Prevention of Metastatic Cancer Using a Novel Vitamin E Analog

描述（由申请人提供）：化疗延长癌症患者生命的能力受到严重副作用的影响，如骨髓毒性和全身免疫抑制。这些缺点促使人们不懈地努力来鉴定和开发新的抗肿瘤剂和治疗方式，这些抗肿瘤剂和治疗方式不仅会破坏现有的癌症，对宿主具有最小的毒性，而且还能预防疾病复发。可能具有这些性质的一种药物是α-生育酚氧基乙酸（α-TEA）。α-TEA是一种亲脂性、酯酶抗性、天然维生素E（RRR-alpha-生育酚）的半合成类似物，可在体外选择性诱导癌细胞凋亡，并在临床前动物模型中抑制肿瘤生长。将a-TEA化学疗法的临床前发现转化为临床受到其脂溶性的阻碍，所述脂溶性需要将其溶解在用于人类不切实际的有机溶剂中。我们已经开发了一种新形式的α-TEA，囊泡化α-TEA（Va-TEA），其更具水溶性并且与临床使用更相关。本研究的目的是采用Va-TEA与树突状细胞（DC）疫苗接种相结合，以防止乳腺癌转移的既定和残留的疾病设置。在初步研究中，我们已经表明Va-TEA在体外有效地杀死肿瘤细胞，引起DC成熟并在体内抑制肿瘤生长。待检验的假设是口服Va-TEA加DC疫苗接种的组合将在预防癌症传播方面高度有效，具有最小的宿主毒性。该假设的基本原理是基于以下证据：α-TEA诱导肿瘤细胞的凋亡和继发性坏死，并且DC能够吞噬杀死的肿瘤细胞并将肿瘤相关抗原交叉呈递给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加DC疫苗接种在预防癌症转移扩散中的有效性和2）阐明Va-TEA介导的抗肿瘤活性的免疫学机制。完成这项研究后，我们将开发出一种新的方法来控制原发性癌症的扩散，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具有治疗转移性癌症的高转化潜力。

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.