Showing papers by "Vincent C. O. Njar published in 2023"
TL;DR: In this article , the authors reported that compound 2 was better tolerated by the normal male CD-1 mice than the male Nude mice, and the maximum tolerated dose (MTD) was estimated to be between 25 < 50 mg/kg.
2 citations
TL;DR: Galeterone, 3β-(hydroxy)-17-(1H-benzimidazole-1-yl)androsta-5,16-diene (Gal, 1) and VNPP433-3β (4 and 5) are promising Phase 3 and Phase 1 drug candidates, respectively as discussed by the authors .
TL;DR: Thomas et al. as discussed by the authors reported that VNLG-152R significantly upregulates Synoviolin (SYVN1) with concomitant degradation of Mnk1/2.
Abstract:
Introduction: Breast cancer remains a major concern as the second leading cause of cancer-related death in women in the United States and the most frequently diagnosed cancer in women globally. Among all the subtypes, triple negative breast cancer (TNBC) is highly resilient and eludes currently available treatment modalities. This study describes the mechanism of action of VNLG-152R in inhibiting TNBC tumor growth.
Methods: TNBC cell lines MDA-MB-231 and MDA-MB-468 originated from TNBC patients of Caucasian American and African American descend, respectively, were challenged with VNLG-152R in vitro. The mechanism of action was studied by immunoblotting key proteins, proteasomal degradation assay of Mnk1/2 and transcriptome analysis by RNA-seq. The therapeutic potential of VNLG-152R is demonstrated in NRG mice bearing either MDA-MB-231 or MDA-MB-468 tumor xenografts.
Results: We report for the first time, that, VNLG-152R significantly upregulates Synoviolin (SYVN1) in TNBC cell lines MDA-MB-231 and MDA-MB-468 with concomitant degradation of Mnk1/2. SYVN1 is a known E3-ubiquitin ligase and it ubiquitinates its target proteins, rendering them to proteasomal degradation. However, there was no significant change in Mnk1/2 levels upon treatment with VNLG-152R in presence of SYVN1 inhibitor LS102. A similar result is obtained upon siRNA knockdown of SYVN1. Subsequently, the decreased level of Mnk1/2 diminished the phosphorylation of eIF4E with a concurrent decrease in levels of eIF4E-validated downstream targets, Bcl-2 and Cyclin D1, resulting in tumor growth inhibition. Inhibition of proteasomal degradation by MG-132 prior to treating cells with VNLG-152R further supports that VNLG-152R promotes SYVN1-mediated ubiquitin-proteasomal degradation of Mnk1/2. Further, RNA-seq and Gene Set Enrichment Analysis (GSEA) of differentially expressed genes demonstrate inhibition of mTORC1 (mammalian target of rapamycin complex 1) and NUP153 (Nucleoporin 153) pathways and activation of p53 pathway thereby inhibiting tumor progression. Finally, oral administration of VNLG-152R to mice bearing tumor xenografts of either MDA-MB-231 or MDA-MB-468 significantly inhibited tumor growth and resulted in 87% and 80% tumor growth inhibition, respectively, without apparent host toxicity. Immunoblots of tumor tissue further demonstrate elevated levels of SYVN1 and decreased Mnk1/2 and p-eIF4E, which further confirms the role of SYVN1-mediated proteasomal degradation of Mnk1/2 in inhibiting TNBC tumor growth by VNLG-152R.
Conclusion: As VNLG-152R potently inhibits development and progression of TNBC of different origins by upregulating E3 ubiquitin ligase SYVN1 leading to ubiquitination and proteasomal degradation of Mnk1/2 thereby decreased oncogenic phosphorylation of eIF4E by Mnk1/2, VNLG-152R could potentially be developed for the treatment of TNBC, irrespective of racial origin.
Citation Format: Elizabeth Thomas, Retheesh S. Thankan, Puranik Purushottamachar, Vincent C. Njar. Mechanistic studies on VNLG-152R-mediated tumor inhibition of triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB235.
TL;DR: In this article , the authors demonstrate the potential role of VNPP433-3β as molecular glue that induces physical proximity between the Androgen Receptor and MDM2 E3 ligase in prostate cancer cells.
Abstract: Simple Summary In this study, we demonstrate the potential role of VNPP433-3β as molecular glue that induces physical proximity between the Androgen Receptor and MDM2 E3 ligase in prostate cancer cells. The interaction promotes MDM2-mediated ubiquitination of AR and its subsequent proteasomal degradation resulting in growth inhibition of prostate cancer cells. Abstract Targeted protein degradation is a fast-evolving therapeutic strategy to target even the traditionally undruggable target proteins. Contrary to the traditional small-molecule inhibitors of enzyme or receptor antagonists that bind the active site pockets in the target protein, molecular glue degraders facilitate interaction of target proteins with E3 ubiquitin ligases by stabilizing the ternary complex and induce physical proximity, thereby triggering ubiquitination and subsequent proteasomal degradation. AR plays a key role in all stages of prostate cancer. It is activated by the binding of androgenic hormones and transcriptionally regulates multiple genes including the ones that regulate cell cycle. Using HiBiT CRISPR cell line, biochemical methods, and RNA sequencing, we report the potential role of VNPP433-3β, the next generation galeterone analog as molecular glue that brings together AR, the key driver of prostate cancer and MDM2, an E3 ubiquitin ligase leading to ubiquitination and subsequent degradation of f-AR and AR-V7 in prostate cancer cells.