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：针对癌症的战场在癌症转移和Theen中很有趣。 需要全身疗法。 分子 - 最终可以使用的药物。 击败治疗剂，因为初始治疗的副作用会限制剂量，也是因为 它们不会杀死非增殖细胞，例如癌细胞。 抗性和再生肿瘤。 增殖，非增殖和耐药性癌细胞，为癌症患者提供新的范式来击败 癌症：我们已经确定了具有这些属性的药物： CLE Feraheme（FH）。 铁的出口，随后突出显示细胞内铁。 和刺激性。 使癌细胞易于进一步耗尽其抗氧化能力的药物。 首先，它的利用能力。 低甲状腺素低的易感癌细胞中催化的羟基自由基，导致细胞死亡。 提供甚至更高的效果，因为正常细胞不仅在第一个中碰到 位置，但还可以通过使用铁蛋白导出来排毒引入铁的能力： 这种方法符合所有标准 Meostasis仅在癌症中仅受到干扰，以促进生长，而正常细胞具有较高的铁托蛋白并保持 他们的稳态平衡。 Capace，我们表明我们可以使用MRI来检测高铁水平，这可以用作预测性的bi- 最后，我们表明FH与临床使用的癌症药物协同 增加氧化应激，可以显着增加肿瘤特异性，同时降低副作用。 pothesis：鉴于我们的初步数据 将能够通过在癌细胞上低音低下的MRI来预测功效 铁蛋白具有高铁，我们的目标是提供物理学的数据 CIAN如何最好地利用Feraheme来用于激素难治性前列腺癌，无论是标签外还是通过FO- 临床试验的特定目的：为了测试我们的假设 Feraheme在体外和体内，使用Xenographs和患者衍生的前列腺癌器官（2）评估 非侵入性MR T2*对肿瘤反应的敏感性； 与其他抗癌药物结合使用。