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Project description:Metastatic castrate-resistant prostate cancer (mCRPC) is a genetically and phenotypically heterogeneous cancer where advancements are needed in biomarker discovery and targeted therapy. A critical and often effective component of treatment includes taxanes. We performed one of the first high throughput screens across a cohort of 30 diverse patient-derived CRPC organoids to a library of 78 drugs. Combining quantitative response measures with transcriptomic analyses demonstrated that HNF1 Homeobox A (HNF1A) drives a transcriptional program of taxane resistance, dependent upon cellular inhibitor of apoptosis protein 2 (cIAP2). Monotherapy with cIAP2 inhibitor LCL161 was sufficient to treat HNF1A+ models of mCRPC previously resistant to docetaxel.
2024-04-01 | GSE252216 | GEO
Project description:Metastatic castrate-resistant prostate cancer (mCRPC) is a genetically and phenotypically heterogeneous cancer where advancements are needed in biomarker discovery and targeted therapy. A critical and often effective component of treatment includes taxanes. We performed one of the first high throughput screens across a cohort of 30 diverse patient-derived CRPC organoids to a library of 78 drugs. Combining quantitative response measures with transcriptomic analyses demonstrated that HNF1 Homeobox A (HNF1A) drives a transcriptional program of taxane resistance, dependent upon cellular inhibitor of apoptosis protein 2 (cIAP2). Monotherapy with cIAP2 inhibitor LCL161 was sufficient to treat HNF1A+ models of mCRPC previously resistant to docetaxel.
2024-04-01 | GSE252203 | GEO
Project description:Castrate Resistant Prostate Cancer Response to Taxane is Determined by an HNF1-dependent Apoptosis Resistance Circuit
| PRJNA1058578 | ENA
Project description:Castrate Resistant Prostate Cancer Response to Taxane is Determined by an HNF1-dependent Apoptosis Resistance Circuit (ChIP-Seq)
| PRJNA1058537 | ENA
Project description:Castrate Resistant Prostate Cancer Response to Taxane is Determined by an HNF1-dependent Apoptosis Resistance Circuit (RNA-Seq)
| PRJNA1058598 | ENA
Project description:Taxanes are the only chemotherapies used to treat patients with metastatic castration-resistant prostate cancer (CRPC). Despite the initial efficacy of taxanes in treating CRPC, all patients ultimately fail due to the development of drug resistance. In this study, we show that ERG overexpression in in vitro and in vivo models of CRPC is associated with decreased sensitivity to taxanes. ERG affects several parameters of microtubule dynamics and inhibits effective drug-target engagement of docetaxel or cabazitaxel with tubulin. Finally, analysis of a cohort of 34 men with metastatic CRPC treated with docetaxel chemotherapy reveals that ERG-overexpressing prostate cancers have twice the chance of docetaxel resistance than ERG-negative cancers. Our data suggest that ERG plays a role beyond regulating gene expression and functions outside the nucleus to cooperate with tubulin towards taxane insensitivity. Determining ERG rearrangement status may aid in patient selection for docetaxel or cabazitaxel therapy and/or influence co-targeting approaches.
| S-EPMC4244604 | biostudies-literature
Project description:Purpose of reviewPrior to 2010, docetaxel was the only treatment shown to prolong survival in metastatic castrate-resistant prostate cancer (CRPC). In the past 3 years, several therapeutic agents have demonstrated survival improvements for CRPC after the receipt of prior docetaxel, leading to multiple approvals by the US Food and Drug Administration.Recent findingsThe development of these novel agents, each with a distinct mechanism of action, is the fruition of sedulous preclinical research and well designed clinical trials. Cabazitaxel, a next generation taxane, was the first Food and Drug Administration-approved drug for the postdocetaxel setting. The recognition of sustained androgen dependence of CRPC has led to the identification of more potent and selective inhibitors of androgen synthesis and androgen-receptor signaling, such as abiraterone and enzalutamide, respectively. Radium-223, an α-emitting radionuclide still under regulatory review, recently showed a significant survival benefit for CRPC. Finally, sipuleucel-T, a form of immunotherapy, may benefit a subset of patients in the postdocetaxel setting.SummaryPost-docetaxel management of CRPC has undergone a dramatic yet welcome paradigm change in the past 3 years. With multiple life-prolonging agents available, it now becomes imperative to coordinate how and when these new therapies should be used and sequenced to achieve optimal patient outcomes.
| S-EPMC4486479 | biostudies-literature
Project description:Expression of tumor necrosis factor-? (TNF?) in the serum of prostate cancer patients is associated with poorer outcome and progression to castrate-resistant (CRPC) disease. TNF? promotes the activity of NF?B, which regulates a number of anti-apoptotic and proinflammatory genes, including those encoding the inhibitor of apoptosis proteins (IAPs); however, in the presence of IAP antagonists, TNF? can induce cell death. In the presence of recombinant or macrophage-derived TNF?, we found that IAP antagonists triggered degradation of cIAP1 and induced formation of Complex-IIb, consisting of caspase-8, FADD and RIPK1 in CRPC models; however, no, or modest levels of apoptosis were induced. This resistance was found to be mediated by both the long (L) and short (S) splice forms of the caspase-8 inhibitor, FLIP, another NF?B-regulated protein frequently overexpressed in CRPC. By decreasing FLIP expression at the post-transcriptional level in PC3 and DU145 cells (but not VCaP), the Class-I histone deacetylase (HDAC) inhibitor Entinostat promoted IAP antagonist-induced cell death in these models in a manner dependent on RIPK1, FADD and Caspase-8. Of note, Entinostat primarily targeted the nuclear rather than cytoplasmic pool of FLIP(L). While the cytoplasmic pool of FLIP(L) was highly stable, the nuclear pool was more labile and regulated by the Class-I HDAC target Ku70, which we have previously shown regulates FLIP stability. The efficacy of IAP antagonist (TL32711) and Entinostat combination and their effects on cIAP1 and FLIP respectively were confirmed in vivo, highlighting the therapeutic potential for targeting IAPs and FLIP in proinflammatory CRPC.
| S-EPMC6197283 | biostudies-literature
Project description:The effective treatment of castrate-resistant prostate cancer (CRPC) has proven to be very challenging. Until recently, docetaxel was the only therapeutic demonstrated to extend overall patient survival. Yet recently, a considerable number of new therapeutics have been approved to treat CRPC patients. These remarkable advances now give new tools for the therapeutic management of late-stage prostate cancer. In this review, we will examine mechanistic and clinical data of several newly approved therapeutics including the chemotherapeutic cabazitaxel, antiandrogen enzalutamide, endocrine disruptor abiraterone acetate, immunotherapy sipuleucel-T, and bone-targeting radiopharmaceutical alpharadin. In addition, we will examine other promising therapeutics that are currently in Phase III trials.
| S-EPMC3678432 | biostudies-literature
Project description:Recent advances in tumor biology have made remarkable achievements in the development of therapy for metastatic castrate-resistant prostate cancer. These advances reflect a growing appreciation for the role of the tumor microenvironment in promoting prostate cancer progression. Prostate cancer is no longer viewed predominantly as a disease of abnormally proliferating epithelial cells but rather as a disease of complex interactions between prostate cancer epithelial cells (epithelial compartment) and the surrounding tissues (stromal compartment) in which they reside. For example, prostate cancers frequently metastasize to bone, an organ that contains a microenvironment rich in extracellular matrix proteins and stromal cells including hematopoietic cells, osteoblasts, osteoclasts fibroblasts, endothelial cells, adipocytes, immune cells, and mesenchymal stem cells. Multiple signaling pathways provide crosstalk between the epithelial and the stromal compartments to enhance tumor growth, including androgen receptor signaling, tyrosine kinase receptor signaling, and immune surveillance. The rationale to disrupt this "two-compartment" crosstalk has led to the development of drugs that target tumor stromal elements in addition to the cancer epithelial cell.
| S-EPMC4176261 | biostudies-literature