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Sequencing Small Non-coding RNA from Formalin-fixed Tissues and Serum-derived Exosomes from Castration-resistant Prostate Cancer Patients
Published on: November 19, 2019
Transcriptome profiling reveals that VNPP433-3β, the lead next-generation galeterone analog inhibits prostate cancer
Elizabeth Thomas1,2, Retheesh S Thankan1,3,4, Puranik Purushottamachar1,2
1Department of Pharmacology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
Abstract:
Cancer stem cells (CSCs) virtually present in all tumors albeit in small numbers are primarily responsible for driving cancer progression, metastasis, drug resistance, and recurrence. Prostate cancer (PCa) is the second most frequent cancer in men worldwide, and castration resistant prostate cancer (CRPC) remains a major challenge despite the tremendous advancements in medicine. Currently, none of the available treatment options are effective in treating CRPC. We earlier reported that VNPP433-3β, the lead next-generation galeterone analog is effective in treating preclinical in vivo models of CRPC. In this study using RNA-seq, cytological, and biochemical methods, we report that VNPP433-3β inhibits prostate CSCs by targeting key pathways critical to stemness and epithelial-mesenchymal transition. VNPP433-3β inhibits CSCs in PCa, presumably by degrading the androgen receptor (AR) thereby decreasing the AR-mediated transcription of several stem cell markers including BMI1 and KLF4. Transcriptome analyses by RNA-seq, Ingenuity Pathway Analysis, and Gene Set Enrichment Analysis demonstrate that VNPP433-3β inhibits transcription of several genes and functional pathways critical to the prostate CSCs thereby inhibiting CSCs in PCa besides targeting the bulk of the tumor.
Insights
VNPP433-3β, a novel galeterone analog, effectively targets prostate cancer stem cells (CSCs) by degrading the androgen receptor (AR). This action inhibits key pathways driving cancer progression and resistance, offering new hope for castration-resistant prostate cancer treatment.
Area of Science:
- Oncology
- Cancer Biology
- Molecular Medicine
Background:
- Cancer stem cells (CSCs) drive tumor progression, metastasis, and treatment resistance.
- Castration-resistant prostate cancer (CRPC) presents a significant therapeutic challenge with limited effective options.
- Prostate cancer (PCa) is a leading cancer affecting men globally.
Purpose of the Study:
- To investigate the efficacy of VNPP433-3β, a next-generation galeterone analog, in inhibiting prostate cancer stem cells (CSCs).
- To elucidate the molecular mechanisms by which VNPP433-3β targets CSCs in prostate cancer.
Main Methods:
- RNA sequencing (RNA-seq) for transcriptome analysis.
- Cytological and biochemical assays to assess cellular effects.
- Ingenuity Pathway Analysis (IPA) and Gene Set Enrichment Analysis (GSEA) for pathway identification.
Main Results:
- VNPP433-3β effectively inhibits prostate CSCs by targeting stemness and epithelial-mesenchymal transition pathways.
- The compound likely functions by degrading the androgen receptor (AR), reducing AR-mediated transcription of stem cell markers like BMI1 and KLF4.
- Transcriptome analysis confirmed the inhibition of critical genes and pathways essential for prostate CSC function.
Conclusions:
- VNPP433-3β demonstrates potent inhibition of prostate CSCs, impacting both stemness and bulk tumor cells.
- This novel galeterone analog represents a promising therapeutic strategy for castration-resistant prostate cancer.
- Targeting CSCs with VNPP433-3β offers a potential approach to overcome treatment resistance in prostate cancer.
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