A prospective observational study evaluating intestinal microbiome as a biomarker to predict the efficacy and toxicity of BRCA1/2 mutant metastatic castration resistant prostate cancer patietns receiveing PARP inhibitors
Ontology highlight
ABSTRACT:
DISEASE(S): Prostate Cancer
PROVIDER: 2695487 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
Similar Datasets
Project description:Interventions: case series:None
Primary outcome(s): side effects
Study Design: Sequential
| 2707329 | ecrin-mdr-crc
Project description:The majority of prostate cancer (PCa) cases are diagnosed as a localized disease. Definitive treatment, active surveillance or watchful waiting are employed as therapeutic paradigms. The current standard of care for the treatment of metastatic PCa is either medical or surgical castration. Once PCa progresses in spite of castrate androgen levels it is termed 'castration-resistant prostate cancer' (CRPC). Patients may even exhibit rising PSA levels with possible bone, lymph node or solid organ metastases. In 2010, the only agent approved for the treatment of CRPC was docetaxel, a chemotherapeutic agent. It is now known that cells from patients with CRPC express androgen receptors (AR) and remain continuously influenced by androgens. As such, treatments with novel hormonal agents that specifically target the biochemical conversion of cholesterol to testosterone have come to the forefront. The use of cytochrome P450c17 (CYP17A1) inhibitor underlies one of the most recent advances in the treatment of CRPC. Abiraterone acetate (AA) was the first CYP17A1 inhibitor approved in the United States. This review will discuss CRPC in general with a specific focus on AA and novel CYP17A1 inhibitors. AA clinical trials will be reviewed along with other novel adjunct treatments that may enhance the effectiveness of abiraterone therapy. Furthermore, the most recently identified CYP17A1 inhibitors Orteronel, Galeterone, VT-464, and CFG920 will also be explored.
| S-EPMC4323677 | biostudies-literature
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:Resistance to standard of care taxane and androgen deprivation therapy (ADT) causes the vast majority of prostate cancer (PC) deaths worldwide. We have developed RapidCaP, an autochthonous genetically engineered mouse model of PC. It is driven by the loss of PTEN and p53, the most common driver events in PC patients with life-threatening diseases. As in human ADT, surgical castration of RapidCaP animals invariably results in disease relapse and death from the metastatic disease burden. Fatty Acid Binding Proteins (FABPs) are a large family of signaling lipid carriers. They have been suggested as drivers of multiple cancer types. Here we combine analysis of primary cancer cells from RapidCaP (RCaP cells) with large-scale patient datasets to show that among the 10 FABP paralogs, FABP5 is the PC-relevant target. Next, we show that RCaP cells are uniquely insensitive to both ADT and taxane treatment compared to a panel of human PC cell lines. Yet, they share an exquisite sensitivity to the small-molecule FABP5 inhibitor SBFI-103. We show that SBFI-103 is well tolerated and can strongly eliminate RCaP tumor cells in vivo. This provides a pre-clinical platform to fight incurable PC and suggests an important role for FABP5 in PTEN-deficient PC.
| S-EPMC10871093 | 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:The clinical development of farnesyltransferase inhibitors (FTI) for HRAS -mutant tumors showed mixed responses dependent on cancer type. Co-occurring mutations may affect response. We aimed to uncover cooperative genetic events specific to HRAS -mutant tumors and study their effect on FTI sensitivity. Using targeted sequencing data from MSK-IMPACT and DFCI-GENIE databases we identified co-mutations in HRAS - vs KRAS - and NRAS -mutant cancers. HRAS -mutant cancers had a higher frequency of co-altered mutations (48.8%) in MAPK, PI3K, or RTK pathways genes compared to KRAS - and NRAS -mutant cancers (41.4% and 38.4%, respectively; p < 0.05). Class 3 BRAF , NF1, PTEN, and PIK3CA mutations were more prevalent in HRAS -mutant lineages. To study the effect of comutations on FTI sensitivity, Hras G13R was transfected into 'RASless' ( Kras lox/lox ; Hras -/- ; Nras -/- ) mouse embryonic fibroblasts (MEFs) which sensitized non-transfected MEFs to tipifarnib. Comutation in the form of Pten or Nf1 deletion or Pik3ca H1047R or Braf G466E transduction led to relative resistance to tipifarnib in Hras G13R MEFs in the presence or absence of Kras WT . Combined treatment of tipifarnib with MEK inhibition sensitized cells to tipifarnib, including in MEFs with PI3K pathway comutations. HRAS -mutant tumors demonstrate lineage demonstrate lineage-dependent MAPK/PI3K pathway alterations that confer relative resistance to tipifarnib. Combined FTI and MEK inhibition is a promising combination for HRAS -mutant tumors.
| S-EPMC10371077 | biostudies-literature
Project description:affy_molecularmechanism_medicago - affy_molecularmechanism_medicago - -Aphanomyces euteiches (Ae), a soilborne oomycete, is the causal agent of pea root rot, a major disease on various cultivated legume species. To gain insight into the mechanism underlying partial resistance to this pathogen, a pathosystem has been developed using the model legume Medicago truncatula (Mt). Two Mt accessions A17 and F83005.5 have been shown to display differential responses upon infection with Ae (partially resistance and susceptibility, respectively). Genetic analyses using a RIL population derived from a cross between those two lines lead to the identification of, prAe1, a major QTL involved in the observed partial resistance. Near isogenic lines (NIL) NR2 and NS2 whose genomes are identical except at the prAe1 locus (resistant alleles for NR2, susceptible alleles for NS2) have been generated, and the same differential response toward Ae has been found. The aim of this experiment is to analyse and compare NR2 and NS2 transcriptomes at 1 and 6 days after Ae inoculation to identify gene networks that are regulated in a prAe1 dependent manner.--Fifteen-day-old NR2 or NS2 plants were grown in vitro on M medium. The entire roots were then inoculated (or not = 0dpi) with a A. euteiches zoospores (75000zsp/ml) and harvested one or six days after inoculation. Three independent repeats were performed.
2014-02-28 | GSE31198 | GEO
Project description:Protein profiles of insecticide resistance Ae. aegypti in Penang island, Malaysia
2022-04-14 | MSV000089259 | MassIVE
Project description:affy_molecularmechanism_medicago - affy_molecularmechanism_medicago - -Aphanomyces euteiches (Ae), a soilborne oomycete, is the causal agent of pea root rot, a major disease on various cultivated legume species. To gain insight into the mechanism underlying partial resistance to this pathogen, a pathosystem has been developed using the model legume Medicago truncatula (Mt). Two Mt accessions A17 and F83005.5 have been shown to display differential responses upon infection with Ae (partially resistance and susceptibility, respectively). Genetic analyses using a RIL population derived from a cross between those two lines lead to the identification of, prAe1, a major QTL involved in the observed partial resistance. Near isogenic lines (NIL) 5B2 and 5D2 whose genomes are identical except at the prAe1 locus (resistant alleles for 5B2, susceptible alleles for 5D2) have been generated, and the same differential response toward Ae has been found. The aim of this experiment is to analyse and compare 5B2 and 5D2 transcriptomes at 1 and 6 days after Ae inoculation to identify gene networks that are regulated in a prAe1 dependent manner.--Fifteen-day-old 5B2 or 5D2 plants were grown in vitro on M medium. The entire roots were then inoculated (or not = 0dpi) with a A. euteiches zoospores (75000zsp/ml) and harvested one or six days after inoculation. Three independent repeats were performed. 18 arrays - Medicago; resistance vs susceptibility comparison,time course,treated vs untreated comparison
2014-02-28 | E-GEOD-31198 | biostudies-arrayexpress
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