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

遗传性子宫肌瘤病和肾细胞癌是一种常染色体显性遗传性癌症。 由编码基因的一个等位基因的种系失活突变引起的综合征 三元酸(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(PRCC2)。癌组织显示出一种- FH基因的杂合性，表明双等位基因FH失活(FH-/-)是肿瘤发生的关键事件。 这些肿瘤往往很早就转移，限制了手术干预的有效性。此外，这些肿瘤 对所有已知的化疗、靶向和放射疗法具有耐药性，使PRCC2成为 HLRCC患者。因此，迫切需要针对HLRCC的治疗策略。 FH-/-赋予癌细胞非常特殊的变化。特别是，FH-/-癌细胞积累了高水平的 TCA循环的中间产物富马酸，它以非常特殊的方式改变细胞信号。识别这些跳频- 因此，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。 此应用程序利用了我们最近发现的FH/-特定漏洞。具体地说，FH-/-更改 细胞铁信号，使细胞对铁依赖的细胞死亡机制敏感，称为 铁性下垂。我们推测，抑制FH-/-癌细胞中的铁蛋白将进一步增强其 对铁性下垂的敏感性，同时抑制铁蛋白依赖的促增殖信号。 我们将通过以下目标来验证我们的假设：(1)定义和比较由 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 铁下垂诱导化合物(FINS)的体外抑制作用，并确认其作用机制。(3) 在体内验证联合应用铁蛋白抑制和FINS的效果。从这项研究中获得的见解将 对其他铁性下垂敏感型肿瘤的治疗有积极影响。

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.