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

项目总结/摘要 1型神经纤维瘤病（NF1）是一种常见的癌症易感综合征，其特征是发展为 周围神经系统的良性和恶性肿瘤。良性丛状组织的个体 神经纤维瘤（PNF）发生恶性外周神经鞘瘤（MPNST）的风险增加， 一种高度侵袭性的软组织肉瘤，进展迅速，在出现以下症状的患者中一律致命： 不可切除的疾病。大多数NF1 MPNST来自预先存在的神经纤维瘤，这表明这些神经纤维瘤可能是神经纤维瘤的一部分。 前驱病变为MPNST的发育起源和鉴定新的MPNST提供了重要线索。 MPNST治疗和预防的治疗策略。我们的校内和校外团队 研究人员已经证明，PNF的恶性转化通常通过以下过程发生： 非典型神经纤维瘤（ANF），其特征在于独特的组织病理学和分子特征，包括复制 CDKN 2 A/B肿瘤抑制基因座的数量丢失。自然史数据显示，这些癌前病变 病变是MPNST的直接先兆。虽然我们小组领导的临床试验已经刺激了变革性的 治疗NF1相关PNF的进展，包括FDA和EMA批准的司美替尼（MEK 为了治疗儿科PNF，我们发现MEK抑制剂不会诱导治疗 在大多数ANF的反应，并没有出现防止MPNST。ANF的手术切除已成为一种 预防MPNST的策略。然而，手术可能与显著的发病率或不可行相关， ANF位置或存在多个ANF。应对治疗和预防恶性肿瘤的挑战 在这个脆弱的患者人群中，我们将利用一个强大的ANF前体病变的转化， 基础设施跨越临床前到临床的连续性，以快速测试和转化新的治疗方法 临床治疗ANF的策略，并确定响应生物标志物。我们的工作将集中在 CDK4/6抑制策略性地对抗由CDKN 2 A/B损失诱导的失调信号传导。的 本项目的总体目标是（1）开发ANF的单药和/或联合治疗， 通过自发发展ANF和MPNST的临床前小鼠模型，允许询问治疗性ANF和MPNST， 在肿瘤进展的每个阶段进行干预，（2）建立一个管道，以加速第一阶段的转化， 为临床提供一种有效治疗ANF和预防恶性转化的方法，（3）确定稳健的 与治疗反应相关的分子生物标志物。利用翻译的专业知识 NCI的临床研究人员，以及NF1生物学和治疗开发方面的校外专家， 合作努力将采用最先进的方法在临床前建模，机会窗口试验， 单细胞分析和非侵入性液体活检结合综合多组学分析， ANF到MPNST的演变，并推动治疗创新，以治疗日益侵袭性的孤儿癌症， 现有的治疗方案。

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.