Exploiting ferroportin for cancer imaging and therapy

利用铁转运蛋白进行癌症成像和治疗

• 批准号: 10170300
• 负责人: Jan Grimm
• 金额: $ 52.17万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-09 至 2022-05-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10170300
• 关键词: Address; Advanced Malignant Neoplasm; Affect; Antineoplastic Agents; Antioxidants; Biological; Biological Response Modifier Therapy; Cancer Patient; Cell Death; Cell Proliferation; Cell Survival; Cells; Clinic; Clinical; Clinical Trials; Data; Dose; Drug Carriers; Drug resistance; Epithelial Cells; Grant; Growth; Homeostasis; Hormones; Human; Hydroxyl Radical; In Vitro; Iron; Knowledge; Label; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of prostate; Measures; Molecular Profiling; Natural regeneration; Neoplasm Metastasis; Normal Cell; Organoids; Oxidation-Reduction; Oxidative Stress; Patients; Pharmaceutical Preparations; Pharmacology; Phenotype; Physicians; Prediction of Response to Therapy; Prognosis; Proliferating; Prostate; Public Health; Reaction; Reactive Oxygen Species; Resistance; Safety; Solid; Solid Neoplasm; Systemic Therapy; T2 weighted imaging; Testing; Therapeutic; Therapeutic Index; Work; Xenograft procedure; base; cancer cell; cancer imaging; cancer stem cell; cancer therapy; cell growth; cell killing; cost; drug candidate; erastin; exhaust; ferumoxytol; fighting; hepcidin; hormone refractory prostate cancer; hormone therapy; improved; in vivo; iron oxide; iron oxide nanoparticle; iron supplementation; macrophage; malignant breast neoplasm; metal transporting protein 1; neoplastic cell; prostate cancer cell; refractory cancer; response; side effect; small molecule; tumor; tumor molecular fingerprint; tumor specificity

ABSTRACT: Problem: The battle field against cancer is constantly in flux. Cancers metastasize and then require systemic therapy. They frequently become resistant to hormone therapies, biologicals, and small molecules - eventually depleting the arsenal of drugs that can be used against them. They are able to readily defeat therapeutics because initial treatments have side effects that limit dose and efficacy and also because they do not kill non-proliferating cells, such as cancer stem cells. This allows remaining tumor cells to ac- quire resistance and to regenerate tumors. Accordingly, there is an urgent need for treatments that can kill proliferating, non-proliferating, and drug resistant cancer cells, giving cancer patients a new paradigm to beat cancer. Solution: We have identified an agent with exactly these attributes: the clinical iron oxide nanoparti- cle Feraheme (FH). Many aggressive cancers have decreased levels of ferroportin, the sole known cellular exporter of iron, and subsequently higher intracellular iron. This cancer cell signature enables cell growth and proliferation. Yet, the increased redox-active iron in cells also generates deleterious hydroxyl radicals, making cancer cells susceptible to agents that further exhaust their antioxidant capacity. Feraheme is un- precedented in its ability to exploit this vulnerability. First, it increases redox-active intracellular iron and iron- catalyzed hydroxyl radicals in susceptible cancer cells with low ferroportin, leading to cell death. Second, it provides for an even higher tumor-specific effect, since normal cells are not only less susceptible in the first place, but also have the ability to detoxify introduced iron by using ferroportin to export it. Preliminary Data: This approach fulfills all the criteria for a pharmacologically highly promising target: We show that iron ho- meostasis is only perturbed in cancer to promote growth while normal cells have higher ferroportin and keep their iron homeostasis balanced. We demosntrate that Feraheme decompensates cancer cell’s antioxidant capacity, and we show we can use MRI to detect high iron levels, which could serving as a predictive bi- omarker of response. Lastly, we show that FH works synergistically with clinically used cancer drugs that increase oxidative stress, thereby significantly increasing tumor specificity while reducing side effects. Hy- pothesis: Given our preliminary data, we hypothesize that FH will kill even challenging cancers and that we will be able to predict efficacy with MRI based on the cancer cells’ unique molecular signature of low ferroportin with high iron. By focusing initially on prostate cancer, our objective is to provide data for physi- cians how to best exploit Feraheme for hormone refractory prostate cancer, either off-label or through fo- cused clinical trials. Specific Aims:To test our hypotheses, we will (1) Explore the therapeutic index of Feraheme in vitro and in vivo, using xenografts and patient-derived prostate cancer organoids (2) evaluate sensitivity of noninvasive MR T2* imaging to predict the tumor response; and (3) evaluate use of Feraheme in combination with other anti-cancer agents.

摘要：问题：癌症的战场是不断变化的。癌症会转移， 需要系统治疗。他们经常成为抵抗激素疗法，生物制剂，和小 分子-最终耗尽了可以用来对付它们的药物库。他们能够轻易地 因为初始治疗具有限制剂量和功效的副作用， 它们不杀死非增殖细胞，例如癌症干细胞。这使得剩余的肿瘤细胞能够- quire抗性和再生肿瘤。因此，迫切需要能够杀死 增殖，非增殖和耐药癌细胞，为癌症患者提供了一个新的范例， 癌解决方案：我们已经确定了一种具有这些属性的药物：临床氧化铁纳米颗粒， Cle Feraheme（FH）.许多侵袭性癌症具有铁转运蛋白水平的降低，铁转运蛋白是唯一已知的细胞转运蛋白。 铁的输出，随后更高的细胞内铁。这种癌细胞特征使细胞生长 和扩散。然而，细胞中增加的氧化还原活性铁也会产生有害的羟基自由基， 使癌细胞对进一步耗尽其抗氧化能力的药剂敏感。Feraheme是不- 在利用这一漏洞方面是前所未有的。首先，它增加了氧化还原活性的细胞内铁和铁- 在具有低铁转运蛋白的易感癌细胞中催化羟基自由基，导致细胞死亡。二是 提供了甚至更高的肿瘤特异性效应，因为正常细胞不仅在第一次给药时较不敏感， 地方，但也有能力解毒引入铁通过使用ferroportin输出它。初步数据： 这种方法满足了一个非常有前途的目标的所有标准：我们表明，铁HO-1， 肿瘤细胞的动态平衡仅受到干扰以促进生长，而正常细胞具有更高的膜铁转运蛋白并保持 他们的铁平衡平衡我们证明Feraheme使癌细胞的抗氧化剂失代偿 能力，我们表明我们可以使用MRI来检测高铁水平，这可以作为一个预测性的双 回应的标志。最后，我们表明FH与临床使用的抗癌药物协同作用， 增加氧化应激，从而显著增加肿瘤特异性，同时减少副作用。嘿 假设：根据我们的初步数据，我们假设FH将杀死甚至具有挑战性的癌症， 将能够根据癌细胞独特的低分子特征预测MRI的疗效 铁含量高的ferroportin。通过最初关注前列腺癌，我们的目标是为物理治疗提供数据。 医生如何最好地利用Feraheme治疗激素难治性前列腺癌，无论是标签外还是通过药物治疗， 进行临床试验。具体目的：为了验证我们的假设，我们将（1）探索治疗指数 Feraheme在体外和体内，使用异种移植物和患者来源的前列腺癌类器官（2）评估 非侵入性MR T2* 成像预测肿瘤反应的敏感性;（3）评估Feraheme的使用 与其他抗癌剂联合使用。