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，例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识别和开发新型抗肿瘤药物和治疗方式，这些药物和治疗方式不仅可以破坏现有的癌症，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-生育酚氧乙酸（a-TEA）。 Alpha-TEA 是一种亲脂性、抗酯酶性、天然维生素 E (RRR-α-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。 a-TEA 化疗的临床前研究成果向临床转化受到其脂溶性的阻碍，脂溶性需要将其溶解在有机溶剂中，而这对于人体来说是不切实际的。我们开发了一种新型的 a-TEA，即囊状 a-TEA (Va-TEA)，它水溶性更好，更适合临床使用。本研究的目标是采用 Va-TEA 与树突状细胞 (DC) 疫苗接种相结合，以预防已形成和残留疾病环境中的乳腺癌转移。初步研究表明，Va-TEA 在体外能有效杀死肿瘤细胞，在体内引起 DC 成熟并抑制肿瘤生长。待检验的假设是口服 Va-TEA 与 DC 疫苗的组合将非常有效地预防癌症传播，且宿主毒性最小。这一假设的基本原理是基于以下证据：a-TEA 诱导肿瘤细胞凋亡和继发性坏死，并且 DC 能够摄取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。本研究的具体目标是：1) 确定 Va-TEA 加 DC 疫苗接种在预防癌症转移扩散方面的有效性；2) 阐明 Va-TEA 介导的抗肿瘤活性的免疫机制。这项研究完成后，我们将开发出一种控制原发性癌症扩散的新方法，并提高我们对 Va-TEA 介导的肿瘤免疫的理解。这些目标的实现对于治疗转移性癌症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.