The Role of MELK in Stromal Reorganization of Aggressive Breast Cancers
Abstract
Triple-negative breast cancer (TNBC) and inflammatory breast cancer (IBC) are aggressive breast cancer subtypes with poor clinical outcomes due to the lack of well-validated and actionable targets and the onset of chemoresistant metastasis. The 5-year overall survival rate for TNBC is only 60%-70% and IBC is only 62%-68% with multimodality treatment, largely due to a lack of U.S. Food and Drug Administration (FDA)-approved targeted therapies. Poor TNBC and IBC outcomes are related to the propensity of these two tumor types to metastasize. Our previous studies show that a that a protein called MELK (maternal embryonic leucine zipper kinase) is present in higher amounts in TNBC and IBC than in other breast cancer types. Further, the amount of time patients with breast cancer survived was correlated to the amount of MELK in their tumor cells: the lower the amount of MELK, the longer the survival time and vice versa. These findings suggest that drugs that reduce the level of MELK in tumors will allow patients with TNBC and IBC to live longer. Therefore, we identified MELK inhibitors that reduce the amount of MELK in TNBC and IBC cells and reduce metastasis. The proposed project builds up on the findings of our preliminary data and will focus on (i) whether combining a MELK inhibitor with the standard of care (paclitaxel) in TNBC and IBC preclinical animal models will prevent the spread of TNBC and IBC to distant sites, (ii) the clinical significance of MELK as a biomarker and in patient outcomes, and (iii) understanding how MELK promotes metastasis by modulating the tumor cell microenvironment. The following three specific aims will be pursued: Aim 1: Evaluate MELK as a novel therapeutic target in models of metastatic TNBC and TN-IBC. Aim 2: Determine the prognostic and predictive significance of MELK in TNBC and IBC. Aim 3: Determine if MELK modulation of fibronectin affects tumor cell microenvironment in aggressive breast cancers. Because our inhibitor specifically targets MELK, we expect that MELK-targeted therapy would have low toxicity with fewer side effects than are seen with conventional therapies. We will use cell culture-based approaches and mouse models to identify how MELK modifies the microenvironment and promotes metastasis. We will also test the MELK inhibitor in patient-derived xenograft mouse models that harbor tumors from patients with breast cancer and humanized mice to ensure the clinical relevance of the proposed study. Impact: These contributions will have a significant impact because they will address the need for targeted therapies to reduce mortality due to metastasis in patients with TNBC and IBC. Our study is highly translational as we expect that this research will lead to a novel approach and will help significantly reduce TNBC and IBC-related deaths by adding a new treatment option and establishing biomarkers by validating protein substrates and efficacy data of inhibitors. Our work is expected to lead to an effective clinical trial with a MELK inhibitor in combination with standard of care in the next 3-5 years. This unique grant is in line with Fiscal Year 2022 Overarching Challenges: (1) Identify why some breast cancers become metastatic. (2) Eliminate the mortality associated with metastatic breast cancer with state-of-the-art drug development to address aggressive cancers. We are grateful for this opportunity to work toward conquering this highly fatal, aggressive disease through our research.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310087
Entities
People
- Chandra Bartholomeusz
Organizations
- The University of Texas MD Anderson Cancer Center
- United States Army