PSK as Neoadjuvant Therapy for Locally Advanced Breast Cancer

描述(申请人提供)：局部晚期乳腺癌(LABC)是指已在局部进展，但临床上尚未扩散到乳房和区域淋巴结以外的乳腺癌。LABC的临床治疗仍然具有挑战性，因为患者有很高的复发风险。对于HER2+/ER-和三阴性(HER2-ER-PR-)类型的LABC尤其如此。新辅助(术前)化疗后手术已经发展成为新诊断的LABC的标准治疗策略。经新辅助治疗获得病理完全应答(PCR)的患者术后复发率较低，总体生存率高于那些残留显微镜下病变的患者。然而，目前可用的新辅助治疗，包括针对HER2+BC的化疗和单抗治疗，以及针对TNBC的化疗，仅在少数患者中实现了PCR。需要新的治疗策略才能彻底根除肿瘤。我们建议将从药用蘑菇中提取的无毒免疫调节剂多糖克雷斯汀(PSK)添加到标准的新辅助治疗中，以提高PCR率和OS率。PSK是Toll样受体2(Toll-like Receptor 2，TLR2)的激动剂，其对DC和T细胞的免疫刺激作用是通过TLR2介导的。PSK的TLR激动剂活性可能为DC提供“危险信号”，增强交叉反应。因此，紫杉醇和PSK可能会共同作用，使自身肿瘤的患者产生自身免疫，从而产生肿瘤破坏性免疫。我们的初步研究还表明，PSK可以增强Traztuzumab介导的ADCC。因此，我们假设在紫杉醇和曲妥珠单抗的标准新辅助治疗中加入PSK将增强抗肿瘤免疫，并导致HER2+/ER-和TN LABC模型小鼠的PCR率和总存活率提高。这一假设将在neu转基因小鼠(HER2+/ER-LABC模型)和C3(1)T-Ag小鼠(TN LABC模型)中进行验证。该提案的具体目的是：(1)确定在HER2+/ER-和TN LABC的标准新辅助治疗中加入PSK是否会增加新转基因小鼠和C3(1)-Tag小鼠的PCR率和总存活率；(2)确定在HER2+/ER-和TN LABC的标准新辅助治疗中加入PSK是否会导致支持抗肿瘤免疫的促炎肿瘤微环境的产生，以及这种作用是否依赖于TLR2的激活；(3)确定在HER2+/ER-LABC的标准新辅助治疗中加入PSK对全身(适应性)免疫反应的潜在增强作用，以及这种作用是否依赖于TLR2的激活。这里产生的数据将为补充和替代医学(CAM)疗法潜在地整合到LABC的新辅助治疗中奠定基础。 与公共健康相关：PSK是一种蘑菇提取物，长期以来在亚洲被用于抗癌和免疫刺激作用。这项拟议的研究将使用人HER2+和三阴性乳腺癌的转基因小鼠模型来探索PSK在局部晚期乳腺癌中的作用机制。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: PSK is a mushroom extract that has long been used in Asia for its anti-cancer and immunostimulatory effects. This proposed study will use transgenic mouse models of human HER2+ and triple negative breast cancer to explore the mechanism of action of PSK in locally advanced breast cancer.