Publications by authors named "Ruth Riisnaes"
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.
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- The study investigates the effectiveness of the AKT inhibitor capivasertib when combined with enzalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC) who did not respond well to prior treatments with abiraterone acetate and docetaxel.
- Conducted as a double-blind, randomized phase 2 trial with 100 men, the primary focus was on the composite response rate, which showed no significant improvement with the combination treatment compared to placebo.
- Analysis revealed that patients with PTEN loss had poorer overall survival regardless of treatment, with common side effects including diarrhea and fatigue, indicating that while the combination was tolerable, it did not enhance treatment outcomes.
Therapies 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.
View Article and Find Full Text PDFPurpose: Approximately 10% to 15% of triple-negative breast cancers (TNBC) have deleterious mutations in BRCA1 and BRCA2 and may benefit from PARP inhibitor treatment. PARP inhibitors may also increase exogenous replication stress and thereby increase sensitivity to inhibitors of ataxia telangiectasia and Rad3-related (ATR) protein. This phase II study examined the activity of the combination of PARP inhibitor, olaparib, and ATR inhibitor, ceralasertib (AZD6738), in patients with advanced TNBC.
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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.
Article Synopsis
- 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.
Importance: Patients with platinum-resistant or refractory ovarian high-grade serous carcinoma (PR-HGSC) have a poor prognosis and few therapeutic options. Preclinical studies support targeting PI3K/AKT/mTOR signaling in this setting, and a phase 1 study of the dual mTORC1/mTORC2 inhibitor vistusertib with weekly paclitaxel showed activity.
Objective: To evaluate whether the addition of vistusertib to weekly paclitaxel improves clinical outcomes in patients with PR-HGSC.
Systematic study of tissue factor expression in solid tumors.
Cancer Rep (Hoboken)
February 2023
Article Synopsis
- Elevated tissue factor (TF) expression is linked to poor prognosis in various solid cancers, with a systematic analysis conducted to compare its prevalence and localization across multiple tumor types for the first time.
- The study involved patient biopsies from different cancers, revealing that TF was most prominent in pancreatic, cervical, colon, glioblastoma, head and neck squamous cell carcinoma, and non-small cell lung cancer, with varying expression patterns noted in individual cases.
- Findings indicate that while TF is widely present across solid tumors and remains consistent over time for most patients, individual variability exists, suggesting potential implications for disease progression and treatment.
Article Synopsis
- - Gastric cancer ranks as the third leading cause of cancer-related deaths worldwide, highlighting a significant need for effective treatments.
- - Researchers examined the effectiveness of ATR inhibitors (ATRi) in combating gastric cancer and discovered mechanisms of resistance involving mutations in SMG8 and SMG9, which hinder the effectiveness of ATRi.
- - The study indicates that ATRi can effectively suppress tumor growth in gastric cancer, but resistance can develop through changes in the SMG8/9/1 pathway, pointing to potential targets for improving treatment 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
- CT900 is a new small molecule drug that inhibits thymidylate synthase and targets tumors overexpressing the α-folate receptor (α-FR).
- In a clinical trial, doses between 1-12 mg/m2 were tested on patients with high-grade serous ovarian cancer, focusing on a dose of 12 mg/m2 given every two weeks.
- The trial showed manageable side effects and a 21.9% overall response rate, with better outcomes in patients who had higher α-FR expression, indicating that CT900 has potential for further study.
Article Synopsis
- - The study evaluated the combined effects of guadecitabine and pembrolizumab on patients with advanced solid tumors, aiming to see if guadecitabine can make tumors more sensitive to pembrolizumab, which targets immune checkpoints.
- - In a phase 1 trial with 34 participants, the recommended dosage was established as guadecitabine 30 mg/m on specific days alongside pembrolizumab; common side effects included neutropenia and fatigue, but there were no treatment-related deaths reported.
- - Preliminary results showed a 7% objective response rate and 37% of patients achieved disease control for 24 weeks or more; notably, a significant reduction in DNA methylation was observed in
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 PDFBackground: Metastatic castration-resistant prostate cancer (mCRPC) is a heterogeneous disease in which molecular stratification is needed to improve clinical outcomes. The identification of predictive biomarkers can have a major impact on the care of these patients, but the availability of metastatic tissue samples for research in this setting is limited.
Objective: To study the prevalence of immune biomarkers of potential clinical utility to immunotherapy in mCRPC and to determine their association with overall survival (OS).
Article Synopsis
- - 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.
Background: Anti-programmed cell death protein 1 and programmed cell death ligand 1 (PD-L1) agents are broadly used in first-line and second-line treatment across different tumor types. While immunohistochemistry-based assays are routinely used to assess PD-L1 expression, their clinical utility remains controversial due to the partial predictive value and lack of standardized cut-offs across antibody clones. Using a high throughput immunoassay, the reverse phase protein microarray (RPPA), coupled with a fluorescence-based detection system, this study compared the performance of six anti-PD-L1 antibody clones on 666 tumor samples.
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- - The study investigates the expression of HER3 in lung adenocarcinoma, focusing on identifying how it is regulated and its potential role in treatment options.
- - In a sample of 45 patients, HER3 was found to be overexpressed in 42.2% of cases, and this overexpression wasn't explained by copy number variations.
- - The analysis indicates a correlation between HER3 RNA expression levels and MEK activity, suggesting HER3's significance as a therapeutic target due to its frequent overexpression and downstream signaling effects.
Article Synopsis
- * The TOPARP-B phase II clinical trial showed that APC patients with homozygous deletions benefit the most from olaparib treatment, especially those with biallelic mutations.
- * Loss of ATM protein is linked to improved outcomes, and RAD51 foci loss helps identify tumors with specific genetic alterations that respond well to PARP inhibition.
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.