Selective Killing of FH-/- Cancer Cells by Targeting Cellular Iron Homeostasis

通过靶向细胞铁稳态选择性杀死 FH-/- 癌细胞

基本信息

批准号：
10310485
负责人：
Aikseng Ooi
金额：
$ 32.36万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-12-24 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10310485
关键词：
Age Alleles Autophagocytosis CCI-779 Cancer Biology Cancer Patient Cancer cell line Cause of Death Cell Death Cell Line Cell Proliferation Cells Citric Acid Cycle Deferoxamine Disease remission Drug Combinations Drug Design Effectiveness Engineering Enzymes Event Exhibits Ferritin Fumarate Hydratase Fumarates Future Genes Growth Hereditary Leiomyomatosis and Renal Cell Cancer Hereditary Neoplastic Syndromes Homeostasis In Vitro Iron Iron Chelating Agents Iron Chelation Loss of Heterozygosity Malignant Neoplasms Methods Mutation Neoplasm Metastasis Normal Cell Operative Surgical Procedures Oxidation-Reduction Papillary Pathway interactions Pharmacology Proteins Radio Relapse Renal Cell Carcinoma Renal carcinoma Reporting Resistance Signal Transduction Sirolimus Testing Therapeutic Intervention Tissues Translations Triapine Work Xenograft procedure base cancer cell cell growth cellular targeting comparative efficacy compare effectiveness effective therapy efficacy evaluation efficacy validation in vivo insight knock-down mouse model novel novel drug combination prevent protein expression therapeutic development treatment strategy tumor tumorigenesis

项目摘要

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant hereditary cancer syndrome caused by a germline inactivating mutation in one of the alleles of the gene encoding the tricarboxylic acid (TCA) cycle enzyme, fumarate hydratase (FH). HLRCC patients are predisposed to develop aggressive papillary renal cell carcinoma type 2 (PRCC2) at an early age. The cancer tissues exhibit a loss-of- heterozygosity at the FH locus, indicating biallelic FH inactivation (FH-/-) as a critical event in tumorigenesis. These tumors often metastasize early, limiting the effectiveness of surgical intervention. Moreover, the tumors are resistant to all known chemo, targeted, and radio therapies, making PRCC2 a major cause of death among HLRCC patients. Therefore, a treatment strategy against HLRCC is urgently needed. FH-/- imparts very specific changes to the cancer cells. Particularly, FH-/- cancer cells accumulate high level of the TCA cycle intermediate, fumarate, which alters cellular signaling in very specific ways. Identifying these FH- /- specific cellular changes will therefore offer ways to target the FH-/- cancer cells, while sparing normal cell. This application exploits a FH-/--specific vulnerability that we discovered recently. Specifically, FH-/- alters cellular iron signaling, making the cells sensitive to an iron dependent cell death mechanism known as ferroptosis. We hypothesized that ferritin inhibition in FH-/- cancer cells will further enhance their sensitivity to ferroptosis while concurrently inhibiting the ferritin-dependent pro-proliferative signaling. We will test our hypothesis through the following aims: (1) Define and compare pathway alterations induced by different methods of ferritin inhibition in FH-/- cancer cells. (2) Evaluate the efficacy of combining ferritin inhibition with ferroptosis inducing compounds (FINS) in vitro and confirm their mechanisms of action. (3) Validate the efficacy of combining ferritin inhibition with FINS in vivo. Insights gained from this study will positively impact the treatment of other ferroptosis sensitive tumors.

遗传性平滑肌瘤病和肾细胞癌（HLRCC）是常染色体显性遗传癌综合征是由种系在编码基因的一个等位基因之一中灭活突变引起的三羧酸（TCA）循环酶，富马酸水合物（FH）。 HLRCC患者倾向于发展攻击性乳头状肾细胞癌在很小的时候。癌组织表现出 - FH基因座的杂合性，表明双重FH失活（FH - / - ）是肿瘤发生中的关键事件。这些肿瘤通常会尽早转移，从而限制了手术干预的有效性。而且，肿瘤对所有已知的化学疗法，靶向和无线电疗法具有抵抗力，使PRCC2成为主要的死亡原因 HLRCC患者。因此，迫切需要针对HLRCC的治疗策略。 FH - / - 对癌细胞进行了非常具体的变化。特别是，FH - / - 癌细胞积累了高水平 TCA循环中间，富马酸盐，以非常特定的方式改变细胞信号。确定这些FH- / - 特定的细胞变化将提供靶向FH - / - 癌细胞的方法，同时保留正常细胞。该应用程序利用了我们最近发现的FH - / - 特定漏洞。具体而言，FH - / - 改变细胞铁信号传导，使细胞对依赖铁的细胞死亡机制敏感铁凋亡。我们假设FH - / - 癌细胞中的铁蛋白抑制作用将进一步增强其同时抑制铁蛋白依赖性的促增殖性信号传导的同时，对铁铁作用的敏感性。我们将通过以下目的检验我们的假设：（1）定义并比较由 FH - / - 癌细胞中铁蛋白抑制的不同方法。（2）评估结合铁蛋白的功效在体外诱导化合物（FIN）抑制作用，并确认其作用机理。（3）验证将铁蛋白抑制与体内的鳍片结合的功效。从这项研究中获得的见解将积极影响其他铁铁毒性敏感肿瘤的治疗。