Identification of PAX3-FOXO1 Fusion Oncogene Degraders Using a Novel HiBiT System for the Therapy of Fusion-Positive Rhabdomyosarcoma
Abstract
Rationale and Objective: Rhabdomyosarcoma is a cancer of the muscle that occurs in children. Although rhabdomyosarcoma is rare, it is the most common cancer in the category of soft tissue cancers in children. Majority of rhabdomyosarcoma comes in two major types, with one having a unique mutation called PAX3-FOXO1. Children with rhabdomyosarcoma that have the PAX3-FOXO1 mutation are more likely to relapse and more likely to present with advanced disease. Survival rates for these patients are very low. Rhabdomyosarcoma with the PAX3-FOXO1 mutation is dependent on the PAX3-FOXO1 mutant gene and when PAX3-FOXO1 is decreased, the cancer cells die. Given this fact, we wanted to search for a new drug which could decrease PAX3-FOXO1. For this purpose, we designed rhabdomyosarcoma cells to emit light in proportion to the amount of PAX3-FOXO1. This way we can easily monitor which drugs decrease PAX3-FOXO1 simply by following the level of light. We tested the cells to see if they performed as we would expect, using a drug we know can decrease PAX3-FOXO1. As expected, the light decreased with drug treatment. We also tested the cells to see if they can be used to easily test thousands of compounds using robots. We again saw that the cells tolerated the procedure and produced easy to read results. Our objective is to use this customized cell to find drugs that can decrease PAX3-FOXO1. First, we propose to screen drugs that are already being used in humans for other diseases to see if we can repurpose the drug for rhabdomyosarcoma. Second, we propose to screen completely new drugs to find novel drugs for rhabdomyosarcoma. Lastly, we propose to make another customized cell that emits a different type of light, which can allow us to locate where in the cancer cell PAX3-FOXO1 is located. Knowing where PAX3-FOXO1 is in the cell can help us learn new information about how PAX3-FOXO1 works so that we can exploit this new knowledge for treatment. Focus Area(s): Our proposal focuses on two areas: (1) Biology and Etiology and (2) Therapy. We will use drugs with known targets to help understand the weaknesses of rhabdomyosarcoma. We will use customized cells that emit light to learn where the PAX3-FOXO1 mutant protein is located inside the cell. We will use our customized cells to find drugs that kill rhabdomyosarcoma cells. What Types of Patients Will It Help and How Will It Help Them? Patients with rhabdomyosarcoma which have the PAX3-FOXO1 mutation can benefit from our proposal. By using our customized cells, we will be able to find drugs that can decrease PAX3-FOXO1 and kill the cancer cells. If the drugs are already being used in humans, they can be repurposed for use in rhabdomyosarcoma. If they are completely novel, our lab plans to characterize the new drug so that the drug can eventually make it to human trials. What Are the Potential Clinical Applications, Benefits, and Risks? Our proposal hopes to bring new drug candidates to clinical trials for the treatment of rhabdomyosarcoma. Potential benefits are that these new drugs can increase patient survival. Potential risks are that these new drugs may have unforeseen side effects. What is the Projected Time Anticipated to Achieve a Clinically Relevant Outcome? For the drugs that are already being used in humans, repurposing these drugs for rhabdomyosarcoma will depend primarily on Food and Drug Administration (FDA) approval for human trials. Typically, when starting a phase 1 human trial it can take a year for FDA approval. For novel drugs identified in our proposal, characterization of the drug before human trials can take 3 to 6 years followed by a year before FDA approval for human trials. What Are the Likely Contributions of This Study to Advancing Rare Cancers Research? If our customization of cancer cells is successful, other scientists who study cancers can use the same method to customize their cancer cells for drug studies. Also, som
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210856
Entities
People
- Yong Yean Kim
Organizations
- National Cancer Institute
- United States Army