Prevention of Metastatic Cancer Using a Novel Vitamin E Analog

使用新型维生素 E 类似物预防转移性癌症

基本信息

批准号：
7630957
负责人：
EMMANUEL T. AKPORIAYE
金额：
$ 17.17万
依托单位：
PROVIDENCE PORTLAND MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-04-01 至 2011-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7630957
关键词：
Acids Adverse effects Animal Model Apoptosis Biological Assay Breast Cancer Model Cancer Control Cancer Patient Cell Maturation Cells Class Clinic Clinical Dendritic Cell Vaccine Dendritic Cells Development Disease Disseminated Malignant Neoplasm Distant Metastasis Effectiveness Goals Human Immune Immunity Immunologics Immunosuppression Immunotherapy In Vitro Life Light Major Histocompatibility Complex Malignant Neoplasms Marrow Mediating Modality Molecular Chaperones Monitor Mus Neoplasm Metastasis Oral Organic solvent product Outcome Peptides Pharmaceutical Preparations Plague Prevention Primary Neoplasm Property Proteins Recurrence Recurrent disease Residual Tumors Resistance T-Lymphocyte Tea Testing Therapeutic immunosuppression Tissues Toxic effect Transgenic Model Translating Translations Tumor Antigens Tumor Cell Necrosis Tumor Debulking Tumor Immunity Vaccination Vitamin E Water Water-Soluble Vitamin alpha Tocopherol analog antigen processing base cancer cell chemotherapy cytokine cytotoxicity esterase immunogenic improved in vitro Assay in vivo interest killings lipid solubility malignant breast neoplasm mortality multicatalytic endopeptidase complex neoplastic neoplastic cell novel novel strategies pre-clinical prevent response tumor tumor growth

项目摘要

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.

描述（由申请人提供）：化学疗法延长癌症患者寿命的能力受到严重的副作用（例如骨髓毒性和普遍的免疫抑制）的损害。这些缺点助长了不懈的努力，以识别和发展新型的抗肿瘤剂和治疗方式，这些剂不仅会破坏现有的癌症，对宿主的毒性很小，而且还可以防止疾病复发。一种可能具有这些特性的药物是α-植酸乙酸（A-TEA）。 α-TEA是一种亲脂性，酯酶耐药性，半合成类似物的半合成类似物（RRR-Alpha-生育酚），在预临床动物模型中选择性地诱导体外癌细胞的凋亡并抑制肿瘤生长。将A-TEA化疗的临床前发现转化为诊所的转化受到其脂质溶解度的阻碍，该溶解度需要将其溶解在不切实际的有机溶剂中，这些溶剂不切实际地用于人类。我们已经开发了一种新型的A-TEA，囊泡A-TEA（VA-TEA）的新型形式，它更具有水溶性，并且与临床使用更相关。这项研究的目的是将VA-TEA与树突状细胞（DC）疫苗接种结合使用，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，我们表明VA-TEA有效地在体外杀死肿瘤细胞，导致DC成熟并抑制体内肿瘤的生长。要检验的假设是，口服VA-TEA Plus DC疫苗接种的组合将在防止癌症毒性最少的癌症传播方面非常有效。该假设的基本原理是基于证据表明，A-TEA诱导肿瘤细胞的凋亡和继发性坏死，并且DC能够摄入杀死肿瘤细胞并交叉肿瘤相关抗原对T淋巴细胞诱导肿瘤特异性免疫。这项研究的具体目的是：1）确定VA-TEA和直流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，我们将开发出一种新的方法来控制原发性癌症的传播并提高我们对VA-TEA介导的肿瘤免疫力的理解。这些目标的实现应具有治疗转移性癌症的高转化潜力。