Preclinical-clinical trials collaboration to effectively advance new combination therapies for atypical neurofibroma in neurofibromatosis type 1

临床前-临床试验合作有效推进1型神经纤维瘤病非典型神经纤维瘤的新联合疗法

• 批准号: 10611130
• 负责人: David W Clapp
• 金额: $ 49.56万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-07 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10611130
• 关键词: Acceleration; Address; Benign; Biological Markers; Biology; CDK4 gene; CDKN2A gene; Cells; Cessation of life; Childhood; Clinic; Clinical; Clinical Investigator; Clinical Research; Clinical Trials; Clonal Evolution; Collaborations; Combined Modality Therapy; Coupled; Data; Development; Disease; Epigenetic Process; Evolution; Excision; Extramural Activities; Genetic Transcription; Genomics; Goals; Histology; Human; Individual; Infrastructure; Lead; Lesion; Location; MAP2K1 gene; MEK inhibition; MEKs; Malignant - descriptor; Malignant Neoplasms; Medical; Molecular; Monitor; Morbidity - disease rate; Mus; Natural History; Neurofibromatosis 1; Neurofibrosarcoma; Operative Surgical Procedures; Orphan; Patients; Peripheral Nervous System Malignant Neoplasms; Persons; Pharmaceutical Preparations; Phase; Phase 0 Trial; Phosphotransferases; Plexiform Neurofibroma; Population; Pre-Clinical Model; Prevention; Proteomics; Research Personnel; Risk; Sampling; Series; Signal Induction; Soft tissue sarcoma; Syndrome; Testing; Therapeutic; Therapeutic Intervention; Translating; Translations; Tumor Suppressor Proteins; Tumor stage; Unresectable; Work; biomarker identification; cancer predisposition; cancer prevention; inhibitor; innovation; interdisciplinary approach; liquid biopsy; molecular marker; mouse model; multiple omics; neurofibroma; new combination therapies; novel; novel therapeutic intervention; participant enrollment; patient population; pre-clinical; predicting response; premalignant; premature; prevent; resistance mechanism; response; response biomarker; small molecule inhibitor; targeted agent; targeted treatment; therapeutic development; transcriptomics; translational scientist; treatment response; tumor; tumor progression

PROJECT SUMMARY/ABSTRACT Neurofibromatosis type 1 (NF1) is a common cancer predisposition syndrome characterized by the development of a spectrum of benign and malignant tumors of the peripheral nervous system. Individuals with benign plexiform neurofibromas (PNF) are at increased risk of developing malignant peripheral nerve sheath tumor (MPNST), a highly aggressive soft tissue sarcoma that rapidly progresses and is uniformly fatal in patients who present with unresectable disease. The majority of NF1 MPNST arise from pre-existing neurofibromas, suggesting that these precursor lesions hold important clues to the developmental origins of MPNST and for identifying novel therapeutic strategies for MPNST treatment and prevention. Work by our team of intramural and extramural investigators has demonstrated that malignant transformation of PNF often occurs through the development of atypical neurofibroma (ANF), characterized by distinct histopathological and molecular features including copy number loss of the CDKN2A/B tumor suppressor locus. Natural history data shows that these pre-malignant lesions are direct precursors of MPNST. While clinical trials lead by our group have spurred transformative advances for the treatment of NF1-associated PNF, including FDA and EMA approval of selumetininb (MEK inhibitor) for the treatment of pediatric PNF, we have discovered that MEK inhibition does not induce treatment responses in most ANF and does not appear to prevent MPNST. Surgical resection of ANF has become a strategy to prevent MPNST. However, surgery may be associated with significant morbidity or infeasible due to ANF location or presence of multiple ANF. To address the challenges of treating and preventing malignant transformation of ANF precursor lesions in this vulnerable patient population, we will leverage a robust infrastructure spanning the preclinical-to-clinical continuum to rapidly test and translate novel therapeutic strategies to the clinic for the treatment of ANF and to identify response biomarkers. Our work will center on CDK4/6 inhibition to strategically oppose the dysregulated signaling induced by CDKN2A/B loss. The overarching goals of this project are to (1) develop single agent and/or combination therapies for ANF informed by preclinical murine models that spontaneously develop ANF and MPNST, allowing interrogation of therapeutic interventions at each stage of tumor progression, (2) establish a pipeline to accelerate the translation of first-in- kind therapies to the clinic to effectively treat ANF and prevent malignant transformation, and (3) identify robust molecular biomarkers associated with treatment response. Harnessing the specialized expertise of translational and clinical investigators at the NCI, and extramural experts in NF1 biology and therapeutic development, this collaborative effort will employ state-of-the-art approaches in preclinical modeling, window of opportunity trials, single cell analytics, and non-invasive liquid biopsy coupled with integrative multi-omic profiling to understand ANF to MPNST evolution and drive therapeutic innovation for increasingly aggressive orphan cancers where no current treatment options exist.

项目摘要/摘要 1型神经纤维瘤病(NF1)是一种常见的癌症易感综合征，其发病特点为 周围神经系统良性肿瘤和恶性肿瘤的谱系。良性丛状结构的个体 神经纤维瘤(PNF)患恶性周围神经鞘膜瘤(MPNST)的风险增加。 高度侵袭性的软组织肉瘤进展迅速，在表现为 无法切除的疾病。大多数NF1 MPNST来自先前存在的神经纤维瘤，这表明这些 前驱病变对MPNST的发育起源和识别新的 MPNST治疗和预防的治疗策略。我们的内部和外部团队的工作 研究人员已经证明，PNF的恶变通常发生在 不典型神经纤维瘤(ANF)，以独特的组织病理学和分子特征为特征，包括复制 CDKN2A/B抑癌基因缺失。自然历史数据显示，这些癌前病变 病变是MPNST的直接前驱。虽然我们团队领导的临床试验刺激了变革性的 NF1相关性PNF的治疗进展，包括FDA和EMA批准赛乐美汀(MEK) 我们发现，抑制MEK并不能诱导治疗。 在大多数ANF中的反应，似乎并不能阻止MPNST。外科手术切除ANF已成为一种 预防MPNST的策略。然而，由于以下原因，手术可能与显著的发病率或不可行有关 ANF位置或存在多个ANF。应对治疗和预防恶性肿瘤的挑战 在这一脆弱的患者群体中，ANF前体病变的转化，我们将利用强大的 跨越临床前到临床连续体的基础设施，以快速测试和转换新的治疗方法 为ANF的临床治疗和识别反应生物标志物提供策略。我们的工作将集中在 抑制CDK4/6，从策略上对抗CDKN2A/B缺失引起的信号转导失调。这个 该项目的主要目标是(1)开发ANF的单一药物和/或联合疗法 通过自发发展ANF和MPNST的临床前小鼠模型，允许询问治疗 在肿瘤进展的每个阶段进行干预，(2)建立一条管道，以加速First-in-in- 为临床提供有效治疗ANF和防止恶变的良好疗法，以及(3)确定稳健 与治疗反应相关的分子生物标志物。利用翻译的专业知识 和NCI的临床研究人员，以及NF1生物学和治疗开发的校外专家，这 协作工作将在临床前建模、机会之窗试验、 单细胞分析、无创液体活检和综合多基因组图谱相结合，以了解 ANF到MPNST的进化，并推动治疗创新，以治疗日益侵袭性的孤儿癌症 目前的治疗选择是存在的。