Publications by authors named "Antje Neeb"
Purpose: Advanced prostate cancer (PCa) is invariably fatal with the androgen receptor (AR) being a major therapeutic target. AR signaling inhibitors have improved overall survival for men with advanced PCa, but treatment resistance is inevitable and includes reactivation of AR signaling. Novel therapeutic approaches targeting these mechanisms to block tumor growth is an urgent unmet clinical need.
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- * BCL2, an anti-apoptotic protein, is upregulated in these aggressive prostate cancers, which presents a potential target for therapy and highlights the importance of studying its expression in metastatic CRPC (mCRPC).
- * Research shows that BCL2 is more prevalent in AR-negative mCRPC and is linked to poorer survival outcomes; also, its regulation involves DNA methylation and a transcription factor called ASCL1, suggesting the need for combination therapies to improve treatment efficacy.
BACKGROUNDClinical trials have suggested antitumor activity from PARP inhibition beyond homologous recombination deficiency (HRD). RNASEH2B loss is unrelated to HRD and preclinically sensitizes to PARP inhibition. The current study reports on RNASEH2B protein loss in advanced prostate cancer and its association with RB1 protein loss, clinical outcome, and clonal dynamics during treatment with PARP inhibition in a prospective clinical trial.
View Article and Find Full Text PDFTherapies that abrogate persistent androgen receptor (AR) signaling in castration-resistant prostate cancer (CRPC) remain an unmet clinical need. The N-terminal domain of the AR that drives transcriptional activity in CRPC remains a challenging therapeutic target. Herein we demonstrate that BCL-2-associated athanogene-1 (BAG-1) mRNA is highly expressed and associates with signaling pathways, including AR signaling, that are implicated in the development and progression of CRPC.
View Article and Find Full Text PDFInflammation is a hallmark of cancer. In patients with cancer, peripheral blood myeloid expansion, indicated by a high neutrophil-to-lymphocyte ratio, associates with shorter survival and treatment resistance across malignancies and therapeutic modalities. Whether myeloid inflammation drives progression of prostate cancer in humans remain unclear.
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- BAG-1L is a key protein that enhances the androgen receptor's function, playing a role in the progression of prostate cancer.
- Researchers developed a new antibody specific to BAG-1L to study its expression in various prostate cancer stages and breast cancer tissues.
- Higher BAG-1L levels were found in metastases of castration-resistant prostate cancer compared to untreated cases, but no correlation was found between BAG-1L levels and patient outcomes or responses to treatments, highlighting some limitations in the study's findings.
Unlabelled: The pro-oncogenic activities of estrogen receptor alpha (ERα) drive breast cancer pathogenesis. Endocrine therapies that impair the production of estrogen or the action of the ERα are therefore used to prevent primary disease metastasis. Although recent successes with ERα degraders have been reported, there is still the need to develop further ERα antagonists with additional properties for breast cancer therapy.
View Article and Find Full Text PDFTherapy resistance to second-generation androgen receptor (AR) antagonists, such as enzalutamide, is common in patients with advanced prostate cancer (PCa). To understand the metabolic alterations involved in enzalutamide resistance, we performed metabolomic, transcriptomic, and cistromic analyses of enzalutamide-sensitive and -resistant PCa cells, xenografts, patient-derived organoids, patient-derived explants, and tumors. We noted dramatically higher basal and inducible levels of reactive oxygen species (ROS) in enzalutamide-resistant PCa and castration-resistant PCa (CRPC), in comparison to enzalutamide-sensitive PCa cells or primary therapy-naive tumors respectively.
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- Germline mutations in the ATM gene, found in 0.5-1% of the population, are linked to a higher risk of aggressive prostate cancer (PC), but their clinical features are not well understood.
- This study focused on patients with advanced metastatic castration-resistant prostate cancer (CRPC) who had these mutations identified through initial tumor DNA sequencing, collecting data on demographic details, family history, and clinical outcomes.
- Among the seven identified patients (0.6%), most had a family history of various cancers, with a median overall survival from diagnosis of 7.1 years, indicating that the presence of these mutations could be significant in understanding PC progression and patient outcomes.
Article Synopsis
- B7-H3 is a key protein found on the surface of prostate cancer cells, particularly in castration-resistant prostate cancer (CRPC), and its role in cancer therapy is being studied to help target treatments more effectively.
- Researchers analyzed samples from 98 prostate cancer patients, comparing hormone-sensitive and castration-resistant biopsies to evaluate B7-H3 expression and link it to genomic data.
- The study found that B7-H3 is highly expressed in the majority of CRPC cases and remained stable during the transition from hormone-sensitive to castration-resistant stages, indicating its potential as a target for antibody-drug conjugate therapies.
Article Synopsis
- Therapies targeting the androgen receptor have improved outcomes for castration-sensitive prostate cancer, but the role of the AR splice variant-7 (AR-V7) as a biomarker in this context is not well understood.
- The study evaluated methods to measure AR-V7 mRNA and protein in various prostate cancer models and found that AR-V7 levels were low in castration-sensitive cases compared to castration-resistant cases, with the efficacy of different antibodies varying.
- Ultimately, the research suggests that AR-V7 is not currently a reliable predictive biomarker for treatment response in castration-sensitive prostate cancer and requires further validation before clinical application.
Purpose: Prostate-specific membrane antigen (PSMA) targeting therapies such as Lutetium-177 (177Lu)-PSMA-617 are affecting outcomes from metastatic castration-resistant prostate cancer (mCRPC). However, a significant subset of patients have prostate cancer cells lacking PSMA expression, raising concerns about treatment resistance attributable at least in part to heterogeneous PSMA expression. We have previously demonstrated an association between high PSMA expression and DNA damage repair defects in mCRPC biopsies and therefore hypothesized that DNA damage upregulates PSMA expression.
View Article and Find Full Text PDFBAG1 is a family of polypeptides with a conserved C-terminal BAG domain that functions as a nucleotide exchange factor for the molecular chaperone HSP70. BAG1 proteins also control several signaling processes including proteostasis, apoptosis, and transcription. The largest isoform, BAG1L, controls the activity of the androgen receptor (AR) and is upregulated in prostate cancer.
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- - Researchers found that HER3, a protein often overexpressed in aggressive prostate cancer, is linked to faster progression to castration resistance and lower survival rates.
- - The study identified that NRG1, a ligand for HER3, is primarily produced by certain immune cells in the tumor environment, and its presence promotes cancer cell growth.
- - Targeting HER3 with specific therapies, like the antibody-drug conjugate U3-1402, shows promise in fighting HER3-positive prostate cancer, suggesting the need for further clinical trials.
The microbiota comprises the microorganisms that live in close contact with the host, with mutual benefit for both counterparts. The contribution of the gut microbiota to the emergence of castration-resistant prostate cancer (CRPC) has not yet been addressed. We found that androgen deprivation in mice and humans promotes the expansion of defined commensal microbiota that contributes to the onset of castration resistance in mice.
View Article and Find Full Text PDFExpression of the immediate-early response gene IER2 has been associated with the progression of several types of cancer, but its functional role is poorly understood. We found that increased IER2 expression in human melanoma is associated with shorter overall survival, and subsequently investigated the mechanisms through which IER2 exerts this effect. In experimental melanoma models, sustained expression of IER2 induced senescence in a subset of melanoma cells in a p53/MAPK/AKT-dependent manner.
View Article and Find Full Text PDFContext: Prostate-specific membrane antigen (PSMA) is a promising, novel theranostic target in advanced prostate cancer (PCa). Multiple PSMA-targeted therapies are currently in clinical development, with some agents showing impressive antitumour activity, although optimal patient selection and therapeutic resistance remain ongoing challenges.
Objective: To review the biology of PSMA and recent advances in PSMA-targeted therapies in PCa, and to discuss potential strategies for patient selection and further therapeutic development.
Article Synopsis
- Better blood tests are needed for metastatic castration-resistant prostate cancer (mCRPC) to guide treatment decisions, and low-pass whole-genome sequencing (lpWGS) of circulating tumor DNA (ctDNA) shows promise in providing insights into mCRPC behavior.
- The study examined plasma lpWGS data from 188 mCRPC patients undergoing two phase 3 clinical trials, with an aim to assess its prognostic value and its ability to correlate with treatment response.
- Findings suggest that plasma tumor fraction is a strong predictor of overall survival and is more informative than existing biomarkers, while genomic instability indicated by large-scale transition scores was linked to previous treatments but not to others like taxane or radiation therapy.*
Article Synopsis
- Endocrine resistance in advanced prostate cancer is driven by proteins like AR-V7, with JMJD6 being a key regulator of its production.
- The study found that increasing levels of JMJD6 correlate with higher AR-V7 levels and reduced survival rates in patients.
- JMJD6 knockdown led to reduced prostate cancer cell growth and less AR-V7, suggesting that targeting JMJD6 could be a promising therapy for combating prostate cancer.
Article Synopsis
- CD38 is an ectoenzyme that contributes to the production of adenosine, which plays a role in how tumors evade the immune system, particularly in prostate cancer.* -
- The study aimed to analyze CD38 expression in prostate cancer cells and immune cells, using samples from multiple patient cohorts to link this expression to clinical outcomes.* -
- Findings showed that higher CD38 mRNA levels in metastatic castration-resistant prostate cancer (mCRPC) were linked to activated immune signaling pathways, specifically involving certain interleukins.*
Purpose: Although enzalutamide (ENZ) has been widely used to treat or castration-resistant metastatic prostate cancer, resistance develops and disease progression is ultimately inevitable. There are currently no approved targeted drugs to specifically delay or overcome ENZ resistance.
Experimental Design: We selected several ENZ-resistant cell lines that replicated clinical characteristics of the majority of patients with ENZ-resistant disease.
Resistance to androgen receptor (AR) blockade in castration-resistant prostate cancer (CRPC) is associated with sustained AR signaling, including through alternative splicing of AR (AR-SV). Inhibitors of transcriptional coactivators that regulate AR activity, including the paralog histone acetyltransferase proteins p300 and CBP, are attractive therapeutic targets for lethal prostate cancer. Herein, we validate targeting p300/CBP as a therapeutic strategy for lethal prostate cancer and describe CCS1477, a novel small-molecule inhibitor of the p300/CBP conserved bromodomain.
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- The study investigates the role of ATM (Ataxia Telangiectasia Mutated) gene alterations in metastatic prostate cancer, revealing that about 11% of patients show ATM loss in biopsies, which is often linked to genomic instability.
- Researchers utilized advanced techniques like immunohistochemistry and next-generation sequencing to analyze cancer biopsies and created modified cell models to test drug responses, finding that ATM-deficient cancers respond variably to PARP inhibitors but exhibit better results with combined ATR and PARP inhibition.
- Despite ATM loss not correlating with worse clinical outcomes, it signifies a distinct and potentially targetable subtype of aggressive prostate cancer, emphasizing the need for tailored treatment strategies.
Background: Prostate-specific membrane antigen (PSMA; folate hydrolase) prostate cancer (PC) expression has theranostic utility.
Objective: To elucidate PC PSMA expression and associate this with defective DNA damage repair (DDR).
Design, Setting, And Participants: Membranous PSMA (mPSMA) expression was scored immunohistochemically from metastatic castration-resistant PC (mCRPC) and matching, same-patient, diagnostic biopsies, and correlated with next-generation sequencing (NGS) and clinical outcome data.