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DICER1-Driven Cancers: Models, Mechanisms and Therapies

University of Texas Southwestern Medical Center at Dallas
James Amatruda, MD/PhD
Grant Type: 
Innovation Grants
Year Awarded: 
Type of Childhood Cancer: 
Wilms Tumor
Project Description: 


We recently sequenced Wilms tumors, a childhood kidney cancer. We discovered a novel type of missense mutation at position G1809 in the enzyme DICER1, a critical part of the microRNA biogenesis machinery. This mutation, which appears to distort the geometry of the DICER1 active site, destroys the ability of DICER1 to produce the let-7 class of tumor-suppressing microRNAs.

We will identify small molecules capable of directing the refolding of the enzyme, leading to restored activity, generation of effective let-7 microRNAs and impaired tumor growth. Current chemotherapy regimens for cancer are not always effective and cause toxicity to normal tissue. Treatments that target abnormalities specific to cancer cells have the potential to be effective while having minimal effects on normal, non-cancer tissue. Use of small molecules to refold defective tumor-suppressing proteins is a promising approach that has been described for a handful of proteins including p53.

Project Goal

We will identify such small molecules for the DICER1 G1809R mutation, which we discovered in Wilms tumor and which has now been described in several other pediatric and adult cancers, including pleuropulmonary blastoma, chondromesenchymal hamartomas, carcinoid tumors of the lung and endometrial cancers. Success in these aims could be the first step in an entirely new type of therapy for these cancers.

"I am thrilled to be supported by Alex's Lemonade Stand Foundation. This generous funding will allow us to study how mutations in a gene called "DICER1" contribute to a wide variety of cancers in children and young adults. We want to both understand the cause of the cancers and develop new and more effective treatments. The Innovation Award is a great honor and we're grateful to ALSF and all its supporters for making it possible for us to engage in this important research."  -Jim Amatruda