New Approaches to Prevent or Treat Breast Cancer Metastases

预防或治疗乳腺癌转移的新方法

基本信息

批准号：
7582320
负责人：
CLAUDIA GRAVEKAMP
金额：
$ 18.68万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-01 至 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7582320
关键词：
Address Affect Antibodies Antigen Presentation Apoptosis Biopsy CD8B1 gene Cancer Patient Cancer Vaccines Cell Differentiation process Cell Maturation Cells Clinical Clinical Trials Combined Modality Therapy Cultured Tumor Cells Curcumin Cytotoxic T-Lymphocytes DNA DNA Vaccines Dendritic Cells Development Diagnosis Disease Frequencies Genes Homologous Gene Human Immune Immune response Immunocompetent In Vitro Interferons Interleukin-2 Interleukin-6 Interleukins Lead Malignant Neoplasms Mammary Neoplasms Mature T-Lymphocyte Metastatic to Modeling Morbidity - disease rate Mus NF-kappa B Neoplasm Metastasis Operative Surgical Procedures Outcome Pathway interactions Pre-Clinical Model Primary Neoplasm Process Production Radiation Research Research Proposals S-Phase Fraction STAT3 gene Site Spleen System T-Cell Activation T-Lymphocyte Testing Time Transcription Coactivator Transducers Translations Tumor Cell Line Tumor Necrosis Factor-alpha Tumor Necrosis Factors Tumor Weights Vaccinated Vaccination Vaccine Therapy Vaccines Woman annexin A5 cancer therapy clinically relevant improved in vivo inhibitor/antagonist lymph nodes malignant breast neoplasm mortality mouse model neoplastic cell novel novel strategies pre-clinical prevent public health relevance research clinical testing response tumor tumor growth vaccination strategy vaccine efficacy vaccine evaluation

项目摘要

DESCRIPTION (provided by applicant): About 40% of the women diagnosed with breast cancer will progress to metastatic disease. However, metastases cannot be removed by surgery or radiation, and most metastases are chemoresistant. Therefore, therapies that specifically prevent or eliminate metastases offer great promise in the outcome. Recent studies indicate that enhancement of specific helper or cytotoxic T lymphocyte (CTL) responses to breast tumors through vaccination could potentially lead to the specific elimination of micro-metastases. However, poor vaccine-induced immune and clinical responses underscore the need for improved vaccine strategies. This research proposal is focused on the improvement of vaccine therapy against metastatic breast cancer by combining vaccination with the IL-6 inhibitor curcumin, using the preclinical metastatic mouse breast tumor model 4T1. We previously demonstrated that Mage-b DNA vaccination provides significant protection against breast cancer metastases in this model, albeit not completely. Interleukin (IL)-6 may contribute to decreased vaccine efficacy. It is highly up regulated in the 4T1 primary tumors and metastases, probably via the Nuclear Factor Kappa B (NFkB), and is a potent regulator of dendritic cells (DC) differentiation in vivo. IL-6 activates the expression of transducer and activator of transcription (STAT)3 in immature DC, preventing the DC from maturation and subsequent presentation of antigens to T cells. This may lead to T cell unresponsiveness. Agents that are able to inhibit IL-6 may lead to enhanced vaccine efficacy. Curcumin could be such an agent, since it inhibits IL-6 production. Both Mage-b and IL-6 are frequently detected in human breast cancer, which makes the 4T1 model clinically relevant. The long-term objective of this proposal is to develop a novel non- toxic combination therapy of Mage-b vaccination and curcumin in the 4T1 model, with a focus on its translation into human clinical trials, if successful. The hypothesis is that curcumin improves T cell activation and subsequent immune responses upon Mage-b DNA vaccination, resulting in further reduction of the frequency of breast cancer metastases. The specific aims are as follows:(1) Testing the effect of Mage-b vaccination with and without curcumin on tumors and metastases. For this purpose, mice will be immunized preventively or therapeutically with Mage-b DNA vaccine and challenged with 4T1 tumor cells. As soon as the primary tumor can be felt curcumin will be administered daily. Frequency of metastases, tumor size, and survival times will be determined; (2) Testing the direct effect(s) of curcumin on vaccine- and tumor-induced immune responses, and on proliferation and apoptosis of tumor cells. For this purpose, spleen, lymph nodes, tumors and metastases of treated and control mice will be analyzed for the presence of activated CD4 and CD8 T cells, regulatory T cells and mature DC. In addition, tumors and metastases of treated and control mice will also be analyzed for the expression of NFkB and NFkB-regulated genes that are directly involved in immune responses such as IL-6, TNF1, and STAT3, and for proliferation and apoptosis. PUBLIC HEALTH RELEVANCE: Current treatment of cancer is ineffective against metastases. In this research proposal a novel non-toxic combination therapy of Mage-b vaccination and curcumin will be developed that is effective against breast cancer metastases, using a preclinical mouse model that reflects metastatic breast cancer in humans.

描述（由申请人提供）：大约 40% 被诊断患有乳腺癌的女性将进展为转移性疾病。然而，转移瘤不能通过手术或放射线切除，而且大多数转移瘤具有化疗耐药性。因此，专门预防或消除转移的疗法在结果上提供了巨大的希望。最近的研究表明，通过疫苗接种增强对乳腺肿瘤的特异性辅助或细胞毒性 T 淋巴细胞 (CTL) 反应可能会导致微转移的特异性消除。然而，疫苗引起的免疫和临床反应不佳凸显了改进疫苗策略的必要性。该研究计划的重点是使用临床前转移性小鼠乳腺肿瘤模型 4T1，通过将疫苗接种与 IL-6 抑制剂姜黄素相结合来改进针对转移性乳腺癌的疫苗治疗。我们之前证明，在该模型中，Mage-b DNA 疫苗接种可以对乳腺癌转移提供显着的保护，尽管并不完全。白细胞介素 (IL)-6 可能会导致疫苗功效降低。它可能通过核因子 Kappa B (NFkB) 在 4T1 原发性肿瘤和转移瘤中高度上调，并且是体内树突状细胞 (DC) 分化的有效调节剂。 IL-6 激活未成熟 DC 中转导子和转录激活子 (STAT)3 的表达，防止 DC 成熟并随后将抗原呈递给 T 细胞。这可能会导致 T 细胞无反应。能够抑制 IL-6 的药物可能会增强疫苗功效。姜黄素可能就是这样一种药物，因为它可以抑制 IL-6 的产生。 Mage-b 和 IL-6 都经常在人类乳腺癌中检测到，这使得 4T1 模型具有临床意义。该提案的长期目标是在 4T1 模型中开发一种新型无毒 Mage-b 疫苗接种和姜黄素联合疗法，重点是如果成功的话将其转化为人体临床试验。假设姜黄素可改善 Mage-b DNA 疫苗接种后的 T 细胞激活和随后的免疫反应，从而进一步降低乳腺癌转移的频率。具体目的如下：(1)测试含姜黄素和不含姜黄素的Mage-b疫苗接种对肿瘤和转移瘤的影响。为此，将使用 Mage-b DNA 疫苗对小鼠进行预防性或治疗性免疫，并用 4T1 肿瘤细胞进行攻击。一旦感觉到原发肿瘤，就会每天注射姜黄素。将确定转移频率、肿瘤大小和生存时间； (2)测试姜黄素对疫苗和肿瘤诱导的免疫反应以及对肿瘤细胞增殖和凋亡的直接影响。为此，将分析治疗小鼠和对照小鼠的脾脏、淋巴结、肿瘤和转移瘤中活化的 CD4 和 CD8 T 细胞、调节性 T 细胞和成熟 DC 的存在。此外，还将分析治疗小鼠和对照小鼠的肿瘤和转移瘤中直接参与免疫反应（例如 IL-6、TNF1 和 STAT3）的 NFkB 和 NFkB 调节基因的表达，以及增殖和凋亡。公共卫生相关性：目前的癌症治疗对转移无效。在这项研究提案中，将开发一种新型无毒的 Mage-b 疫苗接种和姜黄素联合疗法，该疗法可有效对抗乳腺癌转移，使用反映人类转移性乳腺癌的临床前小鼠模型。