Publications by authors named "S Balk"
Androgen receptor (AR) splice variants, of which ARv7 is the most common, are increased in castration-resistant prostate cancer, but the extent to which they drive AR activity is unclear. We generated a subline of VCaP cells (VCaP16) that is resistant to the AR inhibitor enzalutamide (ENZ). AR activity in VCaP16 is driven by ARv7, independently of full-length AR (ARfl), and its cistrome and transcriptome mirror those of ARfl in VCaP cells.
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- * BCL2, an anti-apoptotic protein, is upregulated in these aggressive prostate cancers, which presents a potential target for therapy and highlights the importance of studying its expression in metastatic CRPC (mCRPC).
- * Research shows that BCL2 is more prevalent in AR-negative mCRPC and is linked to poorer survival outcomes; also, its regulation involves DNA methylation and a transcription factor called ASCL1, suggesting the need for combination therapies to improve treatment efficacy.
Background: Cyclin-dependent kinase 9 (CDK9) stimulates oncogenic transcriptional pathways in cancer and CDK9 inhibitors have emerged as promising therapeutic candidates.
Methods: The activity of an orally bioavailable CDK9 inhibitor, CDKI-73, was evaluated in prostate cancer cell lines, a xenograft mouse model, and patient-derived tumor explants and organoids. Expression of CDK9 was evaluated in clinical specimens by mining public datasets and immunohistochemistry.
Article Synopsis
- Current treatments for advanced prostate cancer mainly focus on androgen receptor pathways, but issues like castration-resistant prostate cancer (CRPC) pose significant challenges.
- The study introduces BSJ-5-63, a new triple degrader that targets specific cyclin-dependent kinases (CDK12, CDK7, CDK9) to reduce both DNA repair genes and androgen receptor signaling, enhancing treatment efficacy.
- BSJ-5-63 creates a lasting "BRCAness" state, allowing for effective sequential therapy with PARP inhibitors while reducing drug-related side effects and resistance, potentially benefiting a wide range of CRPC patients.