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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA138547-04
Application #
8403555
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Yovandich, Jason L
Project Start
2010-03-08
Project End
2014-12-31
Budget Start
2013-01-01
Budget End
2014-12-31
Support Year
4
Fiscal Year
2013
Total Cost
$247,259
Indirect Cost
$88,908
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Yang, Yi; Inatsuka, Carol; Gad, Ekram et al. (2014) Protein-bound polysaccharide-K induces IL-1* via TLR2 and NLRP3 inflammasome activation. Innate Immun 20:857-66
Inatsuka, Carol; Yang, Yi; Gad, Ekram et al. (2013) Gamma delta T cells are activated by polysaccharide K (PSK) and contribute to the anti-tumor effect of PSK. Cancer Immunol Immunother 62:1335-45
Engel, Abbi L; Sun, Guan-Cheng; Gad, Ekram et al. (2013) Protein-bound polysaccharide activates dendritic cells and enhances OVA-specific T cell response as vaccine adjuvant. Immunobiology 218:1468-76
Engel, Abbi L; Holt, Gregory E; Lu, Hailing (2011) The pharmacokinetics of Toll-like receptor agonists and the impact on the immune system. Expert Rev Clin Pharmacol 4:275-89
Lu, Hailing; Yang, Yi; Gad, Ekram et al. (2011) Polysaccharide krestin is a novel TLR2 agonist that mediates inhibition of tumor growth via stimulation of CD8 T cells and NK cells. Clin Cancer Res 17:67-76
Lu, Hailing; Yang, Yi; Gad, Ekram et al. (2011) TLR2 agonist PSK activates human NK cells and enhances the antitumor effect of HER2-targeted monoclonal antibody therapy. Clin Cancer Res 17:6742-53