Preclinical and Clinical Targeting of Inflammatory Mediators in Triple Negative Breast Cancer
Abstract
The incidence of breast cancer is the number one cause of cancer in women globally. Due to the complex heterogeneous diversity of this disease, certain classifications of breast cancer have developed targeted therapeutic strategies whereas other breast cancer classifications still remain without any effective therapies. Triple negative breast cancer (TNBC) is a pathology that currently relies on conventional chemotherapy and has historical poor prognosis due to chemo-resistance, distant metastasis, and patient relapse. This dissertation focuses on the results of preclinical and clinical studies inhibiting inflammatory mediators propagating chemo-resistance in TNBC. Previous work by our lab and others have established that IL-6 and inducible nitric oxide synthase (iNOS) are utilized by TNBC to resist chemotherapy by inducing cancer stem cells, cancer proliferation and metastasis. Clinical trials targeting IL-6 has not been thoroughly investigated in the context of breast cancer and previously it is not yet known which patients would benefit from anti IL-6 therapy. In experiment 1, we found that a specific molecular subtype of TNBC resisted chemotherapy by mitogen-activated protein kinase (MAPK) induced autocrine IL-6. In contrast, a different TNBC subtype had no MAPK activation following chemotherapy, which led to unaltered IL-6 production. Utilizing TNBC xenografts in female mouse models, we investigated the efficacy of tocilizumab, anti-IL-6R antagonist. Tocilizumab combined with chemotherapy provided significant tumor growth reduction compared to chemotherapy alone in mice with MAPK active TNBC xenografts. Conversely, the combinational regimen provided no benefit in mice with MAPK inactive TNBC xenografts. Our lab has previously investigated the durability of an iNOS inhibitor decreasing TNBC burden in mice xenograft studies. In experiment 2, we investigated a phase I/II trial on the safety and efficacy of the iNOS inhibitor in TNBC patients with local advanced or metastatic disease. The inhibitor was well tolerated, and the objective response rate was 81.8% for local advanced patients and 15.4% for metastatic patients. We also observed that 86% of patients with progressive disease had detectable IL-6 in sera through two courses of iNOS therapy which may give rationale for exploring the efficacy of tocilizumab in combination with iNOS inhibition in future clinical trials.
Citation
Chung, Andrew (2023). Preclinical and Clinical Targeting of Inflammatory Mediators in Triple Negative Breast Cancer. Doctoral dissertation, Texas A&M University. Available electronically from https : / /hdl .handle .net /1969 .1 /198932.