A prospective observational study evaluating intestinal microbiome as a biomarker to predict the efficacy and toxicity of prostate cancer patients receiveing PARP inhibitors alone or combined with novel ADT agents
Ontology highlight
ABSTRACT:
DISEASE(S): Prostate Cancer
PROVIDER: 2707329 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
Similar Datasets
Project description:Interventions: case series:Nil
Primary outcome(s): ORR;OS;PFS;AE
Study Design: Sequential
| 2695487 | ecrin-mdr-crc
Project description:Prostate cancer (PCa) metastasis is considered the leading cause of cancer death in males. Therapeutic strategies and diagnosis for stage-specific PCa have not been well understood. Rho guanine nucleotide exchange factor 38 (ARHGEF38) is related to tumor cell polarization and is frequently expressed in PCa. Microarray data of PCa were downloaded from GEO and TCGA databases. A total of 243 DEGs were screened, of which, 32 genes were upregulated. The results of enrichment analysis showed the participation of these DEGs in the tumor cell metastasis pathway. ARHGEF38 was significantly up-regulated in the four most prevalent cancers worldwide (p < 0.05), and its expression was higher in the tumor samples with higher Gleason score (GS). IHC, qRT-PCR, and western-blot analyses showed the higher expression of ARHGEF38 in PCa than benign prostatic hyperplasia (BPH). In addition, IHC results demonstrated a higher expression of ARHGEF38 in high-grade PCa than the low-grade PCa.
| S-EPMC7083745 | biostudies-literature
Project description:The current study presents the design, synthesis, and evaluation of novel cytochrome P450 17A1 (CYP17A1) ligands. CYP17A1 is a key enzyme in the steroidogenic pathway that produces androgens among other steroids, and it is implicated in prostate cancer. The obtained compounds are potent enzyme inhibitors (sub µM) with antiproliferative activity in prostate cancer cell lines. The binding mode of these compounds is also discussed.
| S-EPMC7402352 | biostudies-literature
Project description:Twenty new compounds, targeting CYP17A1, were synthesized, based on our previous work on a benzimidazole scaffold, and their biological activity evaluated. Inhibition of CYP17A1 is an important modality in the treatment of prostate cancer, which remains the most abundant cancer type in men. The biological assessment included CYP17A1 hydroxylase and lyase inhibition, CYP3A4 and P450 oxidoreductase (POR) inhibition, as well as antiproliferative activity in PC3 prostate cancer cells. The most potent compounds were selected for further analyses including in silico modeling. This combined effort resulted in a compound (comp 2, IC50 1.2 µM, in CYP17A1) with a potency comparable to abiraterone and selectivity towards the other targets tested. In addition, the data provided an understanding of the structure-activity relationship of this novel non-steroidal compound class.
| S-EPMC8961587 | biostudies-literature
Project description:BackgroundThe prostate-specific membrane antigen (PSMA) is a relevant target in prostate cancer, and immunohistochemistry studies showed associations with outcome. PSMA-ligand positron emission tomography (PET) is increasingly used for primary prostate cancer staging, and the molecular imaging TNM classification (miTNM) standardizes its reporting. We aimed to investigate the potential of PET-imaging to serve as a noninvasive imaging biomarker to predict disease outcome in primary prostate cancer after radical prostatectomy (RP).MethodsIn this retrospective analysis, 186 primary prostate cancer patients treated with RP who had undergone a 68Ga-PSMA-11 PET up to three months prior to the surgery were included. Maximum standardized uptake value (SUVmax), SUVmean, tumor volume (TV) and total lesion (TL) were collected from PET-imaging. Moreover, clinicopathological information, including age, serum prostate-specific antigen (PSA) level, and pathological characteristics, was assessed for disease outcome prediction. A stage group system for PET-imaging findings based on the miTNM framework was developed.ResultsAt a median follow-up after RP of 38 months (interquartile range (IQR) 22-53), biochemical recurrence (BCR) was observed in 58 patients during the follow-up period. A significant association between a positive surgical margin and miN status (miN1 vs. miN0, odds ratio (OR): 5.428, p = 0.004) was detected. miT status (miT ≥ 3a vs. miT < 3, OR: 2.696, p = 0.003) was identified as an independent predictor for Gleason score (GS) ≥ 8. Multivariate Cox regression analysis indicated that PSA level (hazard ratio (HR): 1.024, p = 0.014), advanced GS (GS ≥ 8 vs. GS < 8, HR: 3.253, p < 0.001) and miT status (miT ≥ 3a vs. miT < 3, HR: 1.941, p = 0.035) were independent predictors for BCR. For stage I disease as determined by PET-imaging, a shorter BCR-free survival was observed in the patients with higher SUVmax (IA vs. IB stage, log-rank, p = 0.022).ConclusionPreoperative miTNM classification from 68Ga-PSMA-11 PET correlates with postoperative GS, surgical margin status and time to BCR. The association between miTNM staging and outcome proposes 68Ga-PSMA-11 PET as a novel non-invasive imaging biomarker and potentially serves for ancillary pre-treatment stratification.
| S-EPMC8380207 | biostudies-literature
Project description:Background and purposeThe purpose of this study was to determine whether single nucleotide polymorphisms disrupting microRNA targets (mirSNPs) can serve as predictive biomarkers for toxicity after radiotherapy for prostate cancer and whether these may be differentially predictive depending on radiation fractionation.Materials and methodsWe identified 201 men treated with two forms of definitive radiotherapy for prostate cancer at two institutions: 108 men received conventionally-fractionated radiotherapy (CF-RT) and 93 received stereotactic body radiotherapy (SBRT). Germline DNA was evaluated for the presence of functional mirSNPs. Random forest, boosted trees and elastic net models were developed to predict late grade ≥2 GU toxicity by the RTOG scale.ResultsThe crude incidence of late grade ≥2 GU toxicity was 16% after CF-RT and 15% after SBRT. An elastic net model based on 22 mirSNPs differentiated CF-RT patients at high risk (71.5%) versus low risk (7.5%) for toxicity, with an area under the curve (AUC) values of 0.76-0.81. An elastic net model based on 32 mirSNPs differentiated SBRT patients at high risk (64.7%) versus low risk (3.9%) for toxicity, with an area under the curve (AUC) values of 0.81-0.87. These models were specific to treatment type delivered. Prospective studies are warranted to further validate these results.ConclusionPredictive models using germline mirSNPs have high accuracy for predicting late grade ≥2 GU toxicity after either CF-RT or SBRT, and are unique for each treatment, suggesting that germline predictors of late radiation sensitivity are fractionation-dependent. Prospective studies are warranted to further validate these results.
| S-EPMC8979583 | biostudies-literature
Project description:Lymphatic spread determines treatment decisions in prostate cancer (PCa) patients. 68Ga-PSMA-PET/CT can be performed, although cost remains high and availability is limited. Therefore, computed tomography (CT) continues to be the most used modality for PCa staging. We assessed if convolutional neural networks (CNNs) can be trained to determine 68Ga-PSMA-PET/CT-lymph node status from CT alone. In 549 patients with 68Ga-PSMA PET/CT imaging, 2616 lymph nodes were segmented. Using PET as a reference standard, three CNNs were trained. Training sets balanced for infiltration status, lymph node location and additionally, masked images, were used for training. CNNs were evaluated using a separate test set and performance was compared to radiologists' assessments and random forest classifiers. Heatmaps maps were used to identify the performance determining image regions. The CNNs performed with an Area-Under-the-Curve of 0.95 (status balanced) and 0.86 (location balanced, masked), compared to an AUC of 0.81 of experienced radiologists. Interestingly, CNNs used anatomical surroundings to increase their performance, "learning" the infiltration probabilities of anatomical locations. In conclusion, CNNs have the potential to build a well performing CT-based biomarker for lymph node metastases in PCa, with different types of class balancing strongly affecting CNN performance.
| S-EPMC7042227 | biostudies-literature
Project description:BACKGROUND:Immune checkpoint inhibitors (anti-CTLA-4, anti-PD-1, or the combination) enhance anti-tumor immune responses, yielding durable clinical benefit in several cancer types, including melanoma. However, a subset of patients experience immune-related adverse events (irAEs), which can be severe and result in treatment termination. To date, no biomarker exists that can predict development of irAEs. METHODS:We hypothesized that pre-treatment antibody profiles identify a subset of patients who possess a sub-clinical autoimmune phenotype that predisposes them to develop severe irAEs following immune system disinhibition. Using a HuProt human proteome array, we profiled baseline antibody levels in sera from melanoma patients treated with anti-CTLA-4, anti-PD-1, or the combination, and used support vector machine models to identify pre-treatment antibody signatures that predict irAE development. RESULTS:We identified distinct pre-treatment serum antibody profiles associated with severe irAEs for each therapy group. Support vector machine classifier models identified antibody signatures that could effectively discriminate between toxicity groups with >?90% accuracy, sensitivity, and specificity. Pathway analyses revealed significant enrichment of antibody targets associated with immunity/autoimmunity, including TNF? signaling, toll-like receptor signaling and microRNA biogenesis. CONCLUSIONS:Our results provide the first evidence supporting a predisposition to develop severe irAEs upon immune system disinhibition, which requires further independent validation in a clinical trial setting.
| S-EPMC5880088 | biostudies-literature
Project description:Prostate cancer (PCa) is a leading cause of cancer mortality in men and despite high cure rates with surgery and/or radiation, 30-40% of patients will eventually develop advanced disease. Androgen deprivation is the first line therapy for standard of care for men with advanced disease. Eventually however all men will progress to castration-resistant prostate cancer (CRPC). Insight into the molecular mechanisms of androgen resistance has led to the development of alternative novel hormonal agents. Newer hormonal agents such as abiraterone, enzalutamide and TOK-001; and the first cancer vaccine, Sipuleucel T have been approved for use in men with CRPC. The recognition of the importance of bone health and morbidity associated with skeletal related events has led to the introduction of the receptor activator of nuclear factor kappa-B-ligand inhibitor denosumab. Other molecularly targeted therapies have shown promise in pre-clinical studies, but this has not consistently translated into clinical efficacy. It is increasingly evident that CRPC is a heterogeneous disease and an individualized approach directed at identifying primary involvement of specific pathways could maximize the benefit from targeted therapies. This review focuses on targeted therapy for PCa with special emphasis on therapies that have been Food and Drug Administration approved for use in men with CRPC.
| S-EPMC4007389 | biostudies-other
Project description:Tumoral cells not only depend on oncogenic abnormalities to maintain its malignant phenotype but on non-oncogenic vulnerabilities. Targeting epigenomics can modify specific cellular functions required for malignant transformation. The Bromodomain (BRD) family mediates their effect by recruiting proteins of the transcription machinery, recognizing acetylated-lysine residues in nucleosomal histones. Bromodomain and extra-terminal (BET) inhibitors have shown to produce growth inhibition in several tumors through the inhibition of the expression of several transcription factors. In this review we will discuss the current knowledge regarding BET inhibitors in breast cancer. Recent data demonstrates their antiproliferative effect in several cancer subtypes, including the triple negative subtype, or when combined with cell signaling inhibitors. We will also describe options for therapeutic combinations or potential mechanisms of resistance, with special emphasis on their future clinical development.
| S-EPMC5642636 | biostudies-literature