Mixed-Lineage Kinases as Novel Targets for the Treatment of Endocrine-Resistant, ER-Positive Breast Cancer
Abstract
The majority of breast tumors express estrogen receptor (ER), and are treated with ER-targeted endocrine therapies such as antiestrogens (AEs) and aromatase inhibitors (AIs). AEs and AIs have been used successfully to treat many women with breast cancer. However, resistance to these agents frequently occurs, especially in metastatic disease, and this resistance results in relapse and patient mortality. Once ER-positive tumors are endocrine-resistant, the major therapeutic option available to patients is chemotherapy, which has limited efficacy and is associated with considerable morbidity. Our research has identified a kinase inhibitor that blocks cell division and induces cell death in ER-positive breast cancer cells in culture. This inhibitor was previously tested in clinical trials for Parkinson s disease and was found to have minimal toxicity. The proposed research therefore addresses two of the overarching challenges: eliminate the mortality associated with metastatic breast cancer, and revolutionize treatment regimens by replacing interventions that have life-threatening toxicities with ones that are safe and effective. Endocrine resistance is often associated with activation of intracellular signaling pathways, and strategies to treat resistant tumors have focused on co-targeting these pathways along with ER. We have examined the role of a family of protein kinases called Mixed Lineage Kinases (MLKs) in ER-positive breast cancer cells. MLKs are intracellular kinases that function downstream of multiple cell surface receptors and upstream of multiple effector molecules that are known to play a role in breast cancer. We therefore reasoned that inhibiting MLK activity might block signals initiated by multiple growth factors and prevent activation of several different effector molecules. Our cell culture results support this possibility. We have demonstrated that blocking MLK activity with a small molecule inhibitor called CEP-1347 results in cell cycle arrest and apoptosis (cell death) in ER-positive breast cancer cell lines, including one with acquired endocrine resistance, while having no detectable effect on non-tumorigenic mammary epithelial cells. This suggests that CEP-1347 or other MLK inhibitors may serve as novel therapeutics for the treatment of patients with ER-positive breast cancer. Although cell culture is useful and ideal for mechanistic studies, it does not always reflect the in vivo situation. The major objective of this proposal is to move our research into preclinical animal models in order to evaluate the potential of CEP-1347 as a therapeutic for endocrine-resistant, ER-positive metastatic breast cancer. Our research will make use of two models: the human ER-positive breast cancer cell lines that we have studied in vitro and newly developed patient derived xenografts (PDXs) that were established from patients with ER-positive, endocrine-resistant, metastatic disease. PDXs are derived by continuously passing a tumor in immune compromised mice rather than in cell culture. They have been shown to accurately reflect the biology of human breast tumors, and many are capable of forming metastases in mice. They therefore provide excellent preclinical models for testing potential therapeutics. Human ER-positive breast cancer cell lines and PDXs will be implanted into the mammary fat pad of immune deficient mice, and tumors will be allowed to grow. Once tumors have formed, the mice will be treated with CEP-1347, either alone or in combination with an antiestrogen, and the effects on tumor cell proliferation and death, tumor growth, and tumor metastasis (in the case of PDXs) will be evaluated. Experiments will also be carried out to identify the pathways and molecules by which CEP-1347 is exerting its effects. If CEP-1347 is able to inhibit the growth or metastasis of endocrine-resistant tumors, it will provide strong support for moving forward towards clinical trials for patients with m
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510018
Entities
People
- Susan Conrad
Organizations
- Michigan State University
- United States Army