I am a pediatric oncologist and physician-scientist at the University of Texas Southwestern Medical Center. My long-term goal is to become an independent investigator studying the genetic drivers of Wilms tumor and ways to therapeutically target them. Wilms tumor is the most common pediatric kidney cancer. Although most children are cured, those with high-risk disease continue to have poor outcomes. These tumors are thought to arise from nephron progenitor cells that proliferate instead of differentiating. However, no alternative, targeted therapies have proven effective in Wilms tumor. I previously discovered that some Wilms tumors are driven by mutations that impair production of microRNAs, an important class of molecules involved in gene regulation. Further, Wilms tumors with and without these mutations overexpress the oncogene PLAG1. Thus, the central hypothesis to be tested here is that PLAG1 overexpression in the developing kidney impairs differentiation and drives proliferation, leading to Wilms tumor formation. I will test this hypothesis with the following Specific Aims:
Aim 1. To test whether miRNA repression of Plag1 is required for nephron differentiation.
Aim 2. To determine whether PLAG1 expression is sufficient for tumorigenesis.
Aim 3. To identify the downstream effectors of PLAG1 in nephron progenitor cells (NPCs). To carry out these studies, I have developed an integrated career development plan which will allow me to develop skills with cutting-edge in vitro and in vivo techniques, especially ex vivo culture of NPCs. As part of this plan I have assembled an advisory committee with extensive mentoring experience in cancer biology who will oversee my scientific and career development: Dr. James Amatruda and Dr. Joshua Mendell (co-mentors); Dr. Thomas Carroll; Dr. James Brugarolas; and Dr. Sean Morrison. The studies described herein will allow me to elucidate how PLAG1 contributes to Wilms tumor formation. I anticipate that they will propel me towards a career as an independent investigator studying PLAG1 and other genetic factors contributing to Wilms tumors and other childhood cancers.

Public Health Relevance

/RELEVANCE Wilms tumor is the most common pediatric kidney cancer. Many patients are not cured, and most of those who are cured develop long-term therapy-related toxicities. Developing safer, more effective therapies requires a better understanding of the biology of Wilms tumor formation.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08CA207849-03
Application #
9725923
Study Section
Subcommittee I - Transistion to Independence (NCI)
Program Officer
Bian, Yansong
Project Start
2017-07-15
Project End
2022-06-30
Budget Start
2019-07-01
Budget End
2020-06-30
Support Year
3
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Pediatrics
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Chen, Kenneth S; Fustino, Nicholas J; Shukla, Abhay A et al. (2018) EGF Receptor and mTORC1 Are Novel Therapeutic Targets in Nonseminomatous Germ Cell Tumors. Mol Cancer Ther 17:1079-1089
Chen, Kenneth S; Stroup, Emily K; Budhipramono, Albert et al. (2018) Mutations in microRNA processing genes in Wilms tumors derepress the IGF2 regulator PLAG1. Genes Dev 32:996-1007