Maintenance of genomic stability is a critical determinant of cell survival and relies on the coordinated action of the DNA damage response (DDR), which orchestrates a network of cellular processes, ...including DNA replication, DNA repair and cell-cycle progression. In cancer, the critical balance between the loss of genomic stability in malignant cells and the DDR provides exciting therapeutic opportunities. Drugs targeting DDR pathways taking advantage of clinical synthetic lethality have already shown therapeutic benefit – for example, the PARP inhibitor olaparib has shown benefit in BRCA-mutant ovarian and breast cancer. Olaparib has also shown benefit in metastatic prostate cancer in DDR-defective patients, expanding the potential biomarker of response beyond BRCA. Other agents and combinations aiming to block the DDR while pushing damaged DNA through the cell cycle, including PARP, ATR, ATM, CHK and DNA-PK inhibitors, are in development. Emerging work is also uncovering how the DDR interacts intimately with the host immune response, including by activating the innate immune response, further suggesting that clinical applications together with immunotherapy may be beneficial. Here, we review recent considerations related to the DDR from a clinical standpoint, providing a framework to address future directions and clinical opportunities.
Castration-resistant prostate cancer (CRPC) that has developed resistance to the new-generation androgen receptor (AR) antagonist enzalutamide is a lethal disease. Transcriptome analysis of multiple ...prostate cancer models identified CXCR7, an atypical chemokine receptor, as one of the most upregulated genes in enzalutamide-resistant cells. AR directly repressed
by binding to an enhancer 110 kb downstream of the gene and expression was restored upon androgen deprivation. We demonstrate that CXCR7 is a critical regulator of prostate cancer sensitivity to enzalutamide and is required for CRPC growth
and
. Elevated CXCR7 activated MAPK/ERK signaling through ligand-independent, but β-arrestin 2-dependent mechanisms. Examination of patient specimens showed that CXCR7 and pERK levels increased significantly from localized prostate cancer to CRPC and further upon enzalutamide resistance. Preclinical studies revealed remarkable efficacies of MAPK/ERK inhibitors in suppressing enzalutamide-resistant prostate cancer. Overall, these results indicate that CXCR7 may serve as a biomarker of resistant disease in patients with prostate cancer and that disruption of CXCR7 signaling may be an effective strategy to overcome resistance. SIGNIFICANCE: These findings identify CXCR7-mediated MAPK activation as a mechanism of resistance to second-generation antiandrogen therapy, highlighting the therapeutic potential of MAPK/ERK inhibitors in CRPC.
It has been recognized for decades that ERBB signaling is important in prostate cancer, but targeting ERBB receptors as a therapeutic strategy for prostate cancer has been ineffective clinically. ...However, we show here that membranous HER3 protein is commonly highly expressed in lethal prostate cancer, associating with reduced time to castration resistance (CR) and survival. Multiplex immunofluorescence indicated that the HER3 ligand NRG1 is detectable primarily in tumor-infiltrating myelomonocytic cells in human prostate cancer; this observation was confirmed using single-cell RNA sequencing of human prostate cancer biopsies and murine transgenic prostate cancer models. In castration-resistant prostate cancer (CRPC) patient-derived xenograft organoids with high HER3 expression as well as mouse prostate cancer organoids, recombinant NRG1 enhanced proliferation and survival. Supernatant from murine bone marrow-derived macrophages and myeloid-derived suppressor cells promoted murine prostate cancer organoid growth
, which could be reversed by a neutralizing anti-NRG1 antibody and ERBB inhibition. Targeting HER3, especially with the HER3-directed antibody-drug conjugate U3-1402, exhibited antitumor activity against HER3-expressing prostate cancer. Overall, these data indicate that HER3 is commonly overexpressed in lethal prostate cancer and can be activated by NRG1 secreted by myelomonocytic cells in the tumor microenvironment, supporting HER3-targeted therapeutic strategies for treating HER3-expressing advanced CRPC. SIGNIFICANCE: HER3 is an actionable target in prostate cancer, especially with anti-HER3 immunoconjugates, and targeting HER3 warrants clinical evaluation in prospective trials.
Altered metabolism is a hallmark of cancer. Malignant cells metabolise glutamine to fulfil their metabolic needs. In prostate cancer, androgen receptor signalling promotes glutamine metabolism, which ...is also involved in cholesterol homeostasis. We aimed to determine whether the plasma glutamine levels correlate with the blood lipid profile, clinical characteristics and outcomes in patients with metastatic castration resistance prostate cancer (mCRPC) undergoing taxanes. We retrospectively assessed the glutamine and glutamate levels in plasma samples by a bioluminescent assay. Pre-treatment glutamine, glutamate, cholesterol and triglycerides levels were correlated with patients’ clinical characteristics, taxanes response and clinical outcomes. Seventy-five patients with mCRPC treated with taxanes were included. The plasma glutamine levels were significantly higher in patients that received abiraterone or enzalutamide prior to taxanes (p = 0.003). Besides, patients with low glutamine levels were more likely to present a PSA response to taxanes (p = 0.048). Higher glutamine levels were significantly correlated with shorter biochemical/clinical progression-free survival (PSA/RX-PFS) (median 2.5 vs. 4.2 months; p = 0.048) and overall survival (OS) (median 12.6 vs. 20.3; p = 0.008). High cholesterol levels independently predicted early PSA/RX-PFS (p = 0.034). High glutamine and cholesterol in the plasma from patients with mCRPC were associated with adverse clinical outcomes, supporting the relevance of further research on metabolism in prostate cancer progression.
(1) Background: Androgen deprivation therapy (ADT) and docetaxel (DX) combination is a standard therapy for metastatic hormone-sensitive prostate cancer (mHSPC) patients. (2) Methods: We investigate ...if tumor transcriptomic analysis predicts mHSPC evolution in a multicenter retrospective biomarker study. A customized panel of 184 genes was tested in mRNA from tumor samples by the nCounter platform in 125 mHSPC patients treated with ADT+DX. Gene expression was correlated with castration-resistant prostate cancer-free survival (CRPC-FS) and overall survival (OS). (3) Results: High expression of androgen receptor (AR) signature was independently associated with longer CRPC-FS (hazard ratio (HR) 0.6, 95% confidence interval (CI) 0.3–0.9; p = 0.015), high expression of estrogen receptor (ESR) signature with longer CRPC-FS (HR 0.6, 95% CI 0.4–0.9; p = 0.019) and OS (HR 0.5, 95% CI 0.2–0.9, p = 0.024), and lower expression of tumor suppressor genes (TSG) (RB1, PTEN and TP53) with shorter OS (HR 2, 95% CI 1–3.8; p = 0.044). ARV7 expression was independently associated with shorter CRPC-FS (HR 1.5, 95% CI 1.1–2.1, p = 0.008) and OS (HR 1.8, 95% CI 1.2–2.6, p = 0.004), high ESR2 was associated with longer OS (HR 0.5, 95% CI 0.2–1, p = 0.048) and low expression of RB1 was independently associated with shorter OS (HR 1.9, 95% CI 1.1–3.2, p = 0.014). (4) Conclusions: AR, ESR, and TSG expression signatures, as well as ARV7, RB1, and ESR2 expression, have a prognostic value in mHSPC patients treated with ADT+DX.
Deleterious ATM alterations are found in metastatic prostate cancer (PC); PARP inhibition has antitumour activity against this subset, but only some ATM loss PCs respond.
To characterise ...ATM-deficient lethal PC and to study synthetic lethal therapeutic strategies for this subset.
We studied advanced PC biopsies using validated immunohistochemical (IHC) and next-generation sequencing (NGS) assays. In vitro cell line models modified using CRISPR-Cas9 to impair ATM function were generated and used in drug-sensitivity and functional assays, with validation in a patient-derived model.
ATM expression by IHC was correlated with clinical outcome using Kaplan-Meier curves and log-rank test; sensitivity to different drug combinations was assessed in the preclinical models.
Overall, we detected ATM IHC loss in 68/631 (11%) PC patients in at least one biopsy, with synchronous and metachronous intrapatient heterogeneity; 46/71 (65%) biopsies with ATM loss had ATM mutations or deletions by NGS. ATM IHC loss was not associated with worse outcome from advanced disease, but ATM loss was associated with increased genomic instability (NtAI:number of subchromosomal regions with allelic imbalance extending to the telomere, p = 0.005; large-scale transitions, p = 0.05). In vitro, ATM loss PC models were sensitive to ATR inhibition, but had variable sensitivity to PARP inhibition; superior antitumour activity was seen with combined PARP and ATR inhibition in these models.
ATM loss in PC is not always detected by targeted NGS, associates with genomic instability, and is most sensitive to combined ATR and PARP inhibition.
Of aggressive prostate cancers, 10% lose the DNA repair gene ATM; this loss may identify a distinct prostate cancer subtype that is most sensitive to the combination of oral drugs targeting PARP and ATR.
ATM loss can be detected by immunohistochemistry (IHC) in 10% of advanced prostate cancers; it associates with genomic instability and sensitivity to combined PARP and ATR inhibition in preclinical prostate cancer models. Prospective studies should compare the clinical predictive value of IHC versus next-generation sequencing assays for DNA repair targeting agents.
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Background: Clear cell renal cell carcinoma (ccRCC) is a highly heterogeneous disease with varying prognoses and treatment responses. Understanding the underlying molecular determinants of this ...diversity is key to tailoring effective treatment strategies for each patient (pt). Here, we leveraged single–cell RNA sequencing (scRNA–seq) data to assess intra–tumoral diversity and its impact on pt prognosis. Methods: scRNA–seq raw data from five published studies were processed with Seurat’s standard workflow and integrated to remove biases using Harmony. We then re–analyzed the malignant cell cluster, defined by CA9, NDUFA4L2, and IGFBP3 expression, at a higher resolution. The resulting tumor cell sub–clusters were subjected to differentially expressed gene (DEG) and gene ontology (GO) enrichment analyses. A signature based on all DEGs with a fold change > 1.25 was applied on TCGA–KIRC cohort using single–sample gene set enrichment analysis and then correlated with relapse–free survival (RFS) and overall survival (OS) by Kaplan–Meier and multivariate Cox analyses. Results: We integrated scRNA–seq data from 50 samples from 44 pt’s (40% T3–4, mean age 75, 10% females). A total of 288K cells were classified into 19 clusters. The tumor cluster was re–analyzed and three biologically distinct tumor cell sub–clusters (labeled MC
1
, MC
2
, and MC
3
) were identified, each with unique molecular markers. GO analysis showed enrichment in genes associated with iron sequestration, oxidative phosphorylation, and apoptotic signaling, respectively. In the KIRC cohort, a 23–DEG signature from MC
2
strongly correlated with RFS (HR 0.49; 95% CI 0.35−0.67 p < 0.001; 5-RFS: 74% vs. 54%) and OS (HR 0.44; 95% CI 0.33−0.60 p < 0.001; 5-OS: 75% vs. 51%) and was independent of other clinical variables in the multivariate analysis (Table 1). Moreover, this signature identified a subset of T1–T2 tumors (47.8%) with low risk of relapse (HR 0.38; 95% CI 0.19−0.78, p = 0.008; 5-RFS: 92% vs. 80%) and longer OS (HR 0.35; 95% CI 0.20−0.62 p < 0.001; 5-RFS: 90% vs. 68%). Conclusions: We have identified three distinct tumor cell sub–populations in an integrated scRNA–seq database, each characterized by unique transcriptomic profiles. A gene expression signature based on the MC
2
sub–cluster was prognostic in the TCGA dataset and may help in identifying patients with a higher risk of relapse and candidates to adjuvant therapy.Table: see text
Detection of androgen receptor splice variant-7 (AR-V7) mRNA in circulating tumour cells (CTCs) is associated with worse outcome in metastatic castration-resistant prostate cancer (mCRPC). However, ...studies rarely report comparisons with CTC counts and biopsy AR-V7 protein expression.
To determine the reproducibility of AdnaTest CTC AR-V7 testing, and associations with clinical characteristics, CellSearch CTC counts, tumour biopsy AR-V7 protein expression and overall survival (OS).
CTC AR-V7 status was determined for 227 peripheral blood samples, from 181 mCRPC patients with CTC counts (202 samples; 136 patients) and matched mCRPC biopsies (65 samples; 58 patients).
CTC AR-V7 status was associated with clinical characteristics, CTC counts, and tissue biopsy AR-V7 protein expression. The association of CTC AR-V7 status and other baseline variables with OS was determined.
Of the samples, 35% were CTC+/AR-V7+. CTC+/AR-V7+ samples had higher CellSearch CTC counts (median CTC; interquartile range IQR: 60, 19–184 vs 9, 2–64; Mann-Whitney test p<0.001) and biopsy AR-V7 protein expression (median H-score, IQR: 100, 63–148 vs 15, 0–113; Mann-Whitney test p=0.004) than CTC+/AR-V7− samples. However, both CTC− (63%) and CTC+/AR-V7− (62%) patients had detectable AR-V7 protein in contemporaneous biopsies. After accounting for baseline characteristics, there was shorter OS in CTC+/AR-V7+ patients than in CTC− patients (hazard ratio HR 2.13; 95% confidence interval CI 1.23–3.71; p=0.02); surprisingly, there was no evidence that CTC+/AR-V7+ patients had worse OS than CTC+/AR-V7− patients (HR 1.26; 95% CI 0.73–2.17; p=0.4). A limitation of this study was the heterogeneity of treatment received.
Studies reporting the prognostic relevance of CTC AR-V7 status must account for CTC counts. Discordant CTC AR-V7 results and AR-V7 protein expression in matched, same-patient biopsies are reported.
Liquid biopsies that determine circulating tumour cell androgen receptor splice variant-7 status have the potential to impact treatment decisions in metastatic castration-resistant prostate cancer patients. Robust clinical qualification of these assays is required before their routine use.
Liquid biopsies that identify androgen receptor splice variant-7 positivity, which account for circulating tumour cell counts, could inform treatment decisions in metastatic castration-resistant prostate cancer patients.
Although the neutrophil-lymphocyte ratio (NLR) is prognostic in many oncological settings, its significance in the immunotherapy era is unknown. Mechanistically, PD-1/PD-L1 inhibitors may alter NLR. ...We sought to characterise NLR kinetics in patients with advanced solid tumours treated with PD-1/PD-L1 inhibitors.
Electronic records of patients treated with PD-1/PD-L1 inhibitors on phase I trials across three sites were reviewed. A high NLR (hNLR) was predefined as >5. Univariate logistic regression models were used for toxicity, response analyses and Cox models for overall survival (OS) and progression-free survival analyses. Landmark analyses were performed (cycle two, three). Longitudinal analysis of NLR was performed utilising a mixed effect regression model.
The median OS for patients with hNLR was 8.5 months and 19.4 for patients with low NLR, (hazard ratio HR = 1.85, 95% confidence interval CI 1.15–2.96, p = 0.01). On landmark analysis, hNLR was significantly associated with inferior OS at all time points with a similar magnitude of effect over time (p < 0.05). On multivariate analysis, NLR was associated with OS (HR 1.06, 95% CI 1.01–1.11, p = 0.01). NLR did not correlate with increased immune toxicity. Longitudinally, NLR correlated with response: NLR decreased by 0.09 (95% CI: −0.15 to −0.02; p = 0.01) per month in responders compared with non-responders.
hNLR at baseline and during treatment is adversely prognostic in patients with advanced malignancies receiving PD-1/PD-L1 blockade. Importantly, NLR reduced over time in responders to immunotherapy. Taken together, these data suggest that baseline and longitudinal NLR may have utility as a unique biomarker to aid clinical decision-making in patients receiving immunotherapy.
•High neutrophil-lymphocyte ratio (NLR) at baseline and during treatment is adversely prognostic in patients receiving PD-1/PD-L1 blockade.•NLR does not correlate with risk of immune toxicity.•NLR decreases over time in responders to immunotherapy.
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Background: Immune checkpoint inhibitors (ICI) are the standard of care for metastatic renal cell carcinoma (mRCC). Circadian rhythm drives organisms to properly predict and react to cyclical ...changes in the environment, and also affects the adaptive immune response. Here, we study the relationship between time-of-day ICI administration and outcomes in mRCC patients (pts). Methods: This is a single-center retrospective study of ICI-treated mRCC pts diagnosed from January 2014 to March 2022. Day and time of each ICI infusion (inf) for each pt were obtained from the pharmacy records. Proportion of ICI inf administered after 4:30 pm (ICI430) was calculated based on a prior publication (Quian, Lancet Oncol 2021). The primary outcome was overall survival (OS), and secondary endpoints were time on treatment (TOT), time to next treatment (TNT), and overall response rate (ORR). The proportion of ICI430 as a continuous variable, and the dichotomized data (≥20% and ≥50%) were correlated with OS, TOT and TNT by Kaplan-Meier analysis and Cox regression, and with ORR by logistic regression. Results: Overall, 104 pts and 1763 inf were analyzed (Table). 48 pts were treated with 1st line (1L) ICI. 903 inf were administered (median 12 inf per pt, 1 - 111), 146 (15.6%) after 4:30 pm. 12 (25%) and 2 (4.2%) pts received ≥ 20% and ≥ 50% ICI430. Due to the small number of events (5 deaths and 15 progressions), of ICI430, and heterogeneity of treatments in 1L, we focus on pts treated with 2nd line (2L) ICI. 56 pts were treated with ICI in ≥2L. 860 inf were administered (median 8 inf per pt, 1 - 123), 180 (20.9%) after 4:30 pm. 15 (34.1%) and 9 (20.5%) pts received ≥20% and ≥50% ICI430. Pts who received ≥20% after 4:30pm, received fewer inf (7 vs. 16, p=0.022), had a worse TOT (4.3 vs. 9 m, HR 2.5, p=0.013), a trend to a worse TNT (6.3 vs. 10.5 m, HR 1.9, p=0.06) and a worse OS (16.9 vs. 56.1 m, HR 3.1, p=0.01). Similar results were obtained when using ≥ 50% ICI430 as the cut-off (TOT, 2 vs. 9m, p=0.007; TNT 4.7 vs. 10.5m, p=0.05; OS 16.9 vs. 36.6m, p=0.1), as well as higher frequency of progressive disease (85.7 vs. 21.9%, p=0.006). A significant association with OS (HR 1.02, p=0.03) was shown when analyzing ICI430 as a continuous variable, meaning a 16% increase in the risk of death for each 10% increment of ICI inf after 4:30 pm. Conclusions: Administration of ≥2L ICI after 4:30 pm is associated with poor overall survival. Our results could have a direct impact on pt survival and organization of outpatient clinics, but further research is needed. Table: see text
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