Induction of Lysosomal Trafficking to Target Growth and Metastasis
Abstract
Rationale and Objective: The Epidermal Growth Factor Receptor (EGFR) is one of a family of proteins whose overexpression drives triple-negative breast cancer growth and metastasis. This overexpression is correlated with poor overall survival and aggressive disease. EGFR has many functions as an oncogene, including some that utilize its enzymatic (kinase) activity and some that are kinase-independent. Drugs have been developed to target the kinase (kinase inhibitors, or TKIs, such as Iressa), but even in the cancers where these therapies are effective (such as lung cancer), most patients’ tumors evolve resistance relatively quickly. Importantly, these TKIs show poor activity in breast cancer. Drugs have also been developed – antibodies such as the drug Erbitux – to kill cells that express EGFR. While these drugs work well in some cases (specifically in head and neck cancer and colorectal cancer), in breast cancer they fail to destroy the tumor. We have striven to understand why these drugs fail to work in breast cancer as they do in other cancers. Research from our lab and others shows that in breast cancer (specifically metastatic triple-negative), EGFR functions differently. Instead of sitting at the cell surface and sending out signals, it goes inside the cell and works in unique ways – frequently not even needing its kinase domain. We are now proposing to develop a novel therapeutic that goes inside the cell and causes EGFR to be destroyed. This is based on a set of proteins called Sorting Nexins (or SNX), whose job it is to control what happens to EGFR inside cells. Other labs have shown that overexpression of SNX1 causes EGFR to be degraded. This means it doesn’t matter how it’s working differently in breast cancer, it will be destroyed in the presence of high levels of SNX1. We have made a drug that uses high levels of a SNX1 peptide to cause EGFR to be destroyed and found that it causes triple-negative breast cancer cells in the lab to initially stop migrating, and then after longer time periods, to be destroyed. We will be evaluating whether or not the compound is toxic and if it targets the cellular pathways we expect it to target. This work will form the basis for future studies that would allow us to apply for Investigational New Drug (IND) status and perform clinical trials in breast cancer patients here at the Arizona Cancer Center. Aims: We have proposed three aims in this study. The first is to optimize a therapeutic for which we have preliminary data to show it inhibits survival and migration of triple-negative breast cancer cells. This aim will add chemical modifications to the peptide therapeutic that allow it to survive in patients. Similar drugs for other targets have recently been approved by the Food and Drug Administration (FDA), indicating this is a viable path forward for drug development. In Aim II, we will investigate exactly how the drug works and determine potential toxicities that may arise. Triple-negative breast cancer is a heterogeneous disease, and understanding exactly how our drug works will help us to focus on the right population of patients. In Aim III, we will evaluate the efficacy of the lead drug in mouse models of breast cancer, using models that have human cancer cells, but no immune system, and mouse cancer cells, but a functioning immune system. In this way, we expect to get a clear understanding of how well our therapeutic will work in patients. Overarching Challenge: (1) Revolutionize treatment regimens by replacing them with ones that are more effective, less toxic, and impact survival. (2) Eliminate the mortality associated with metastatic breast cancer. Patient Focus and Clinical Applications: Our proposal is designed to develop a therapeutic for patients with metastatic triple-negative disease. This proposal is designed to optimize a therapy and show it works in models of metastatic triple-negative breast cancer. If this study is succe
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810663
Entities
People
- Joyce Schroeder
Organizations
- United States Army
- University of Arizona