Targeting Ferritin in Glioblastoma

描述(申请人提供)：胶质母细胞瘤(GBM)是人类最致命的癌症之一，传统的治疗方法只能提供姑息治疗。在理解GBM遗传学和对这些肿瘤进行建模方面已经取得了很大进展，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结果。多种化疗药物，包括治疗胶质瘤的一线药物替莫唑胺，已经被开发出来杀死癌细胞。然而，替莫唑胺在GBM中的反应是温和的。放射治疗也是适度有效的，但由于附带辐射对能言善辩的脑组织的损害和放射抗性的发展，这种方法受到限制。显然，有一种尚未得到满足的临床需求，即开发一种新的治疗策略或一种辅助策略来提高现有治疗方法的疗效。随着系统性癌症治疗的改善和脑转移成为一个日益严峻的挑战，这一未得到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计划的合并努力，以开发脑癌治疗的新范例。Connor实验室的新发现是，脑瘤模型中H-铁蛋白的减少会使肿瘤对放射和化疗敏感，他们与Rich实验室结合起来，凭借其对癌症模型和肿瘤微环境的广泛知识，在两个富有成效的研究小组之间创造了协同效应，最大限度地扩大了对神经肿瘤学领域持续影响的潜力。细胞铁稳态的暂时破坏似乎与低氧途径的激活有关，这可能是治疗抵抗的基础。当再加上H-铁蛋白对DNA保护和转录的特定贡献的丧失时，很明显有机会评估H-铁蛋白下调作为脑内辅助治疗的作用 癌症。这项提议还将为铁蛋白在肿瘤增殖和生存中的作用提供新的数据。因此，建议的研究具有创新性，因为(I)它们引入了癌细胞中关键调节蛋白的新功能，(Ii)它们解决了H-铁蛋白如何被诱导表达的机制，(Iii)确定H-铁蛋白是癌症中的一个新的分子靶点，(V)利用相关的H-铁蛋白脂质体递送系统提供了一种新的细胞特异性靶向H-铁蛋白。根据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的分层生长模式和化疗/放射耐受来促进GBM的生长，并且有针对性的抗铁蛋白疗法将扰乱GBM的生长。这两个实验室携手合作，利用最先进的纳米技术，包括细胞特异性药物输送到癌细胞和多光子成像，以及新型和高信息量的胶质瘤小鼠模型，解决了靶向H-铁蛋白的潜在治疗价值，并通过展示铁蛋白的新功能推进了基础科学领域，铁蛋白曾被认为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.