PSK as Neoadjuvant Therapy for Locally Advanced Breast Cancer

PSK 作为局部晚期乳腺癌的新辅助治疗

• 批准号: 8206816
• 负责人: HAILING LU
• 金额: $ 26.3万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-08 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8206816
• 关键词: Agaricales; Agonist; Antigens; Antineoplastic Agents; Asia; Axilla; Biological Markers; Breast; Caliber; Chest wall structure; Clinical; Clinical Management; Complementary and alternative medicine; Data; Developing Countries; Development; Disease; ERBB2 gene; Enrollment; Evaluation; Foundations; Generations; Human; Immune; Immune response; Immunity; Immunomodulators; Immunotherapy; In complete remission; Inflammatory; Malignant Neoplasms; Mammary Neoplasms; Mediating; Microscopic; Minority; Modeling; Monoclonal Antibody Therapy; Mus; Muscle; Neoadjuvant Therapy; Newly Diagnosed; Operative Surgical Procedures; Paclitaxel; Pathologic; Patients; Pharmaceutical Preparations; Polysaccharide-K; Polysaccharides; Principal Investigator; Public Health; Regional Lymph Node Involvement; Relapse; Residual state; Screening procedure; Signal Transduction; Skin; Specimen; T-Lymphocyte; Testing; Time; Toll-Like Receptor 2; Transgenic Mice; Translating; Trastuzumab; Tumor Antigens; Tumor Immunity; United States; Woman; Work; antibody-dependent cell cytotoxicity; base; chemotherapy; fight against; high risk; immunogenic; improved; lymph nodes; malignant breast neoplasm; medically underserved; mouse model; neoplastic cell; novel; novel therapeutics; programs; response; soft tissue; standard care; treatment strategy; triple-negative invasive breast carcinoma; tumor; tumor eradication

Summary: Locally advanced breast cancer (LABC) refers to a breast cancer that has progressed locally but has not yet clinically spread beyond the breast and regional lymph nodes. Clinical management of LABC remains challenging as the patients have a high risk for relapse. This is particularly true for HER2+/ER- and triple negative (HER2-ER-PR-) types of LABC. Neoadjuvant (pre-operative) chemotherapy followed by surgery has evolved as the standard treatment strategy for newly diagnosed LABC. Patients with pathological complete response (PCR) achieved by neoadjuvant therapy have a lower relapse rate after surgery and an improved overall survival compared to those patients with residual microscopic disease. However, with the currently available neoadjuvant therapy, including chemotherapy and monoclonal antibody (mAb) therapy for HER2+ BC and chemotherapy for TNBC, PCR is achieved only in a minority of patients. Novel therapeutic strategies are required to result in complete tumor eradication. We propose to add polysaccharide Krestin (PSK), a non-toxic immunomodulator extracted from medicinal mushroom, to standard neoadjuvant therapy to increase the rate of PCR and OS. Chemotherapy has immunogenic effect due to the release of antigens from dying tumor cells PSK is a potent agonist of toll-like receptor 2 (TLR2) and the immunostimulatory effect of PSK on DC and T cells are mediated via TLR2. The TLR agonist activity of PSK may provide a "danger signal" to DC and enhance crosspriming. Thus paclitaxel and PSK may work together to autoimmunize the patients of their own tumors, resulting in tumor-destructive immunity. Our preliminary study also showed that PSK can enhance traztuzumab-mediated ADCC. Therefore, we hypothesize that the addition of PSK to standard neoadjuvant therapy with paclitaxel and trastuzumab will augment anti-tumor immunity and result in improved PCR rate and overall survival in mouse models of HER2+/ER- and TN LABC. This hypothesis will be tested in neu transgenic mice, a model of HER2+/ER- LABC, and C3(1)T-Ag mice, a model of TN LABC. The Specific Aims of the proposal are to: (1) Determine whether the addition of PSK to standard neoadjuvant therapy for HER2+/ER- and TN LABC will increase the rate of PCR and overall survival in neu-transgenic mice and C3(1)-TAg mice; (2) Determine whether the addition of PSK to standard neoadjuvant therapy for HER2+/ER- and TN LABC will result in the generation of a pro-inflammatory tumor microenvironment that supports anti-tumor immunity and whether this effect is dependent on TLR2 activation; (3) Determine the potential augmentation of a systemic (adaptive) immune response elicited by incorporating PSK into standard neoadjuvant therapy for HER2+/ER- LABC and whether this effect is dependent on TLR2 activation. Data generated here will lay the foundation for the potential integration of complementary and alternative medicine (CAM) therapy into the neoadjuvant treatment of LABC.

总结： 局部晚期乳腺癌（LABC）是指局部进展但尚未完全消退的乳腺癌。 临床上扩散到乳房和局部淋巴结以外。LABC的临床管理仍然存在 因为患者复发的风险很高。这对于HER 2 +/ER-和三重 阴性（HER 2-ER-PR-）LABC。手术后的新辅助（术前）化疗 发展成为新诊断LABC的标准治疗策略。病理完全性 通过新辅助治疗实现的PCR反应（PCR）在手术后复发率较低， 与残留显微镜下病变的患者相比，总生存率。然而，随着目前 可用的新辅助治疗，包括化疗和HER 2 + BC的单克隆抗体（mAb）治疗 和TNBC的化疗，PCR仅在少数患者中实现。新颖的治疗策略是 需要导致完全的肿瘤根除。我们建议添加多糖Krestin（PSK），一种无毒的 从药用蘑菇中提取的免疫调节剂，以标准的新辅助治疗，以提高 化疗由于从垂死的肿瘤细胞中释放抗原而具有免疫原性效应 PSK是一种有效的Toll样受体2（TLR 2）激动剂，PSK对DC和T细胞的免疫刺激作用， 细胞通过TLR 2介导。PSK的TLR激动剂活性可向DC提供“危险信号”， 增强交叉电泳。因此，紫杉醇和PSK可能共同发挥作用，使患者自身免疫 肿瘤，导致肿瘤破坏性免疫。我们的初步研究还表明，PSK可以增强 曲妥珠单抗介导的ADCC。因此，我们假设在标准新辅助治疗中加入PSK， 紫杉醇和曲妥珠单抗治疗将增强抗肿瘤免疫力，并导致PCR率提高， HER 2 +/ER-和TN LABC小鼠模型的总生存期。这一假设将在neu中得到检验 转基因小鼠，HER 2 +/ER-LABC模型，和C3（1）T-Ag小鼠，TN LABC模型。 该提案的具体目的是：（1）确定在标准新辅助治疗中加入PSK是否 HER 2 +/ER-和TN LABC治疗将增加neu转基因小鼠的PCR率和总生存率 和C3（1）-TAg小鼠;（2）确定在标准新辅助治疗中加入PSK是否对C3（1）-TAg小鼠的免疫功能有影响。 HER 2 +/ER-和TN LABC将导致促炎性肿瘤微环境的产生， 支持抗肿瘤免疫，以及这种作用是否依赖于TLR 2活化;（3）确定 通过将PSK并入标准的免疫调节剂中引起的系统性（适应性）免疫应答的潜在增强 HER 2 +/ER-LABC的新辅助治疗以及这种作用是否依赖于TLR 2活化。数据 这里产生的将为补充和替代医学的潜在整合奠定基础 (CAM)LABC的新辅助治疗。