主要死亡原因是恶性肿瘤 周围神经鞘瘤(MPNST)，一种极有可能发展为高度侵袭性的软组织肉瘤 来源于丛状神经纤维瘤，尤其是所谓的“非典型”丛状神经纤维瘤。大约一半的人 MPNST与NF1相关，NF1患者一生中患这种可怕癌症的风险为10%-15%。 MPNSTs转移较早，通常对放疗和化疗耐药。主要的治疗方法是 MPNSTs是外科手术切除，但尽管根治性切除，手术切缘很宽，随后是 放化疗后，由于转移和局部复发，5年存活率很低。NF1患者 可以极大地受益于预防性疫苗接种，以防止良性疾病的恶变 丛状神经纤维瘤变成“非典型”丛状神经纤维瘤和MPNSTs。我们的目标是确定 控制“非典型”丛状神经纤维瘤发展的突变(NF1缺失伴随CDKN2A 丢失)和MPSNT(NF1、CDKN2A和SUZ12丢失)导致反复交替处理的表达 转录本可以表达新抗原并被用作靶标的转录本，如转录诱导的嵌合体 用于预防性疫苗。这样的转录本可以被翻译成下游的新的多肽 编码外显子直读到内含子，从编码外显子错误剪接到内含子引起的移码突变 其他基因中的非规范剪接受体或剪接受体。在大多数情况下，过早终止 翻译这些转录本的核糖体将很快遇到密码子(PTC)。因此，我们 此外，假设这些交替处理的抄本可以表达我们所说的“神秘” 当用抑制早熟密码子利用的药物治疗时，如Ataluren或 庆大霉素。通过这种方式，我们可以接种预防性疫苗，并诱导有条件的主动免疫。 只有在使用药物治疗时才能消除新生肿瘤的反应。

项目成果

Ex vivo to in vivo model of malignant peripheral nerve sheath tumors for precision oncology.

• DOI: 10.1093/neuonc/noad097
• 发表时间: 2023-11-02
• 期刊: Neuro-oncology
• 影响因子: 15.9

Multiplatform molecular profiling uncovers two subgroups of malignant peripheral nerve sheath tumors with distinct therapeutic vulnerabilities.

• DOI: 10.1038/s41467-023-38432-6
• 发表时间: 2023-05-10
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Suppiah, Suganth;Mansouri, Sheila;Mamatjan, Yasin;Liu, Jeffrey C.;Bhunia, Minu M.;Patil, Vikas;Rath, Prisni;Mehani, Bharati;Heir, Pardeep;Bunda, Severa;Velez-Reyes, German L.;Singh, Olivia;Ijad, Nazanin;Pirouzmand, Neda;Dalcourt, Tatyana;Meng, Ying;Karimi, Shirin;Wei, Qingxia;Nassiri, Farshad;Pugh, Trevor J.;Bader, Gary D.;Aldape, Kenneth D.;Largaespada, David A.;Zadeh, Gelareh
• 通讯作者: Zadeh, Gelareh