Immune Biomarkers in Metastatic Castration-resistant Prostate Cancer

Maza, Maria D. Fenor de la; Chandran, Khobe; Rekowski, Jan; Shui, Irene M.; Gürel, Bora; Cross, E.M.; Carreira, Suzanne; Yuan, Wei; Westaby, Daniel; Miranda, Susana; Ferreira, Ana; Seed, George; Figueiredo, Ines; Bertan, Claudia; Gil, Veronica; Riisnaes, Ruth; Sharp, Adam; Rodrigues, Daniel Nava; Rescigno, Pasquale; Tunariu, Nina; Liu, Xiao Qiao; Cristescu, Rǎzvan; Schloss, Charles; Yap, Christina; Bono, Johann S. de

doi:10.1016/j.euo.2022.04.004

Cited by 11 publications

(10 citation statements)

References 25 publications

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“…Next, we determined whether the genes encoding these ligands associate with intratumour myeloid inflammation. The expression of CXCL1 , CXCL2 , IL1RN and PLAUR positively associated with two previously published myeloid gene signatures 10 , 33 in the Stand Up To Cancer–Prostate Cancer Foundation (SU2C–PCF) 34 and RMH CRPC RNA-seq datasets 27 . The associations between CEBPB (RMH) and CXCL8 (SU2C–PCF) with both myeloid gene signatures were observed in one of the two datasets (Supplementary Table 3 ).…”

Section: Cxcr2 Ligands and Myeloid Inflammationmentioning

confidence: 77%

“…Given the association between peripheral and intratumour myeloid compartments, we reasoned that intratumour CD11b + HLA-DR lo CD15 + CD14 − cell infiltration is driven by tumour-derived chemokines. First, we carried out transcriptome analyses associating peripheral blood NLR and neutrophil count with the expression of pan-immune genes (770 gene list from the nCounter PanCancer Immune Profiling Panel 26 ) in bulk RNA-sequencing (RNA-seq) data from contemporaneously collected mCRPC biopsies from 95 patients treated at the RMH 27 who had received at least one taxane and one ARSI. These mCRPC biopsy RNA-seq analyses showed that eight senescence- and myeloid-associated transcripts, including CXCL1 , CXCL2 , CXCL8 ( IL8 ), IL1RN ( IL1RA ), CD68 , PLAUR , NFKB1 and CEBPB , were among the top 20 genes most positively associated with NLR.…”

Section: Cxcr2 Ligands and Myeloid Inflammationmentioning

confidence: 99%

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Targeting myeloid chemotaxis to reverse prostate cancer therapy resistance

Guo,

Sharp,

Gurel

et al. 2023

Nature

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Inflammation is a hallmark of cancer1. 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 modalities2–5. Whether myeloid inflammation drives progression of prostate cancer in humans remain unclear. Here we show that inhibition of myeloid chemotaxis can reduce tumour-elicited myeloid inflammation and reverse therapy resistance in a subset of patients with metastatic castration-resistant prostate cancer (CRPC). We show that a higher blood neutrophil-to-lymphocyte ratio reflects tumour myeloid infiltration and tumour expression of senescence-associated mRNA species, including those that encode myeloid-chemoattracting CXCR2 ligands. To determine whether myeloid cells fuel resistance to androgen receptor signalling inhibitors, and whether inhibiting CXCR2 to block myeloid chemotaxis reverses this, we conducted an investigator-initiated, proof-of-concept clinical trial of a CXCR2 inhibitor (AZD5069) plus enzalutamide in patients with metastatic CRPC that is resistant to androgen receptor signalling inhibitors. This combination was well tolerated without dose-limiting toxicity and it decreased circulating neutrophil levels, reduced intratumour CD11b+HLA-DRloCD15+CD14− myeloid cell infiltration and imparted durable clinical benefit with biochemical and radiological responses in a subset of patients with metastatic CRPC. This study provides clinical evidence that senescence-associated myeloid inflammation can fuel metastatic CRPC progression and resistance to androgen receptor blockade. Targeting myeloid chemotaxis merits broader evaluation in other cancers.

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Section: Cxcr2 Ligands and Myeloid Inflammationmentioning

confidence: 77%

Section: Cxcr2 Ligands and Myeloid Inflammationmentioning

confidence: 99%

Targeting myeloid chemotaxis to reverse prostate cancer therapy resistance

Guo,

Sharp,

Gurel

et al. 2023

Nature

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“…Human biological samples were sourced ethically, and their research use was in accordance with the terms of the informed consent provided as detailed previously 35 . A total of 159 mCRPC transcriptomes generated by the SU2C–PCF Prostate Cancer Dream Team 110 and 95 mCRPC transcriptomes from patients treated at Royal Marsden Hospital and Institute of Cancer Research (RMH/ICR) were analyzed 111 using TopHat2-Cufflinks pipeline. Gene expression as fragments per kilobase of transcript per million mapped reads (FPKM) was calculated.…”

Section: Methodsmentioning

confidence: 99%

AR coactivators, CBP/p300, are critical mediators of DNA repair in prostate cancer

Sardar,

McNair,

Ravindranath

et al. 2024

Preprint

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Castration resistant prostate cancer (CRPC) remains an incurable disease stage with ineffective treatments options. Here, the androgen receptor (AR) coactivators CBP/p300, which are histone acetyltransferases, were identified as critical mediators of DNA damage repair (DDR) to potentially enhance therapeutic targeting of CRPC. Key findings demonstrate that CBP/p300 expression increases with disease progression and selects for poor prognosis in metastatic disease. CBP/p300 bromodomain inhibition enhances response to standard of care therapeutics. Functional studies, CBP/p300 cistrome mapping, and transcriptome in CRPC revealed that CBP/p300 regulates DDR. Further mechanistic investigation showed that CBP/p300 attenuation via therapeutic targeting and genomic knockdown decreases homologous recombination (HR) factorsin vitro,in vivo, and in human prostate cancer (PCa) tumorsex vivo. Similarly, CBP/p300 expression in human prostate tissue correlates with HR factors. Lastly, targeting CBP/p300 impacts HR-mediate repair and patient outcome. Collectively, these studies identify CBP/p300 as drivers of PCa tumorigenesis and lay the groundwork to optimize therapeutic strategies for advanced PCa via CBP/p300 inhibition, potentially in combination with AR-directed and DDR therapies.

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“…Study approval. Approval for patient involvement in this study was granted by the Royal Marsden Hospital Ethics Review committee (reference 04/Q0801/60), as described in Fenor de la Maza et al (50).…”

Section: Methodsmentioning

confidence: 99%

“…These findings likely reflect the effect of NU7441 in 2 distinct cell backgrounds and variation in utilizing microarray (38) and RNA-Seq (47) for transcriptomics analyses (Supplemental Figure 18A). (Supplemental Figure 20A) (20,49,50). These analyses demonstrated that PRKDC mRNA expression significantly positively associated with AR mRNA expression in both cohorts (SU2C/PCF, r = 0.19, P = 0.019; ICR/RMH, r = 0.31, P = 0.003) and with AR-V7 mRNA expression in the SU2C/PCF cohort (r = 0.21, P = 0.008) but not the ICR/RMH cohort (r = 0.19, P = 0.067) (Figure 4H and Supplemental Figure 20B).…”

Section: Figure 1 Ar-v7 Proximal Biotinylation Experiments Identify K...mentioning

confidence: 99%

The catalytic subunit of DNA-PK regulates transcription and splicing of AR in advanced prostate cancer

Adamson,

Brittain,

Walker

et al. 2023

Journal of Clinical Investigation

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The ICR has a commercial interest in abiraterone, PARP inhibition in DNA repair-defective cancers, and PI3K/ AKT pathway inhibitors (with no financial interest). JSDB was named as an inventor, with no financial interest for patent 8,822,438 (Methods and Compositions for Treating Cancer), submitted by Janssen, which covers the use of abiraterone acetate with corticosteroids. He has been the chief investigator/principal investigator of many industry-sponsored clinical trials.

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Immune Biomarkers in Metastatic Castration-resistant Prostate Cancer

Cited by 11 publications

References 25 publications

Targeting myeloid chemotaxis to reverse prostate cancer therapy resistance

Targeting myeloid chemotaxis to reverse prostate cancer therapy resistance

AR coactivators, CBP/p300, are critical mediators of DNA repair in prostate cancer

The catalytic subunit of DNA-PK regulates transcription and splicing of AR in advanced prostate cancer

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