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，如骨髓毒性和全身性免疫抑制。这些缺点促使人们不懈努力，以确定和开发新的抗肿瘤药物和治疗方式，不仅要摧毁现有的癌症，对宿主的毒性最小，而且要防止疾病复发。一种可能具有这些特性的药物是α -生育酚氧乙酸（a-TEA）。α - tea是一种亲脂、耐酯酶、半合成的天然维生素E （rfr - α -生育酚）类似物，在体外选择性诱导癌细胞凋亡，在临床前动物模型中抑制肿瘤生长。将a-TEA化疗的临床前研究结果转化到临床一直受到其脂溶性的阻碍，这需要将其溶解在有机溶剂中，而有机溶剂对于人类来说是不切实际的。我们已经开发了一种新型的a- tea，即泡状a- tea (Va-TEA)，它的水溶性更强，与临床应用更相关。本研究的目的是将Va-TEA与树突状细胞（DC）疫苗联合使用，以预防已建立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在体外有效杀死肿瘤细胞，导致DC成熟，在体内抑制肿瘤生长。待验证的假设是，口服Va-TEA加DC疫苗的组合将在最小宿主毒性的情况下非常有效地预防癌症传播。这一假设的基本原理是基于a-TEA诱导肿瘤细胞凋亡和继发性坏死的证据，以及dc能够摄取被杀死的肿瘤细胞并向T淋巴细胞交叉呈递肿瘤相关抗原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疫苗预防肿瘤转移扩散的有效性；2)阐明Va-TEA介导的抗肿瘤活性的免疫学机制。在这项研究完成后，我们将开发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在治疗转移性癌症方面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.