Project Goal:

The goals of this project are to improve therapies for adolescents and young adults with Ewing sarcoma who present with multiple tumors at diagnosis (metastatic) or have recurrence of their disease following initial treatment. Because we know that for these patients treatment options are limited, and also that intensifying treatment for patients with metastatic disease has not proven to be effective, my project goals will focus on combining newer targeted therapies that work by affecting certain aspects of Ewing sarcoma tumors. The goal will be to identify different targeted drugs that can be safely used in combination and effectively treat high risk Ewing sarcoma patients. Additionally, we are still learning about Ewing sarcoma and trying to answer questions such as why certain tumors present in multiple sites, or why certain tumors are resistant to the treatments that we give. The other goal of my project will be to identify ways that Ewing sarcoma tumors have figured out how to escape the therapies we treat them with, and use this information to improve the delivery of these newer targeted therapies so they can be used effectively in patients. Ultimately with the information gained from this project, my hope is that we will improve treatment and outcomes for our most vulnerable Ewing sarcoma patients.

Project Update 2024:

My work is aimed at identifying new combination therapeutic strategies for patients with Ewing sarcoma (EwS), an aggressive bone and soft tissue tumor affecting adolescents and young adults (AYA). Specifically, I am investigating how we can effectively use a class of drugs known as bromodomain and extraterminal domain protein (BET) inhibitors. These drugs aim to alter the expression of genes that are critical for EwS cancer cell survival and growth, subsequently leading to cell death. We know that using one drug will not be sufficient to kill all tumor cells so my efforts are focused on identifying additional treatment strategies we can use with BET inhibitors to improve the efficacy of killing tumor cells. Through deep gene expression profiling, phenotypic profiling, and an unbiased drug screen I have discovered that while cells that escape BET inhibition are more invasive and dependent on a protein called focal adhesion kinase (FAK). FAK is a protein that is critical to tumor cell survival, growth, and migration, and has previously been described to be important for EwS tumor cell growth. There are drugs that target FAK, and we are studying the drug Defactinib- a FAK inhibitor in combination with the BET inhibitor. Our studies have identified that the combination of BET and FAK inhibition is synergistic in our lab models, and preliminary results from our animal experiments reveal that it is synergistic in our animal models as well. We are in the process of validating these findings in our animal models, and are hopeful that if we see promising results, that we will propose this combination drug strategy for clinical trial. Additionally, we remain focused on understanding additional ways by which EwS tumor cells escape BET inhibition. One additional hypothesis that we have is that this is occurring through changes in the epigenome, and plan to perform upcoming studies that will look at the changes that occur at this level.