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，但尚未临床扩散到乳房和区域淋巴结以外的乳腺癌。由于患者复发风险高，LABC的临床治疗仍然具有挑战性。对于HER2+/ER-和三阴性（HER2-ER- pr -）类型的LABC尤其如此。手术后的新辅助（术前）化疗已成为新诊断的LABC的标准治疗策略。通过新辅助治疗获得病理完全缓解（PCR）的患者术后复发率较低，与残留显微病变的患者相比，总生存期提高。然而，在目前可用的新辅助治疗中，包括化疗和单克隆抗体（mAb）治疗HER2+ BC和化疗治疗TNBC， PCR仅在少数患者中实现。需要新的治疗策略来彻底根除肿瘤。我们建议在标准的新辅助治疗中加入从药用菌中提取的无毒免疫调节剂多糖Krestin (PSK)，以提高PCR和OS率。PSK是toll样受体2 （TLR2）的一种强效激动剂，PSK对DC细胞和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提供了“危险信号”，增强了交叉杂交。因此，紫杉醇和PSK可能共同作用，使患者自身对肿瘤产生免疫，从而产生肿瘤破坏性免疫。我们的初步研究也表明PSK可以增强曲妥珠单抗介导的ADCC。因此，我们假设PSK加入紫杉醇和曲妥珠单抗的标准新辅助治疗将增强抗肿瘤免疫，并导致HER2+/ER-和TN LABC小鼠模型的PCR率和总生存率提高。这一假设将在HER2+/ER- LABC模型的新型转基因小鼠和TN LABC模型的C3(1)T-Ag小鼠中进行验证。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添加PSK是否会提高新转基因小鼠和C3(1)- tag小鼠的PCR率和总生存率；(2)确定在HER2+/ER-和TN LABC的标准新辅助治疗中加入PSK是否会产生支持抗肿瘤免疫的促炎肿瘤微环境，以及这种作用是否依赖于TLR2的激活；(3)确定将PSK纳入HER2+/ER- LABC的标准新辅助治疗中所引发的系统性（适应性）免疫反应的潜在增强，以及这种作用是否依赖于TLR2的激活。本研究产生的数据将为补充和替代医学（CAM）疗法在LABC新辅助治疗中的潜在整合奠定基础。

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.