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

• 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
• 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

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是一种常染色体显性遗传性肿瘤 综合征是由编码该疾病的基因的等位基因之一中的种系失活突变引起的， 三羧酸（TCA）循环酶、富马酸水合酶（FH）。HLRCC患者易发生 早期侵袭性乳头状肾细胞癌2型（PRCC 2）。癌组织表现出- 在FH基因座处的杂合性，表明双等位基因FH失活（FH-/-）是肿瘤发生中的关键事件。 这些肿瘤通常早期转移，限制了手术干预的有效性。此外，肿瘤 对所有已知的化疗、靶向治疗和放射治疗都有抗药性，这使得PRCC 2成为癌症患者死亡的主要原因。 HLRCC患者。因此，迫切需要针对HLRCC的治疗策略。 FH-/-赋予癌细胞非常特异性的变化。特别地，FH-/-癌细胞积累高水平的 TCA循环中间体富马酸盐，以非常特定的方式改变细胞信号传导。识别这些FH- 因此，FH-/-特异性细胞变化将提供靶向FH-/-癌细胞的方法，同时保留正常细胞。 这个应用程序利用了我们最近发现的一个特定于FH-/-的漏洞。具体而言，FH-/-改变 细胞铁信号传导，使细胞对铁依赖性细胞死亡机制敏感， 铁性下垂我们假设FH-/-癌细胞中的铁蛋白抑制将进一步增强其表达。 同时抑制铁蛋白依赖性促增殖信号传导。 我们将通过以下目标来检验我们的假设：（1）定义和比较由以下因素引起的通路改变： FH-/-癌细胞中铁蛋白抑制的不同方法。(2)评价联合铁蛋白的疗效 在体外用铁凋亡诱导化合物（FINS）抑制，并确认其作用机制。（三） 在体内证实铁蛋白抑制与FINS组合的功效。从这项研究中获得的见解将 积极影响其他铁下垂敏感性肿瘤的治疗。