A Novel Modality to Target Breast Cancer Stem Cells
Abstract
There is a large body of evidence indicating that breast cancer stem cells (CSCs) promote therapy resistance, tumor recurrence, and metastasis. We have made the novel observation that the Somatostatin receptor 2 (Sstr2) is highly expressed in human breast CSC-enriched populations. Sstr2 is a common therapeutic target in human neuroendocrine tumors, so the enhanced expression of Sstr2 in breast CSCs offers an exciting opportunity to target this tumor cell population. Thus, this proposal will address the Breast Cancer Research Program Overarching Challenges of (1) identifying what drives breast cancer growth and determining how to stop it; (2) identifying why some breast cancers become metastatic; and (3) revolutionize treatment regimens by replacing them with ones that are more effective, less toxic, and impact survival. Sstr2 is a hormone receptor that is normally expressed in neuroendocrine cells and is highly expressed in many neuroendocrine tumors. As such, Sstr2 activating drugs are used as primary therapies to suppress excess hormone secretion that is characteristic of many neuroendocrine tumors. More recently, a radioactive Sstr2 hormone has been approved by the U.S. Food and Drug Administration (FDA) for therapeutic use in midgut neuroendocrine tumors that express Sstr2, thus indicating the safety of Sstr2-targeting drug therapies. Importantly, our team has modified the backbone of this drug to enable coupling to a wide variety of cytotoxic cargos, such as those that have been shown previously to target breast CSCs in vitro. Our preliminary data indicates that Sstr2 expression is dramatically enhanced in CSCs from human breast cancer cell lines and that Sstr2 activation may promote CSC function. Based on these data, we hypothesize that Sstr2 overexpression is a common event in breast CSCs and that targeting Sstr2 may have therapeutic benefit. We will address this hypothesis in the following specific aims. In Aim 1, we will assess whether Sstr2 is required to maintain breast cancer stem cells. To accomplish this, we will test for Sstr2 expression in CSCs present in human breast cancer cell lines and human breast tumor microarrays. We will also test whether Sstr2 function is necessary for breast CSC maintenance. In Aim 2, we will determine whether targeting Sstr2 has therapeutic value in vivo. We will determine whether treatment with an FDA-approved, radioactive Sstr2-targeting drug, or with an Sstr2-targeting drug conjugated to an agent shown to kill breast CSCs in vitro, can eliminate breast CSCs in tumors. We will also determine whether combining CSC targeting drugs with paclitaxel results in a synergistic killing of tumors in mouse triple-negative breast cancer models. Completion of these aims will demonstrate the generality of Sstr2 expression in human breast CSCs and will prove the utility of targeting Sstr2 in breast cancer for therapeutic benefit.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210539
Entities
People
- Jeffrey A Frost
Organizations
- United States Army
- University of Texas Health Science Center at Houston