Targeting Neuroendocrine Prostate Cancer with Small-Molecule Drug Conjugates
Abstract
Significant progress has been made in understanding the mechanism of action of SphK1 in promoting neuroendocrine progression. NEPC is known as lipid-rich tumor and elevated lipogenic enzymes have been observed in clinical specimens. In cBioPortal, 22% NePC patients have Sphingosine kinase-1 (SphK1) gene amplification; this enzyme produces sphingosine 1-phosphate (S1P) that is a lipid mediator critical for tumor cell growth, survival, and therapeutic resistance. Also, the elevated SphK1 mRNA and protein expression is detected in NEPC cells. By genomic knockout and transcriptomic approaches, the mechanism of action of SphK1 is identified through S1P receptor-MAP kinase pathway leading to the proteasome degradation of RE1-Silencing Transcription factor (REST) that is known as a master repressor of neuroendocrine differentiation. Based on these discoveries, SphK1 is a new therapeutic target for NePC therapy. Indeed, in vitro data support a good potency of SphK1 small molecule inhibitors (FTY720 or SKI-II) in inhibiting NePC growth; the in vivo data is on the way.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2021
- Accession Number
- AD1172660
Entities
People
- Ganesh V Raj
Organizations
- University of Texas at Dallas