<p>Novel Therapeutic Strategies for CDK4/6 Inhibitors in Metastatic Castrate-Resistant Prostate Cancer</p>

Abstract

The majority of patients with castrate-resistant prostate cancer will have metastatic disease at the time of diagnosis. Investigative efforts on new therapeutics for this patient population have improved with the development of androgen signaling inhibitors, such as abiraterone and enzalutamide, and PARP inhibitors, such as rucaparib and olaparib, to accompany the previously FDA-approved docetaxel, cabazitaxel, sipuleucel-T, and Radium 223. However, new therapeutic strategies are necessary to prolong survival as progression after these agents is inevitable. CDK4/6 inhibitors have advanced the field of estrogen receptor positive breast cancer treatment and are being investigated in prostate cancer given the role of androgen receptor signaling effects on the cell cycle. Response to CDK4/6 inhibitors may be predicted by the tumors' genomic profile and may provide insight into combinatory therapy with CDK4/6 inhibitors in order to delay resistance or provide synergistic effects. Here, we review the use of CDK4/6 inhibitors in prostate cancer and potential combinations based on known resistance mechanisms to CDK4/6 inhibitors, prostate cancer regulatory pathways, and prostate-cancer-specific genomic alterations.

Anticancer function of microRNA‐30e is mediated by negative regulation of HELLPAR, a noncoding macroRNA, and genes involved in ubiquitination and cell cycle progression in prostate cancer

“…Overall, this study provides convincing evidence that miR‐30e exerts a tumor suppressor role through modulation of HELLPAR lncRNA and a number of key oncogenic mRNAs that are clinically significant in PCa and are involved in different signaling pathways, including AR signaling [ 94 ], cell cycle progression [ 95 , 96 ], apoptosis [ 97 ] and ubiquitination pathways [ 98 ]. Thus, our study demonstrates that miR‐30e has a multidimensional role in PCa progression and indicates the significance of miR‐30e as a potential therapeutic target for PCa.…”

Inferring Differential Networks by Integrating Gene Expression Data With Additional Knowledge

“… If the gene is associated with prostate cancer (PCa) or enzalutamide-resistant (ER) according to literature search ( Wu et al, 2006 ; Tam et al, 2007 ; Lin et al, 2015 ; Wang et al, 2018 ; Handle et al, 2019 ; Chen et al, 2020 ; Kase et al, 2020 ; Balijepalli et al, 2021 ; Dickson et al, 2021 ; Furlan et al, 2021 ), a ○ is placed in the corresponding entry. The p -value of each gene is computed by Wilcoxon rank-sum test.…”

“…In this paper, based on gene expression data and additional biological knowledge, we propose a novel differential network estimation method named weighted joint sparse penalized D-trace model (WJSDM), to infer the changes of gene regulatory networks between two different states. By employing D-trace loss function and using a revised Kendall's tau correlation, our method can directly infer the differential network between two different states from gene expression data with missing (Wu et al, 2006;Tam et al, 2007;Lin et al, 2015;Wang et al, 2018;Handle et al, 2019;Chen et al, 2020;Kase et al, 2020;Balijepalli et al, 2021;Dickson et al, 2021;Furlan et al, 2021) values. Furthermore, to integrate the gene expression data collected from different data platforms and utilize the information provided by various prior biological knowledge, we propose a weighted group bridge penalty function, which enable our model to draw support from multiple related data sets.…”

Targeting signaling pathways in prostate cancer: mechanisms and clinical trials

“… 54 – 62 Agents targeting other PCa-related signaling pathways, including cyclin-dependent kinase (CDK)4/6, p53, wingless-type protein (WNT) signaling, vascular endothelial growth factor (VEGF), endothelin A receptor (ETAR), fibroblast growth factor receptor (FGFR), epidermal growth factor receptor (EGFR), receptor tyrosine kinases (RTKs), transforming growth factor beta (TGFβ), proto-oncogene tyrosine-protein kinase Src (SRC), and mitogen-activated protein kinase kinase (MEK), have also entered clinical trials. 63 – 74 Alternative splicing affects genes (such as FGFR , ERG , VEGFA , and AR ) that are clearly linked to the etiology of PCa; therefore, developing novel targeted therapies that modulate alternative splicing for the treatment of PCa are warranted. 75 In this review, we have discussed strategies for targeting signaling pathways in PCa, as well as their mechanisms and related clinical trials.…”