Robin Elizabeth Bachelder
Associate Professor in Pathology

Targeted therapies are not available for triple-negative (TN) breast cancer (lacking Estrogen Receptor, Progesterone Receptor, and HER2). Although many women with locally advanced TN breast cancer show a partial response to neoadjuvant chemotherapy, residual tumor cells are detected in the majority of patients post-treatment. These residual tumor cells predict future tumor recurrence and patient mortality. My laboratory studies signaling pathways associated with TN breast cancer chemotherapy resistance/tumor recurrence. Our goal is to identify novel proteins that: 1) drive TN breast cancer chemo-resistance and 2) can be targeted to eliminate chemo-resistant TN tumor cells. Ultimately, it is our goal to develop combination therapies that prevent TN tumor recurrence and improve patient survival.

The Bachelder laboratory has developed a short-term chemotherapy treatment model for studying triple-negative breast cancer chemo-resistance. In this model, short-term chemotherapy treatment of TN tumor cells enriches for dormant, chemotherapy-resistant tumor cells, representing only 0.1% of the original tumor cell population. Upon removing chemotherapy, these dormant tumor cells resume growth, establishing proliferative colonies. This model resembles recurrent tumor growth observed in cancer patients after completion of chemotherapy treatment. Using this model, we have identified novel signaling pathways contributing to TN breast cancer chemo-resistance.

Project 1: Nuclear Fibroblast growth factor signaling in TN breast cancer recurrence:

Our studies indicate that chemotherapy-enriched, dormant tumor cells express significantly increased levels of a nuclear basic FGF (bFGF) isoform (compared to parental cells). Reducing nuclear bFGF expression in dormant tumor cells decreases cell survival and inhibits colony formation upon chemotherapy removal. Nuclear bFGF maintains dormant tumor cell survival by driving transcription of DNA-dependent protein kinase, a kinase important for double-stranded DNA repair. In collaboration with Kelly Marcom, M.D. we have shown that residual tumor cells from neoadjuvant chemotherapy-treated TN breast cancer patients show increased % nuclear bFGF-positive tumor cells, validating our in vitro model. Currently, we are addressing the hypothesis that a nuclear bFGF receptor cooperates with nuclear bFGF to drive chemo-resistance. This receptor could be targeted with established FGFR inhibitors to eliminate chemo-residual TN tumor cells. 

Project 2: Interleukin 6 (IL6) signaling in TN breast cancer chemo-resistance: 

Microarray analysis indicates that chemo-residual tumor cells emanating from our short term chemotherapy treatment model express increased Interleukin 6, as well as increased IL6 receptor (gp130). Our studies indicate that these chemo-residual tumor cells support autocrine IL6 signaling that drives constitutively Stat3 activity. Furthermore, we have shown that an FDA-approved IL6 receptor-blocking antibody (Tocilizumab, Genetech), eliminates chemo-resistant tumor cells from our short-term chemotherapy treatment model by inhibiting Stat 3. We are currently designing clinical trials to test efficacy of a novel combination therapy (chemotherapy + IL6R-blocking antibody) for TN breast cancer. 

Project 3: Targeting prostate cancer stem-like cells through cell surface-expressed GRP78:

We are collaborating with Salvatore Pizzo, M.D., Ph.D. and Ashley Chi, M.D. to investigate the importance of cell surface GRP78 for prostate cancer stem-like cell growth. In addition to being an endoplasmic reticulum chaperone protein, glucose-regulated protein of 78 kDa (GRP78) is expressed on the surface of tumor cells, 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 tumor cells enriches for a prostate cancer stem-like cell population that expresses cell surface GRP78. Preliminary studies indicate that GRP78-neutralizing antibodies inhibit human prostate cancer stem-like cell growth. We plan to test the impact of these GRP78-neutralizing antibodies on human androgen-independent prostate cancer growth using an animal model. 

Current Appointments & Affiliations

Contact Information

  • Duke University Medical Center Box 3712, Durham, NC 27710
  • Rm 310M Davison Bldg, Durham, NC 27710

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