Publications by authors named "Suzanne Carreira"
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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- - PARP inhibitors show promise in treating castration-resistant prostate cancer (CRPC) with homologous recombination repair (HRR) defects, but the reasons behind resistance are not completely understood.
- - A study from the TOPARP-B trial found that 79% of BRCA2/PALB2-mutated tumors exhibited reversion mutations at the end of treatment, with many related to POLQ-mediated DNA repair mechanisms.
- - In cases of BRCA2 homozygous deletions, rare subclones lacking the BRCA2 deletion are selected for after PARP inhibitor treatment, indicating the necessity for restored HRR function in developing resistance.
Article Synopsis
- * 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 PDFSince genome instability can drive cancer initiation and progression, cells have evolved highly effective and ubiquitous DNA damage response (DDR) programs. However, some cells (for example, in skin) are normally exposed to high levels of DNA-damaging agents. Whether such high-risk cells possess lineage-specific mechanisms that tailor DNA repair to the tissue remains largely unknown.
View Article and Find Full Text PDFBackground: Bone biopsies in metastatic castrate-resistant prostate cancer (mCRPC) patients can be challenging. This study's objective was to prospectively validate a multiparametric bone MRI (mpBMRI) algorithm to facilitate target lesion selection in mCRPC patients with sclerotic bone disease for subsequent CT-guided bone biopsies.
Methods: 20 CT-guided bone biopsies were prospectively performed between 02/2021 and 11/2021 in 17 mCRPC patients with only sclerotic bone disease.
Inflammation 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 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.
DNA damage-induced interaction between a lineage addiction oncogenic transcription factor and the MRN complex shapes a tissue-specific DNA Damage Response and cancer predisposition.
bioRxiv
April 2023
Since genome instability can drive cancer initiation and progression, cells have evolved highly effective and ubiquitous DNA Damage Response (DDR) programs. However, some cells, in skin for example, are normally exposed to high levels of DNA damaging agents. Whether such high-risk cells possess lineage-specific mechanisms that tailor DNA repair to the tissue remains largely unknown.
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- 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
- - 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
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
- The study investigates how acute changes in protein signaling can help predict the sensitivity of non-small cell lung cancer (NSCLC) cells to targeted anticancer drugs, both individually and in combination.
- Researchers examined the effects of seven different drugs on 52 phosphoproteins in 35 NSCLC cell lines and developed machine-learning models that successfully forecasted drug responses better than traditional mutation-based predictions.
- The findings support the use of fast, protein-based analyses of cancer cells from patient samples to enhance treatment choices and potentially improve cancer therapy outcomes.
The bromodomain and extraterminal (BET) family of chromatin reader proteins bind to acetylated histones and regulate gene expression. The development of BET inhibitors (BETi) has expanded our knowledge of BET protein function beyond transcriptional regulation and has ushered several prostate cancer (PCa) clinical trials. However, BETi as a single agent is not associated with antitumor activity in patients with castration-resistant prostate cancer (CRPC).
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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.
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
- - 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.