Prevention of Metastatic Cancer Using a Novel Vitamin E Analog

描述(申请人提供)：化疗延长癌症患者生命的能力受到严重副作用的影响，如骨髓毒性和全身性免疫抑制。这些缺点促使人们不懈地努力寻找和开发新的抗肿瘤药物和治疗方式，这些药物和治疗方式不仅可以摧毁现有的癌症，对宿主的毒性最小，而且可以防止疾病复发。一种可能具有这些特性的药物是α-托苯乙酸乙酯(a-TEA)。α-TEA是一种亲脂性、抗酯酶、半合成的天然维生素E(RRR-α-生育酚)类似物，在体外选择性地诱导癌细胞凋亡，并在临床前动物模型中抑制肿瘤生长。A-TEA化疗的临床前发现由于其脂溶性而阻碍了将其转化到临床上，这需要将其溶解在对人类不切实际的有机溶剂中。我们已经开发了一种新的形式的a-茶，泡化a-茶(Va-TEA)，它更易溶于水，更适合临床使用。这项研究的目标是将Va-TEA与树突状细胞(DC)疫苗相结合，以防止已确诊和残留疾病环境中的乳腺癌转移。在初步研究中，我们已经证明Va-TEA在体外有效地杀死肿瘤细胞，导致DC成熟，并在体内抑制肿瘤生长。需要检验的假设是，口服Va-TEA和DC疫苗的组合将在宿主毒性最小的情况下非常有效地防止癌症扩散。这一假说的理论基础是有证据表明，α-TEA可以诱导肿瘤细胞的凋亡和继发性坏死，DC能够吞噬被杀死的肿瘤细胞，并将肿瘤相关抗原交叉递送到T淋巴细胞，以诱导肿瘤特异性免疫。本研究的具体目的是：1)确定Va-TEA联合DC疫苗预防肿瘤转移的有效性；2)阐明Va-TEA介导的抗肿瘤作用的免疫学机制。这项研究完成后，我们将开发一种新的方法来控制原发癌症的扩散，并提高我们对Va-TEA介导的肿瘤免疫的理解。这些目标的实现应该对转移性癌症的治疗具有很高的转化潜力。

DESCRIPTION (provided by applicant): The ability of chemotherapy to extend the life of cancer patients is compromised by severe side effects such as marrow toxicity and generalized immunosuppression. These drawbacks have fueled tireless efforts to identify and develop novel anti-neoplastic agents and treatment modalities that will not only destroy the existing cancer, have minimal toxicity to the host, but also prevent disease recurrence. One drug that may have these properties is alpha-Tocopheryloxyacetic acid (a-TEA). Alpha-TEA is a lipophilic, esterase resistant, semi-synthetic analog of naturally-occurring vitamin E (RRR-alpha-tocopherol) that selectively induces apoptosis of cancer cells in vitro and suppresses tumor growth in pre-clinical animal models. Translation of the pre-clinical findings of a-TEA chemotherapy to the clinic has been hampered by its lipid solubility that requires dissolving it in organic solvents that are impractical for use in humans. We have developed a novel form of a-TEA, vesiculated a-TEA (Va-TEA) that is more water-soluble and is more relevant for clinical use. The goal of this study is to employ Va-TEA in combination with dendritic cell (DC) vaccination to prevent breast cancer metastases in the established and residual disease settings. In preliminary studies we have shown that Va-TEA efficiently kills tumor cells in vitro, causes DC maturation and inhibits tumor growth in vivo. The hypothesis to be tested is that the combination of oral Va-TEA plus DC vaccination will be highly effective in preventing cancer dissemination with minimal host toxicity. The rationale for this hypothesis is based on evidence that a-TEA induces apoptosis and secondary necrosis of tumor cells and that DCs are capable of ingesting killed tumor cells and cross-presenting tumor-associated antigens to T lymphocytes to induce tumor-specific immunity. The Specific Aims of this study are to: 1) Determine the effectiveness of Va-TEA plus DC vaccination in preventing metastatic spread of cancer and 2) Elucidate the immunologic mechanisms of Va-TEA-mediated anti-tumor activity. Upon completion of this study we would have developed a novel approach to control the spread of primary cancer and improved our understanding of Va-TEA-mediated tumor immunity. The fulfillment of these objectives should have high translational potential for treating metastatic cancer.