Targeting the Polycomb Pathway for Testicular Cancer Therapy in Adolescents and Young Adults
Abstract
The purpose of this project is to validate the concept, provide data on mechanism, and uncover biomarkers of response to support future clinical trials targeting the polycomb pathway in testicular germ cell tumor (TGCT) patients. The major findings in the first two years have shown that targeting the polycomb pathway both pharmacologically and genetically alters cisplatin sensitivity of TGCTs in vitro and in vivo in mice. In terms of mechanism and biomarker identification we have performed a number of unbiased genome-wide studies including RNA-seq, H3K27me3 ChIP-seq and p53 ChIP-seq. Update for year 2. This past year we have performed xenografts with polycomb targeted drug GSKJ4 on a second TGCT cell line and have generated polycomb component KDM6A and KDM6B dual knockdown cells and tested their cisplatin sensitivity in vitro and in vivo (started just last week). We are at the stage of familiarity with the genetically engineered mouse model to start our first therapeutic trail with GSKJ4 plus cisplatin by next month and have conducted further RNA-seq studies on two cell lines treated with cisplatin, GSKJ4, and the combination. We have assessed whether polycomb targeting affects cisplatin sensitivity in somatic cancer cells and we have stained 50 primary TGCT samples with an antibody to the polycomb mark, H3K27me3. We have not encountered any insurmountable issues and are on track to complete all the tasks of the SOW. Our results strongly support that polycomb may be a valuable and useful therapeutic target to treat cisplatin refractory TGCTs. Further, the lab has been working closely with the leadership of the Malignant Germ Cell International Consortium (MaGIC) to conduct a second, large National Clinical Trial Network-wide trial of epidrug and DNA hypomethylating agent, ASTX727, in cisplatin refractory TGCT patients to be started approximately 1 year from now.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2023
- Accession Number
- AD1219009
Entities
People
- Michael Spinella
Organizations
- University of Illinois Urbana–Champaign