Exploiting ferroportin for cancer imaging and therapy

摘要：问题：抗击癌症的战场一直在变化。癌症转移，然后 需要系统的治疗。他们经常对激素疗法、生物制品和小分子药物产生抗药性。 分子--最终耗尽了可以用来对抗它们的药物。他们能够轻易地 使治疗失败是因为最初的治疗有限制剂量和疗效的副作用，而且还因为 它们不会杀死非增殖细胞，如癌症干细胞。这使得剩余的肿瘤细胞能够- Quire抵抗力和再生肿瘤。因此，迫切需要能够致命的治疗方法。 增殖性、非增殖性和抗药性癌细胞，为癌症患者提供了一个新的范式 癌症。解决方案：我们已经确定了一种完全具有这些属性的试剂：临床氧化铁纳米颗粒- Ccle Feraheme(FH)。许多侵袭性癌症都降低了铁蛋白的水平，铁蛋白是唯一已知的细胞 铁的输出者，随后细胞内的铁含量更高。这种癌细胞的特征使细胞生长 和扩散。然而，细胞中氧化还原活性增加的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试剂敏感。费拉希米人不是- 在其利用这一漏洞的能力方面是先例。首先，它增加了氧化还原活性的细胞内铁和铁- 在易感癌细胞中铁转运蛋白含量低的情况下催化羟基自由基，导致细胞死亡。第二，它 提供了更高的肿瘤特异性效应，因为正常细胞不仅在第一次 但也有能力解毒引入的铁，使用铁卟啉出口它。初步数据： 这种方法满足了药理学上非常有希望的靶点的所有标准：我们证明了铁-HO- 当正常细胞中有较高的铁蛋白，而正常细胞保持较高的铁蛋白水平时，癌细胞的生长停滞只是为了促进生长。 他们体内的铁平衡是平衡的。我们证明了亚铁血红素使癌细胞的抗氧化剂失代偿 容量，我们展示了我们可以使用核磁共振来检测高铁水平，这可以作为一种预测性的双水平。 反应的征兆。最后，我们展示了FH与临床使用的抗癌药物的协同作用 增加氧化应激，从而显著提高肿瘤特异性，同时减少副作用。Hy- 假说：根据我们的初步数据，我们假设FH甚至会杀死具有挑战性的癌症，我们 将能够根据癌细胞Low的独特分子特征用MRI预测疗效 含铁较高的磷化铁铁。通过最初关注前列腺癌，我们的目标是为物理学家提供数据- CIAN如何最好地利用法拉希素治疗激素难治性前列腺癌，无论是在标签外还是通过Fo-Fo- 引发了临床试验。具体目标：为了验证我们的假设，我们将(1)探索 铁血红素在体外和体内，使用异种移植和患者来源的前列腺癌有机物(2)评估 无创性磁共振T2*成像预测肿瘤反应的敏感性；以及(3)评价铁血红素的使用 与其他抗癌药物联合使用。

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.