DROSHA Regulates Mesenchymal Expression and Chemosensitivity in Wilms Tumor
Abstract
Scientific Objective and Rationale: Wilms tumor is the most common kidney cancer in children. It usually arises in toddlers, and most patients can be cured with a combination of chemotherapy, surgery, and radiation. Although this therapy is often successful, many survivors are left with long-term health conditions caused by their therapy. In addition, some types of Wilms tumors remain harder difficult to cure. Recently, a newer chemotherapy named irinotecan showed promise in Wilms tumor, and irinotecan is now being tested in other types of Wilms tumor. However, we do not know which Wilms tumor patients will benefit the most from irinotecan. More effective treatments are needed, and the treatments that are given need to be better at targeting the patients who will most benefit. However, our ability to adapt treatments to Wilms tumor subgroups is constrained by our limited understanding of how Wilms tumor mutations cause cancer. One harder-to-treat group of Wilms tumors is known as blastemal-predominant based on how their cells look under a microscope. Wilms tumors generally look like undeveloped kidney cells, but blastemal-predominant Wilms tumors look like the earliest type of undeveloped kidney cells. We found that many of these tumors are caused by tumor-specific mutations in a pathway that makes regulatory molecules called microRNAs. Normally, microRNAs turn off other genes, so cells without microRNAs cannot turn off specific genes. However, many questions remain. We do not know how loss of microRNAs causes cancer. We do not know how this locks cells into the earliest state of kidney development. We do not know how this should affect therapy decisions. To study the effects of losing microRNA production, we studied Wilms tumor cells in the lab; Wilms tumor samples from patients; and mice with the most common mutation seen in Wilms tumor. From these studies, we found that a particular gene named HMGA2 is normally turned off by microRNAs in the first step of kidney development. However, Wilms tumors lacking microRNAs are unable to turn off this gene and are unable to undergo this first step. HMGA2 helps a cell turn other genes on and off, and we believe that high levels of HMGA2 lock a Wilms tumor cell into a primitive state. Studies in colon cancer suggest that cells with HMGA2 respond best to irinotecan. However, little is known about how HMGA2 functions in Wilms tumor. FY22 KCRP Focus Area: Conduct basic biology research to better understand etiology and … therapeutic resistance … of kidney cancer. Wilms tumor is one of the most common cancers in children. Although cure rates are high, the regimen involves about one year of frequent hospitalizations, multiple surgeries, and multiple chemotherapy drugs. These therapies carry a high risk of side-effects and complications; some of these side-effects are temporary, but some may continue for the rest of a survivor’s life. In addition to taking time away from other activities, therapy becomes a significant financial burden and emotional burden for Service Members and their Families. Ultimate Applicability of this Research: This project seeks to improve our understanding of how Wilms tumors form and how they respond to therapy. Immediately, this will help us prioritize which patients should receive irinotecan therapy and which may avoid it. In the longer term, our project will provide fundamental details about how Wilms tumors form. Although we only study one subtype of Wilms tumor here, this is an important subtype to study because it is harder to treat. In addition, because this subtype looks like the earliest kidney cells, improving therapy for this subtype will improve therapy for other types of Wilms tumors that arise from these early cells. Lastly, this project will contribute to our understanding of how kidneys form. Based on the development of promising technologies, we may one day be able to grow a kidney from scratch. Th
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310727
Entities
People
- Kenneth Chen
Organizations
- United States Army
- University of Texas Southwestern Medical Center