IND:138100. A phase I and surgical cohort Study of PTC596 in newly diagnosed children with DIPG and high-grade gliomas

索引号：138100。

• 批准号: 10098852
• 负责人: Rachid Drissi
• 金额: $ 11.97万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-30 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10098852
• 关键词: IND; 138100.; phase; surgical; cohort

ABSTRACT: Diffuse intrinsic pontine glioma (DIPG) is a universally fatal brainstem tumor with survival <1 year despite multimodal therapy. Similarly, other childhood high-grade gliomas (HGG) have a very poor prognosis with 3-year overall survival (OS) of 10-22%. Recent studies have delineated molecularly-distinct subgroups of pediatric HGG, including DIPGs, based on genomic/epigenomic features with clinical and prognostic implications. Despite these strides, radiotherapy remains the only standard therapy in pediatric HGG and DIPG, as no chemotherapeutic regimens have proven effective. This underscores an urgent need for novel therapies to improve outcome in this population. The B-cell-specific Moloney murine leukemia virus integration site 1 (BMI1) protein, widely overexpressed in many cancers, has been implicated in self-renewal of normal and cancer cells and in DNA-damage signaling. We have shown that BMI1 is highly expressed in DIPG, (regardless of molecular subtype) compared to matched normal tissue and that BMI1 downregulation leads to inhibition of i) DIPG patient-derived neurosphere cell proliferation, ii) cell- cycle signaling, iii) self-renewal, and v) DIPG cell migration. Our studies demonstrate that targeted inhibition of BMI1 sensitizes DIPG cells to radiomimetic drug-induced DNA damage. Similarly, BMI1 is highly expressed in pediatric glioblastoma (GBM) and its inhibition in in vitro and in vivo models leads to growth inhibition and cell death. Collectively, our data identify BMI1 as a potential therapeutic target for children with DIPG and HGG, setting the stage for clinical testing of BMI1 modulators such as PTC596. Pre-clinical studies from our group and others have demonstrated in vitro and in vivo efficacy of BMI1 inhibitors, PTC209 and PTC596, in HGG, and DIPG, alone and with radiomimetic agents. We propose to build on our pre-clinical studies to investigate the molecular activity and therapeutic potential of BMI1 inhibition in children with newly-diagnosed DIPG and HGG. The primary aims of this proposal are a) to determine the recommended phase II dose (RP2D) of PTC596 given concurrently with radiotherapy in children with newly- diagnosed HGG and DIPG, characterize its pharmacokinetics (PK); b) at the RP2D, to assess PTC596 intratumoral PK and its ability to inhibit BMI1 activity in tumor in newly-diagnosed DIPG/HGG children who receive PTC596 pre-resection/biopsy in a surgical molecular biology study. This study will assess BMI1 activity and PTC596 PK in tumor and cerebrospinal fluid among children with HGG and DIPG. The trial is being conducted through the Collaborative Network of Neuro-oncology Clinical Trials (CONNECT). These data will be used in the rational design of potential combination studies to improve outcome in children with DIPG and HGG.

抽象的： 弥漫性内在庞然神经胶质瘤（DIPG）是一种普遍致命的脑干肿瘤，生存<1年 尽管多模式疗法。同样，其他童年高级神经胶质瘤（HGG）也有一个非常 预后不良，总体生存率（OS）为10-22％。最近的研究已经描述了 基于基因组/表观基因组学的小儿HGG的分子亚组（包括DIPGS） 具有临床和预后意义的特征。尽管取得了这些进展，但放疗仍然是 仅在没有化学治疗方案的儿科HGG和DIPG中进行标准疗法 有效的。这强调了迫切需要新的疗法来改善结果 人口。 B细胞特异性的Moloney鼠白血病病毒整合位点1（BMI1）蛋白， 在许多癌症中广泛表达过表达，与正常和癌症的自我更新有关 细胞和DNA破坏信号传导。我们已经证明BMI1在DIPG中高度表达， （无论分子亚型如何）与匹配的正常组织相比 下调导致抑制i）DIPG患者衍生的神经圈细胞增殖，ii）细胞 循环信号传导，iii）自我更新和v）DIPG细胞迁移。我们的研究表明了目标 BMI1的抑制使DIPG细胞对放射性药物诱导的DNA损伤敏感。相似地， BMI1在小儿胶质母细胞瘤（GBM）中高度表达及其在体外和体内的抑制作用 模型会导致生长抑制和细胞死亡。总的来说，我们的数据将BMI1识别为潜在 DIPG和HGG儿童的治疗靶标，为BMI1的临床测试奠定了基础 调节器，例如PTC596。来自我们小组和其他人的临床前研究已证明 BMI1抑制剂，PTC209和PTC596，HGG和DIPG的体外和体内功效 并与放射性剂。我们建议以我们的临床前研究为基础，以研究 新诊断儿童BMI1抑制的分子活性和治疗潜力 DIPG和HGG。该提案的主要目的是a）确定建议的 PTC596的II期剂量（RP2D）与新生儿童同时进行放疗 诊断为HGG和DIPG，其特征是其药代动力学（PK）； b）在RP2D上，评估 PTC596肿瘤内PK及其在新诊断的肿瘤中抑制BMI1活性的能力 在手术分子生物学中接受PTC596的DIPG/HGG儿童 学习。这项研究将评估肿瘤和脑脊液中的BMI1活性和PTC596 PK 在患有HGG和DIPG的孩子中。试验是通过合作进行的 神经肿瘤临床试验网络（Connect）。这些数据将用于合理 潜在组合研究的设计以改善DIPG和HGG儿童的预后。