New Approaches to Prevent or Treat Breast Cancer Metastases

预防或治疗乳腺癌转移的新方法

• 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
• 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

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％被诊断出患有乳腺癌的妇女将发展为转移性疾病。但是，转移不能通过手术或辐射去除，大多数转移都是化学抗性的。因此，专门预防或消除转移的疗法在结果中为结果带来了巨大的希望。最近的研究表明，通过疫苗接种对乳腺肿瘤的特定助手或细胞毒性T淋巴细胞（CTL）反应的增强可能导致特异性消除微中焦点酶。但是，疫苗诱导的免疫和临床反应不佳强调了改善疫苗策略的需求。该研究建议的重点是使用临床前转移性小鼠乳腺肿瘤模型4T1将疫苗接种与IL-6抑制剂姜黄素相结合，以改善针对转移性乳腺癌的疫苗治疗。我们先前证明，MAGE-B DNA疫苗接种在该模型中为乳腺癌转移提供了明显的保护，尽管不是完全。白介素（IL）-6可能导致疫苗功效降低。它在4T1原发性肿瘤和转移酶中受到高度调节，可能是通过核因子Kappa B（NFKB）进行的，并且是体内树突状细胞（DC）分化的有效调节剂。 IL-6激活了未成熟DC中转录器和转录活化剂（Stat）3的表达，从而防止了DC的成熟并随后将抗原呈现给T细胞。这可能会导致T细胞无响应。能够抑制IL-6的药物可能会提高疫苗功效。姜黄素可能是这样的药物，因为它抑制了IL-6产生。 MAGE-B和IL-6都经常在人类乳腺癌中检测到，这使得4T1模型在临床上相关。该提案的长期目标是在4T1模型中开发一种新型的MAGE-B疫苗接种和姜黄素的非毒性联合疗法，如果成功的话，将其转化为人类临床试验。假设是姜黄素改善了MAGE-B DNA疫苗接种后的T细胞激活和随后的免疫反应，从而进一步降低了乳腺癌转移的频率。具体目的如下：（1）测试带有姜黄素和不含姜黄素的MAGE-B疫苗接种对肿瘤和转移酶的影响。为此，小鼠将用MAGE-B DNA疫苗进行预防或治疗，并受到4T1肿瘤细胞的挑战。一旦感觉到原发性肿瘤，每天都会服用姜黄素。将确定转移，肿瘤大小和生存时间的频率； （2）测试姜黄素对疫苗和肿瘤诱导的免疫反应的直接作用，以及肿瘤细胞的增殖和凋亡。为此，将分析已激活的CD4和CD8 T细胞，调节性T细胞和成熟的DC的脾脏，淋巴结，肿瘤和对照小鼠的转移。此外，还将分析治疗和对照小鼠的肿瘤和转移，以表达NFKB和NFKB调节的基因，这些基因直接参与了IL-6，TNF1和STAT3等免疫反应，以及增殖和凋亡。公共卫生相关性：当前对癌症的治疗对转移无效。在这项研究建议中，将开发一种新型的MAGE-B疫苗接种和姜黄素的无毒联合疗法，该治疗使用反映人类转移性乳腺癌的临床前小鼠模型有效地针对乳腺癌转移。