Targeting the GPC2 oncoprotein with immune-based therapies in neuroblastoma

项目概要/摘要 我的职业目标是成为一名医生科学家，专注于将新的实验室发现转化为 安全有效的治疗高危儿童实体瘤。该提案描述了一个5- 一年计划，旨在促进我的发展成为一个独立的翻译医生，科学家，通过 获得关键的技术技能，与教学培训和全面的指导相结合， 宾夕法尼亚大学（Penn）和儿童医院的终身教职员工组成的多元化团队 费城（CHOP）我将在下列杰出和行之有效的指导下进行拟议的研究： 博士约翰·马里斯是转化性神经母细胞瘤研究的国际领导者。此外，我的奉献精神 咨询委员会由在癌症方面具有不同专业知识的备受推崇的医生-科学家组成 生物学和免疫疗法。最后，科学合作，资源丰富的研究环境， Penn和CHOP为进行这些转化研究提供了理想的环境。 拟议的研究重点是信号辅助受体磷脂酰肌醇蛋白聚糖-2（GPC 2）。本实验室 发现GPC 2是糖磷脂酰肌醇（GPI）-连接到神经母细胞瘤的细胞外表面， 但在大多数正常儿科组织中没有发现。我还发现神经母细胞瘤依赖于 用于肿瘤生长。为了利用GPC 2的差异表达，我进行了概念验证， 在神经母细胞瘤患者来源的异种移植物（PDX）鼠模型中的体内功效研究显示， 靶向GPC 2的抗体药物缀合物（ADC; D3-GPC 2-PBD）导致持续的肿瘤消退。的 恶性机制和选择性靶向其他磷脂酰肌醇蛋白聚糖，如GPC 3，与免疫为基础的能力， 治疗方法已经得到了很好的研究。然而，GPC 2在促进肿瘤发生中的作用，GPC 2的适用性 作为免疫治疗的安全有效靶点，以及最佳的基于免疫的治疗方法， 目标GPC 2，目前都还没有定义。我假设GPC 2是一个重要的致癌调节因子， 神经母细胞瘤中的信号通路，并且鉴于其稳健的差异表达，是理想的细胞表面 分子用于基于免疫的治疗方法。因此，我建议：（1）定义潜在的机制 神经母细胞瘤中异常GPC 2细胞表面表达和致瘤性，（2）确定疗效和 D3-GPC 2-PBD ADC在神经母细胞瘤中的安全性特征，和（3）工程化GPC 2重定向嵌合 抗原受体（CAR）T细胞，并建立其在神经母细胞瘤中的功效。总之，我会利用 我的导师和咨询委员会的知识力量和业绩记录，以及专业知识， 实验室设施和科学资源，在CHOP和宾夕法尼亚大学，以成功地实现这一目标 提出研究和职业发展计划。这些努力将为我提供一个出色的基础， 职业生涯作为一个物理学家，科学家和一个独立的翻译研究计划的发展。

PROJECT SUMMARY/ABSTRACT My career goals are to become a physician-scientist focused on translating novel laboratory discoveries into safe and efficacious therapies for children with high-risk pediatric solid tumors. This proposal describes a 5- year plan designed to facilitate my development into an independent translational physician-scientist through the acquisition of critical technical skills, integrated with didactic training and comprehensive mentoring from a diverse team of tenured faculty members at the University of Pennsylvania (Penn) and the Children’s Hospital of Philadelphia (CHOP). I will conduct the proposed studies under the outstanding and proven mentorship of Dr. John Maris, an international leader in translational neuroblastoma research. Additionally, my dedicated Advisory Committee is comprised of highly regarded physician-scientists with diverse expertise in cancer biology and immunotherapy. Finally, the scientifically collaborative, resource-rich research environment at Penn and CHOP provides an ideal setting to conduct these translational studies. The proposed research focuses on the signaling co-receptor glypican-2 (GPC2). Our laboratory has discovered that GPC2 is glycophosphatidylinositol (GPI)-linked to the extracellular surface of neuroblastomas, but is not found on a majority of normal pediatric tissues. I have also found that neuroblastomas are dependent on GPC2 for tumor growth. To capitalize on GPC2’s differential expression, I have performed proof-of-concept in vivo efficacy studies in neuroblastoma patient-derived xenograft (PDX) murine models showing that a GPC2-targeted antibody drug conjugate (ADC; D3-GPC2-PBD) results in sustained tumor regression. The malignant mechanisms and the ability to selectively target other glypicans, such as GPC3, with immune-based therapies have been well-studied. However, GPC2’s role in promoting tumorigenesis, the suitability of GPC2 as a safe and effective target for immunotherapeutics, and the optimal immune-based therapy approach to target GPC2, all currently remain undefined. I hypothesize that GPC2 is a critical regulator of oncogenic signaling pathways in neuroblastoma and, given its robust differential expression, is an ideal cell surface molecule for immune-based therapeutic approaches. Thus, I propose to (1) Define the mechanisms underlying aberrant GPC2 cell surface expression and oncogenicity in neuroblastoma, (2) Determine the efficacy and safety profile of the D3-GPC2-PBD ADC in neuroblastoma, and (3) Engineer GPC2-redirected chimeric antigen receptor (CAR) T cells and establish their efficacy in neuroblastoma. In summary, I will take advantage of the intellectual strength and track-record of my mentor and Advisory Committee, as well as the expertise, laboratory facilities, and scientific resources available at CHOP and Penn to successfully accomplish this proposed research and career development plan. These efforts will provide an outstanding foundation for my career as a physician-scientist and the development of an independent translational research program.