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，常规治疗只能起到缓解作用。在了解GBM遗传学和模拟这些肿瘤方面已经取得了巨大的进步，新的靶向治疗正在测试中，但这些进步并没有实质性地转化为改善患者的治疗效果。包括替莫唑胺（一种治疗胶质瘤的一线药物）在内的多种化疗药物已经被开发出来杀死癌细胞。然而，替莫唑胺对GBM的疗效并不明显。辐射也有一定的效果，但由于辐射对脑组织的附带损伤和无线电抗性的发展，这种方法受到局限性的困扰。开发一种新的治疗策略或辅助策略以提高现有治疗方法的疗效显然是一个未满足的临床需求。随着系统性癌症治疗的改善和脑转移成为越来越大的挑战，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。Connor实验室的新发现是，脑肿瘤模型中h -铁蛋白的减少使肿瘤对放射和化疗敏感，他们与Rich实验室结合了他们在癌症模型和肿瘤微环境方面的广泛知识，在两个富有成效的研究小组之间建立了协同作用，以最大限度地发挥对神经肿瘤学领域持续影响的潜力。细胞铁稳态的时间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-铁蛋白下调作为脑辅助治疗的机会就很明显了

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.