The RET Kinase Signaling Axis in Neuroendocrine Prostate Cancer Plasticity
Abstract
Aggressive variant prostate cancer (AVPC) is associated with loss of expression/function of RB1 and/or Tp53. AVPC represents lethal a subgroup prostate cancer with approximately 1-2 years survival rates in patients. Lineage plasticity driven by epigenetic regulators including EZH2 is implemented as a major mechanism driving AVPC. Currently there are no therapeutic approaches to provide durable response in patients who have progressed to AVPC. The receptor tyrosine kinase RET is found to be highly expressed in AVPC patients comparing with CRPC. We generated 1) Pten(floxed/floxed):Rb1(floxed/floxed):RET(+/+); 2)Pten(floxed/floxed):Rb1(floxed/floxed):RET(floxed/+) and 3) Pten(floxed/floxed):Rb1(floxed/floxed):RET(floxed/floxed) mice to determine the dependence of RET kinase as driver and therapeutic target in AVPC. All floxed alleles were targeted by Crerecombinase expression driven by a probasin promoter. This allows to targeted excision exclusive to the mouse prostatitis epithelium. While some complications were encountered, we successfully generated a small number of mice representing all three genotypes. Aging studies are ongoing and will conclude in December 2020 - January 2021. We also collected prostate tissues from 10 weeks-old mice which either Cre+ or Cre- to generate 3D organoids from these mice. 3D organoids are also being generated into2D cell lines.
Document Details
- Document Type
- Technical Report
- Publication Date
- Aug 01, 2020
- Accession Number
- AD1118335
Entities
People
- Leigh Ellis
- Yuzhen Zhou
Organizations
- Dana–Farber Cancer Institute