Contact Information


DUMC  3712
Durham, NC 27710
Phone: 919-684-3072
Email

Bachelder Lab

Bachelder Lab

Robin Bachelder, PhD

Associate Professor of Pathology

Research Interests

My laboratory studies novel molecular determinants of breast and prostate cancer therapy resistance/tumor recurrence. Previous studies of chemo-resistance used long-term chemotherapy selection models to identify mechanisms of tumor cell adaption to chronic chemotherapy exposure. Clinical relevance of these long-term selection models is controversial in light of the “drug holiday” experienced by patients in between chemotherapy cycles. We have developed a short-term chemotherapy treatment model to enrich for growth-arrested, multidrug-resistant tumor cells that resume proliferation following chemotherapy removal (Li et al., 2014; Li et al., 2015). This model resembles the process of recurrent tumor growth in patients after completion of their chemotherapy treatment. We study novel signaling pathways in chemo-residual tumor cells from our model that can be targeted to prevent tumor recurrence.

Project 1: Preclinical studies of a novel combination therapy for triple-negative breast cancer: Although many women with locally advanced triple-negative (TN) breast cancer (lacking Estrogen Receptor, Progesterone Receptor, and HER2) show a partial response to neoadjuvant chemotherapy, residual tumor cells are frequently detected post-treatment. These residual tumor cells predict future tumor recurrence. My laboratory studies signaling pathways associated with TN breast cancer chemotherapy resistance/tumor recurrence. Chemotherapy-enriched, dormant TN tumor cells generated from our model secrete 500-fold increased levels of interleukin 6 (IL6) compared to parental cells, and exhibit increased tyrosine phosphorylation of Stat3, a transcription factor phosphorylated/activated by IL6 signaling. Based on these findings, we are currently testing the hypotheses that: 1) dormant chemo-residual TN tumor cells support autocrine IL6 signaling, which is critical for their survival, and 2) an IL6 receptor-neutralizing antibody (previously approved for treating rheumatoid arthritis patients) prevents TN tumor recurrence by eliminating chemo-residual TN tumor cells.

 Project 2: Precursor N-cadherin regulation of therapy resistance/metastasis: We have identified a novel determinant of tumor resistance to chemotherapy (precursor Neural-cadherin; pro-N-cadherin). Chemotherapy-enriched, dormant tumor cells emanating from our short-term chemotherapy treatment model express significantly increased levels of pro-N-cadherin on the tumor cell surface. Preliminary studies indicate that cell surface pro-N-cadherin drives both therapy resistance and tumor cell invasive behavior. In collaboration with our clinical collaborators, Kelly Marcom, M.D., Jiaoti Huang, M.D., Ph.D., and Andrew Armstrong, M.D., we are determining frequency of cell surface pro-N-cadherin expression in breast and prostate cancers. We are also studying the ability of an antibody specific for the precursor domain of N-cadherin to eliminate therapy-resistant breast and prostate cancer cells. 

 Project 3: Targeting prostate cancer stem-like cells through cell surface-expressed GRP78: My laboratory collaborates with Salvatore Pizzo, M.D., Ph.D. to investigate the importance of cell surface glucose-regulated protein of 78 kDa (GRP78) for prostate cancer stem-like cell growth. GRP78 is expressed on the surface of a variety of tumor types, where it orchestrates numerous signaling pathways. Cell surface GRP78 is an ideal therapeutic target for these cancers because it promotes tumor cell survival and is not detected in normal tissues. Our studies show that short-term chemotherapy treatment of prostate cancer cells enriches for a prostate cancer stem-like cell population that expresses cell surface GRP78. Preliminary findings indicate that GRP78-neutralizing antibodies inhibit human prostate cancer stem-like cell growth. We plan to test the impact of these antibodies on human androgen-independent prostate cancer growth in an animal model.

Bachelder Lab Group

Bachelder Lab 2014: Standing (left to right): Shenduo Li, Matthew Lyes, Margaret Kennedy, Sturgis Payne;
Seated (l to r): Kelly Kennedy, Ph.D., Robin Bachelder, Ph.D.

Publications

REPRESENTATIVE PUBLICATIONS: