A NOVEL STRATEGY FOR THE TREATMENT OF MELANOMA

描述（由申请人提供）：摘要本研究的目的是开发一种用于治疗黑色素瘤的新型有效治疗方法，特别是使用热疗来调节FDA批准的抗癌药物Abraxane（基于人血清白蛋白（HSA）的紫杉醇纳米颗粒）向肿瘤的递送。大约76，000人将被诊断患有黑色素瘤，今年在美国约有9，000人将死于这种疾病。尽管有许多治疗黑色素瘤的选择，但死亡率仍然很高。高死亡率部分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41 ℃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（流式细胞术分析）。相比之下，在相同的热处理后，正常未转化的人成纤维细胞中的HSA水平没有变化。因此，我们假设轻度/中度热疗可以有效地调节Abraxane在体内向肿瘤的递送，并提高治疗黑色素瘤的疗效。在拟议的研究中，我们将用近红外（NIR）染料标记Abraxane，并使用局部和全身热疗来调节Abraxane向体内原位黑素瘤异种移植物和转移性黑素瘤肿瘤的递送。用局部热疗治疗的原位黑色素瘤的工作系统将允许我们观察Abraxane-NIR缀合物在异种移植肿瘤中的积累，并通过比较在不同温度和持续时间下加热的肿瘤中的荧光强度的平均值来优化热处理方案，以最大限度地将Abraxane-NIR缀合物递送至肿瘤。患有肺转移性黑色素瘤的小鼠代表晚期疾病患者，将接受全身高温治疗。这将使我们能够评估使用全身高温来调节Abraxane向转移性肿瘤输送的可行性。注意，热疗已经用于改善血液循环，增加肿瘤细胞膜的渗透性以被动地进行抗癌化学扩散，抑制缺氧肿瘤细胞，并抑制DNA修复以使肿瘤细胞对化疗/放疗更敏感。本申请的新颖性在于：1）发现热处理后肿瘤细胞中HSA的量额外显著增加; 2）在体内使用局部和全身热疗主动调节抗癌药物Abraxane向原发性和转移性黑素瘤的递送; 3）Abraxane与NIR染料缀合以观察抗癌药物生物分布和体内动力学变化。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。成功完成拟议的研究可能会显着降低死亡率和改善黑色素瘤患者的生活质量。

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.