ROLE OF MIDKINE IN MOLECULAR TARGETED THERAPY TO TIP1 FOR LUNG CANCER TREATMENT

项目描述/摘要 非小细胞肺癌（NSCLC）是世界范围内癌症相关死亡率最高的疾病之一。分子 靶向治疗是提高NSCLC治疗效果的一个日益增长的研究课题。一些针对 利用异常蛋白质表达谱的疗法已被批准用于NSCLC。但 通过这些治疗方法观察到的疗效改善的癌症的边际百分比强调 需要发现更多的分子靶点。这项研究具有重要意义，因为它将产生 新的分子靶点和治疗策略。我们建议将脚手架 通过分析癌症基因组图谱数据集鉴定的肺癌新靶点蛋白质TIP 1 和NSCLC肿瘤组织微阵列。TIP 1的功能结构域（PDZ结构域）覆盖TIP 1的C-末端。 调节重要细胞功能的许多不同的细胞蛋白质。击倒TIP 1显示， 在细胞信号传导、癌症发展和进展中起重要作用，使其成为治疗癌症的有吸引力的靶点。 抗癌疗法比较靶向TIP 1的不同表位的抗体，发现抗体 针对TIP 1的PDZ结构域的抗体在诱导肺癌细胞的直接细胞毒性方面最有效，但在诱导肺癌细胞的直接细胞毒性方面没有 正常细胞抗PDZ/TIP 1抗体注射到携带肺癌的小鼠中特异性结合癌细胞 并显著增强肿瘤控制。定量质谱法鉴定Midkine（MDK）为 通过抗PDZ/TIP 1抗体调节这种细胞毒性的推定蛋白质。其他研究表明， β-catenin/Wnt信号通路可能参与了阻断TIP 1后MDK的上调。在一起， 这些研究导致了一个中心假设，即抗PDZ/TIP 1抗体通过β- 连环蛋白/Wnt信号通路，其随后调节下游细胞死亡机制。目标1将 阐明阻断TIP 1的PDZ结构域后诱导MDK的机制。这一目标将 从而鉴定出以前从未考虑过的NSCLC治疗的新分子靶点。 目的2：在小鼠中评价阻断TIP 1功能同时阻断MDK功能的功效 NSCLC模型。这一目标将指导联合治疗的发展，以优化药物的疗效。 NSCLC治疗。这项研究是创新的，因为我们正在研究一种新的分子靶点TIP 1。 阻断TIP 1的功能结构域导致NSCLC细胞死亡。我们还提出了一项创新战略， 双重靶向TIP 1和MDK，以增强NSCLC的治疗效果。基于我的癌症生物学 背景，这个K22奖将使我能够在尖端蛋白质组学和基因组学方法方面进行培训， 特别强调识别新的NSCLC分子靶点。我已经提出了一个研究和培训计划 这将使我具备最高的技能，以确保我作为一名独立调查员取得成功。总体看 我未来研究的长期目标是为新疗法的发展提供新的机会 来治疗肺癌。

PROJECT DESCRIPTION/ ABSTRACT Non-small cell lung cancer (NSCLC) ranks among the highest cancer-related mortalities world-wide. Molecular targeted therapy is a growing topic of investigation to improve therapeutic efficacy for NSCLC. A few targeted therapies that exploit aberrant protein expression profiles have been approved for NSCLC. However, the marginal percentage of cancers with improved efficacy observed with these therapeutic approaches highlights the need for discovery of additional molecular targets. The proposed research is significant as it will generate new molecular targets and treatment strategies for NSCLC therapy. We propose targeting of the scaffold protein TIP1 that is a novel target for lung cancer as identified by analysis of the cancer genome atlas datasets and NSCLC tumor tissue microarrays. The functional domain of TIP1 (PDZ domain) caps the C-terminus of many different cellular proteins that regulate important cellular functions. Knocking down TIP1 revealed that it plays an important role in cell signaling, cancer development, and progression making it an attractive target for anticancer therapeutics. Comparing antibodies targeting different epitopes of TIP1, it was found that antibodies against the PDZ domain of TIP1 were most effective in inducing direct cytotoxicity of lung cancer cells but not normal cells. Anti-PDZ/TIP1 antibodies injected into mice bearing lung cancer bind specifically to cancer cells and substantially enhance tumor control. Quantitative mass spectrometry identified Midkine (MDK) as a putative protein that modulates this cytotoxicity by anti-PDZ/TIP1 antibodies. Additional studies suggested that the β-catenin/Wnt signaling may be involved in this up-regulation of MDK after blocking of TIP1. Together, these studies led to the central hypothesis that MDK is upregulated by the anti-PDZ/TIP1 antibody via the β- catenin/Wnt signaling pathway, which subsequently modulates downstream cell death mechanisms. Aim 1 will elucidate the mechanisms of induction of MDK following blockade of the PDZ domain of TIP1. This aim will lead to identification of novel molecular targets for NSCLC treatment that have never been considered before. Aim 2 will evaluate the efficacy of blocking TIP1 function while simultaneously blocking MDK function in mouse models of NSCLC. This aim will guide the development of combination therapies to optimize efficacy of NSCLC treatment. This research is innovative because we are studying a novel molecular target, TIP1. Blocking the functional domain of TIP1 leads to NSCLC cell death. We also propose an innovative strategy of dual targeting TIP1 and MDK to enhance the therapeutic efficacy of NSCLC. Building on my cancer biology background, this K22 award will allow me to train in cutting edge proteomic and genomic approaches with special emphasis on identifying novel NSCLC molecular targets. I have proposed a research and training plan that will equip me with the highest skills to ensure my success as an independent investigator. Overall, the long-term goal of my future research, is to provide new opportunities for the development of novel therapies to treat lung cancer.