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/概要 1型神经纤维瘤病（NF 1）综合征是一种常染色体显性遗传肿瘤易感综合征， 由编码神经纤维蛋白的NF 1基因的功能缺失突变引起。在NF 1患者中， 罕见的雪旺氏细胞或前体中NF 1的非突变等位基因，沿着其他不明确的因素，导致 良性皮肤或丛状神经纤维瘤。NF 1患者死亡的主要原因是恶性肿瘤。 周围神经鞘瘤（MPNST），一种高度侵袭性的软组织肉瘤，最有可能发展为 丛状神经纤维瘤，特别是所谓的“非典型”丛状神经纤维瘤。的大约一半 MPNST与NF 1相关，NF 1患者有10-15%的终生风险患上这种可怕的癌症。 MPNST转移较早，通常对放疗和化疗有抵抗力。的主要治疗方法 MPNST是手术切除，但是，尽管根治性切除，手术切缘较宽， 放化疗，5年生存率差，由于转移以及局部复发。nf 1患者 可以大大受益于预防性疫苗接种，这将防止良性肿瘤的恶性转化， 丛状神经纤维瘤转化为“非典型”丛状神经纤维瘤和MPNST。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（NF 1丢失，随后是CDKN 2A 缺失）和MPSNT（NF 1、CDKN 2A和SUZ 12缺失）导致反复交替处理的表达。 转录物，如转录诱导的嵌合体，其可以表达新抗原并用作靶标 预防性疫苗。这样的转录物可以被翻译以产生新的肽下游， 由编码外显子通读到内含子、从编码外显子错误剪接到内含子引起的移码突变。 非规范剪接受体或其它基因中的剪接受体。在大多数情况下，提前终止妊娠 密码子（PTC）将被翻译这些转录物的核糖体迅速遇到。所以我们 进一步假设这些交替加工的转录本可以表达我们所说的“隐秘” 当用抑制未成熟密码子利用的药物如Ataluren或 庆大霉素通过这种方式，我们可以给予预防性疫苗并诱导条件主动免疫， 这种反应只有在使用药物治疗时才能消除新生肿瘤。

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