PSK as Neoadjuvant Therapy for Locally Advanced Breast Cancer

描述（由申请人提供）：局部晚期乳腺癌（LABC）是指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的临床管理仍然具有挑战性，因为患者复发的风险很高。这对于HER 2 +/ER-和三阴性（HER 2-ER-PR-）类型的LABC尤其如此。新辅助（术前）化疗后手术已发展为新诊断LABC的标准治疗策略。通过新辅助治疗实现病理完全缓解（PCR）的患者与残留显微镜下病变的患者相比，术后复发率较低，总生存期延长。然而，在目前可用的新辅助治疗中，包括化疗和用于HER 2 + BC的单克隆抗体（mAb）治疗以及用于TNBC的化疗，仅在少数患者中实现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Krestin（PSK）添加到标准的新辅助治疗中，以增加PCR和OS的速率。化疗具有免疫原性效应，这是由于从垂死的肿瘤细胞中释放抗原PSK是Toll样受体2（TLR 2）的有效激动剂，PSK对DC和T细胞的免疫刺激作用是通过TLR 2介导的。PSK的TLR激动剂活性可向DC提供“危险信号”并增强交叉激活。因此，紫杉醇和PSK可能共同作用，使患者自身的肿瘤产生自身免疫，从而产生肿瘤破坏性免疫。我们的初步研究还表明，PSK可以增强曲妥珠单抗介导的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将增强抗肿瘤免疫力，并导致HER 2 +/ER-和TN LABC小鼠模型的PCR率和总生存期改善。将在neu转基因小鼠（HER 2 +/ER-LABC模型）和C3（1）T-Ag小鼠（TN LABC模型）中检验该假设。该提案的具体目的是：（1）确定在HER 2 +/ER-和TN LABC的标准新辅助治疗中加入PSK是否会增加neu转基因小鼠和C3（1）-TAg小鼠的PCR率和总存活率;（2）确定将PSK添加到用于HER 2 +/ER-和TN LABC的标准新辅助疗法中是否会导致产生促HER 2 +/ER-和TN LABC。（3）确定通过将PSK并入HER 2 +/ER-LABC的标准新辅助疗法中引起的全身性（适应性）免疫应答的潜在增强，以及该效应是否依赖于TLR 2活化。这里产生的数据将为补充和替代医学（CAM）疗法潜在整合到LABC的新辅助治疗中奠定基础。 公共卫生相关性：PSK是一种蘑菇提取物，因其抗癌和免疫刺激作用而在亚洲长期使用。这项拟议的研究将使用人HER 2+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.