A NOVEL STRATEGY FOR THE TREATMENT OF MELANOMA

描述(申请人提供)：本研究的目的是开发一种新的、有效的治疗黑色素瘤的方法，特别是利用热疗来调节FDA批准的抗癌药物亚伯沙星(基于人血清白蛋白(HSA)的紫杉醇纳米粒)对肿瘤的输送。大约76,000人将被诊断出患有黑色素瘤，今年美国约有9,000人将死于黑色素瘤。尽管治疗黑色素瘤的选择很多，但死亡率仍然很高。高死亡率在一定程度上反映了缺乏有效的治疗方法，特别是对晚期疾病患者。在一项研究中，我们发现在41oC加热不到1小时的黑色素瘤细胞中，HSA水平增加了10倍以上(流式细胞仪分析)。相比之下，在正常的未转化的人成纤维细胞中，HSA水平在相同的热处理后没有变化。因此，我们假设亚/中度热疗可以有效地调节亚伯拉沙星在体内对肿瘤的转运，从而提高治疗黑色素瘤的疗效。在这项拟议的研究中，我们将用近红外(NIR)染料标记Abraxane，并使用局部和全身加温来调节Abraxane对体内原位黑色素瘤移植瘤和转移性黑色素瘤肿瘤的输送。局部加热治疗原位黑色素瘤的工作系统将使我们能够观察亚伯拉欣-近红外结合物在异种移植瘤中的积聚，并通过比较不同温度和时间加热的肿瘤之间的荧光强度平均值来优化热处理方案，以最大限度地将亚伯生素-近红外偶联物输送到肿瘤。患有肺转移性黑色素瘤的小鼠代表晚期疾病的患者，将接受全身热疗。这将使我们能够评估使用全身热疗来调节亚伯沙星对转移性肿瘤的输送的可行性。值得注意的是，热疗已经被用于改善血液循环，增加肿瘤细胞膜的通透性以被动地抗癌化学扩散，氧化肿瘤细胞的缺氧，并抑制DNA修复以使肿瘤细胞对化疗/放疗更敏感。这一应用的创新之处在于：1)发现加热后肿瘤细胞中HSA的含量增加；2)通过体内局部和全身加温，主动调节抗癌药物Abraxane向原发和转移性黑色素瘤的输送；3)将Abraxane与近红外染料偶联，观察抗癌药物在体内的生物分布和动力学变化。这项研究的结果可能会导致快速的临床试验，因为热疗和抗癌药物Abraxane都已经在使用，尽管目前是单独使用。这项拟议研究的成功完成可能会显著降低黑色素瘤患者的死亡率并提高他们的生活质量。

DESCRIPTION (provided by applicant): Abstract The objective of this study is to develop a novel and effective therapeutic approach for the treatment of melanoma, specifically using hyperthermia to modulate the delivery of the FDA approved anticancer drug Abraxane (human serum albumin (HSA) based paclitaxel-nanoparticle) to tumors. Approximately 76,000 individuals will be diagnosed with melanoma, and about 9,000 will die as a result of the disease this year in the United States. Even though there are many options for the treatment of melanoma, the mortality rate is still high. The high mortality rate partially reflects a lack of effective treatment methods, particularly for patients with late stage disease. In a study, we discovered that HSA levels increased more than 10-fold in melanoma cells heated at 41oC for less than 1 hour (flow cytometry analysis). In contrast, the levels of HSA did not change in normal untransformed human fibroblasts after the same heat treatment. Therefore, we hypothesize that mild/moderate hyperthermia could efficiently modulate Abraxane delivery to tumors in vivo and enhance therapeutic efficacy in the treatment of melanoma. In the proposed study, we will label Abraxane with near infrared (NIR) dye and use both local and whole body hyperthermia to modulate delivery of Abraxane to orthotopic melanoma xenografts and metastatic melanoma tumors in vivo. The working system of orthotopic melanoma treated with local hyperthermia will allow us to observe accumulation of Abraxane-NIR conjugate in xenograft tumors and optimize the heat treatment regimen for maximal delivery of the Abraxane-NIR conjugate to tumors by comparing mean values of fluorescence intensity among tumors heated at different temperatures and durations. The mice with lung metastatic melanoma, which represent patients with late stage disease, will be treated with whole body hyperthermia. This will allow us to assess the feasibility of using whole body hyperthermia to modulate Abraxane delivery to metastatic tumors. Note that hyperthermia has already been used to improve blood circulation, increase tumor cell membrane permeability for anticancer chemical diffusion passively, oxygenate hypoxia tumor cells, and inhibit DNA repair to make tumor cells more susceptible to chemo/radiotherapy. The novelty of this application is: 1) the discovery of additional significant increase in the amount of HSA in tumor cells after heat treatment; 2) actively modulating the delivery of anticancer drug Abraxane to primary and metastatic melanomas using local and whole body hyperthermia in vivo; 3) conjugation of Abraxane with NIR dye to observe the anticancer drug biodistribution and kinetic changes in vivo. Results from this study may lead to rapid clinical trials because both hyperthermia and the anticancer drug Abraxane are already in use, albeit individually at present. Successful completion of the proposed study may significantly reduce mortality and improve quality of life for melanoma patients.