Research: The research in my laboratory is focused on utilizing pre-clinical, syngeneic transgenic mouse models or patient-derived xenograft (PDX) models of metastatic breast cancer (MBC) to understand how genes that impact the tumor microenvironment, particularly transcription factors, such as Hypoxia-Inducible Factor (HIF)-1 and HIF-2, regulate breast cancer progression, metastasis and therapeutic response, and on improving the efficacy and safety of chemotherapy regimens for MBC. I have >25 years of experience using mouse models to study breast biology and to investigate the role of the hypoxic response in breast development and cancer. Since 2017, we have also partnered with expert medicinal chemists to test novel anti-tubulin chemotherapy agents that Target taxane-resistant breast cancers using pre-clinical models of MBC. Our currentOurcurrent areas of research are: 1) to identify novel or understudied HIF-dependent genes that promote metastasis in breast cancer; 2) to identify mechanisms by which HIF-dependent genes induce metastasis or promote therapeutic resistance; 3) to perform pre-clinical screens to discover interventions that block the hypoxic response for the treatment of MBC using either syngeneic, immunocompetent murine models of MBC, and xenograft models, including PDX models; and 4) to test novel colchicine-binding site tubulin inhibitors (CBSIs) for efficacy in taxane-sensitive and taxane-resistant MBC models. We frequently collaborate with other investigators to perform pre-clinical animal model studies to test novel therapeutics, to screen for anti-metastatic potential or to test biological effects of gain- or loss-of function of specific genes. My laboratory is proficient in both mammalian cell culture and the use of mice to model breast cancer. We routinely generate mammary tumor epithelial cell lines from mouse models and perform surgical transplantation/injections into recipient mice to the mammary fat pad (orthotopic), or into the circulation to study experimental metastasis. We are also skilled in lentiviral transduction of cell lines to introduce fluorescent reporters or to modify gene expression, in histopathology techniques, and in flow cytometry/sorting. Institutional ServiceInstitutionalService: I previously directed the animal bio-imaging core at UTHSC in the Center for Cancer Research (2008-2016). I have served as a scientific member on the UTHSC Institutional Animal Care and Use Committee (IACUC) for five years, and I was the President of the College of Medicine Dean’s Faculty Advisory Committee (DFAC) from 2014-2015. have collaborated with Drs. Wei Li and DuaneMillsince 2017 to test novel CBSI tubulin inhibitors, leading to a recently completed Breast Cancer Research Program (BCRP) Department of Defense Partnering PI grant award (BC190092) and 6 publications, with additional manuscripts currently under review. We also collaborate as MPIs on NIH grantCA276152. One CBSI agent, Sabizabulin (VERU-111) is in phase 3 clinical trials for advanced prostate cancer (Veru Inc.)
I previously directed the animal bio-imaging core at UTHSC in the Center for Cancer Research, and my lab has extensive experience in imaging luciferase/fluorescent reporters in live mice. While managing a research lab at UTHSC, I also served as the Associate VC for Research-Core Labs (2015-2024), responsible for oversight of nine institutional-level shared resources. In July of 2024, I will move to Tulane University School of Medicine as Professor and program leader in Tumor Cell Biology for the LA Cancer Research Consortium (LCRC). In sum, I have the scientific background, leadership skills and administrative expertise to support this proposal.
Active projects that I would like to highlight include:
1) W81XWH-22-BCRP-BTA12/BC220493 (PI: Seagroves, TN) 03/01/2023-02/28/2027
Major goals are to target the creatine kinase metabolic pathway to repress breast cancer metastasis to the brain and to treat pre-established brain and bone metastatic lesions.
2) 1 R01 CA276152(MPIs: Wei Li and Tiffany Seagroves) 04/20/2023-03/31/2028
Major goals are to perform structural optimization based on a novel CBSI scaffold that crosses the blood:brain barrier to produce new potent analogs that can overcome taxane resistance for brain metastasis, and to develop novel drug conjugates with bisphosphonates for bone metastasis treatment.
Other completed projects that I would like to highlight include:
1) NIH/NCI 1R01CA192178-01A1 (PI: Lange, CA; subaward: Seagroves, TN) 09/25/2015-08/31/2021
Major goals of this project were to investigate the relationship between environmental stressors including hypoxia and the activation of PTK6 (BRK) biological activities (promotion of invasion, metastasis, chemotherapeutic resistance) using a combination of in vitro and in vivo approaches, including PDX models of MBC.
