Grants and Contracts Details

Description

Identification of Molecular Signatures for Treatment-Responsive and Recurrent Wilms Tumors and Overcoming Resistance to Therapy Abstract Wilms tumor is the most common solid renal malignancy in children. Although the long-term survival rates for Wilms tumor in patients with localized disease are high, morbidity is associated with treatment in these patients. About 15% of children with Wilms tumor relapse and ultimately succumb to the disease. A better understanding of Wilms tumor genomics and biology will allow stratification of: (a) patients that are more likely to relapse in order to provide personalized treatment and diminish the likelihood of relapse, and (b) low risk patients so as to administer them treatments with fewer or no adverse effects. Several studies have indicated that Wilms tumors with anaplastic histology are associated with higher rates of recurrence, metastases, and death. Mutation of the tumor suppressor p53 occurs more frequently in anaplastic tumors that show increased recurrence and decreased patient survival. In addition, the Wilms tumor 1 (WT1) gene located at chromosome 11p13 encodes a zinc-finger protein that serves as a transcriptional regulator and is associated with the biology of Wilms tumors. Initial studies identified WT1 as a tumor suppressor, but subsequent findings suggest that WT1 can function either as a tumor suppressor or an oncogene depending on the cellular context. Importantly, we and others have shown that the tumor suppressor protein Prostate apoptosis response-4, Par-4 (also called PAWR) binds to WT1 protein and suppresses WT1 transcription function. Par-4 was first identified in 1993 by our group at the Markey Cancer Center, University of Kentucky, and treatment strategies that induce the function of this protein are now in clinical trials for prostate and other cancers. Although Par-4 is not known to be mutated in Wilms tumor, its expression is reported to be higher in peritumoral tissues relative to Wilms tumor tissues, and restoration of Par-4 sensitizes the tumor cells to chemotherapeutic agents. A systematic study of Wilms tumors for mutations in aforementioned genes, as well as the expression and regulation of WT1 function by Par-4 is necessary to better understand the biology of Wilms tumors, and develop drugs especially against tumors that relapse. The objective of this application is to: (1) identify mutations in exons, differential gene expression patterns, and Par-4/WT1 expression status of Wilms tumors in Kentucky, in order to develop molecular signatures for treatable versus treatment-resistant (i.e., recurrent) tumors, (2) study Wilms tumor patient-derived xenograft (PDX) models obtained from our collaborator at St. Jude Children’s Research Hospital, and new PDXs generated from the patients’ tumors in Kentucky, for sensitivity to the novel yet safe drug Arylquin-1, which inhibits tumor growth by Par-4-dependent and Par-4-independent mechanisms. This project involves a multidisciplinary approach by a team of basic science/translational researchers, physicians and surgeons, and will result in essential resources for Wilms tumor research in Kentucky that include well-characterized tumor tissue microarrays and PDX models, a better understanding of Wilms tumor biology, and a safe drug to overcome treatment resistance.
StatusActive
Effective start/end date7/1/226/30/24

Funding

  • KY Cabinet for Health and Family Services: $376,407.00

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