Targeting Ferritin in Glioblastoma

描述（由申请人提供）：胶质母细胞瘤（GBM）是最致命的人类癌症之一，常规治疗仅提供姑息治疗。在理解GBM遗传学和建模这些肿瘤方面取得了很大的进步，新的靶向治疗正在测试中，但这些进展并没有实质性地转化为改善患者的预后。多种化疗药物，包括替莫唑胺，神经胶质瘤的一线治疗，已被开发用于杀死癌细胞。然而，替莫唑胺在GBM中的反应是适度的。辐射也是适度有效的，但这种方法受到限制，由于间接辐射损伤的功能脑组织和发展的辐射抗性。显然，开发新的治疗策略或辅助策略以增强现有治疗的疗效的临床需求尚未得到满足。随着系统性癌症治疗的改善和脑转移成为不断增加的挑战，这种未满足的临床需求变得更加紧迫。这项拨款申请代表了两个公认的研究项目的合并努力，以开发脑癌治疗的新范例。康纳实验室，他们的新发现，减少H-铁蛋白在脑肿瘤模型中的肿瘤敏感的放射和化疗，与丰富的实验室结合，他们的广泛知识的癌症模型和肿瘤微环境，创造两个生产性的研究小组之间的协同作用，以最大限度地发挥潜力，对神经肿瘤学领域的持续影响。细胞铁稳态的暂时中断似乎与缺氧途径的激活有关，这可能是治疗抵抗的基础。当H-铁蛋白对DNA保护和转录的特异性贡献丧失时，评估H-铁蛋白下调作为脑损伤的辅助治疗的机会之窗是显而易见的。 癌的这一提议也将为铁蛋白在肿瘤增殖和存活中的作用提供新的数据。因此，所提出的研究是创新性的，因为（i）它们为癌细胞中的关键调节蛋白引入了新的功能，（ii）它们解决了H-铁蛋白表达如何被诱导的机制，（iii）将H-铁蛋白鉴定为癌症中的新型分子靶标，（v）使用H-铁蛋白的治疗相关脂质体递送系统提供了H-铁蛋白的新型细胞特异性靶向。基于这两个实验室已经产生的证据，我们假设H-铁蛋白通过维持致瘤性分级生长模式和化疗/放射抗性来促进GBM生长，并且靶向抗铁蛋白疗法将破坏GBM生长。这两个实验室利用最先进的纳米技术，包括细胞特异性药物递送到癌细胞和多光子成像，以及新型和高度信息化的胶质瘤小鼠模型，共同努力解决靶向H-铁蛋白的潜在治疗价值，并通过证明铁蛋白的新功能来推进基础科学领域，铁蛋白曾经被认为只是细胞内的铁储存蛋白。

DESCRIPTION (provided by applicant): Glioblastoma (GBM) ranks among the most lethal of human cancers with conventional therapy offering only palliation. Great strides have been made in understanding GBM genetics and modeling these tumors, and new targeted therapies are being tested but these advances have not substantially translated into improved patient outcomes. Multiple chemotherapeutic agents, including temozolomide, a first-line treatment in glioma, have been developed to kill cancer cells. However, the response to temozolomide in GBM is modest. Radiation is also moderately effective but this approach is plagued by limitations due to collateral radiation damage to eloquent brain tissue and development of radio-resistance. There is clearly an unmet clinical need, to develop either a novel treatment strategy or an adjuvant strategy to enhance efficacy of existing treatments. This unmet clinical need becomes even more pressing as systemic cancer treatments improve and brain metastases become an ever increasing challenge. This grant application represents the merged efforts of two recognized research programs to develop new paradigms for brain cancer treatment. The Connor laboratory, with their new discovery that reduction of H-ferritin in models of brain tumors sensitizes the tumors to radio and chemotherapy has combined with the Rich laboratory with their extensive knowledge of cancer models and tumor microenvironments to create a synergy between two productive research groups to maximize the potential for sustained impact on the field of Neuro-Oncology. The temporal disruption in cellular iron homeostasis appears linked to activation of hypoxic pathways that may underlie therapy resistance. When coupled with the loss of specific contributions of H- ferritin to DNA protection and transcription, a window of opportunity is evident for evaluation of H-ferritin down-regulation as an adjuvant therapy in brain cancers. This proposal will also provide new data into the role of ferritin in tumor propagation and survival. Thus the proposed studies are innovative because (i) they introduce a new function for a critical regulatory protein in cancer cells, (ii) they address the mechanism of how H-ferritin expression is induced, (iii) identify H-ferritin as a novel molecular target in cancer (v) provide a novel cellular-specific targeting of H-ferritin using a therapeutic relevant liposomal delivery system of H-ferritin. Based on the evidence both laboratories have generated, we hypothesize that H-ferritin promotes GBM growth by maintaining tumorigenic hierarchical growth patterns and chemo-/radio-resistance and that targeted anti-ferritin therapies will disrupt GBM growth. These two laboratories have joined efforts utilizing state of the art nanotechnology, including cell-specific drug delivery to cancer cells and multi-photon imaging and novel and highly informative glioma mouse models address the potential therapeutic value of targeting H-ferritin and advance the basic scientific field by demonstrating novel functions for ferritin that was once considered only an intracellular iron storage protein.