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Nature Nov 2023Inflammation is a hallmark of cancer. In patients with cancer, peripheral blood myeloid expansion, indicated by a high neutrophil-to-lymphocyte ratio, associates with...
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. 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 CD11bHLA-DRCD15CD14 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.
Topics: Humans; Male; Chemotaxis; Disease Progression; Drug Resistance, Neoplasm; Inflammation; Lewis X Antigen; Myeloid Cells; Neoplasm Metastasis; Prostate; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Androgen Receptor Antagonists; Antineoplastic Agents
PubMed: 37844613
DOI: 10.1038/s41586-023-06696-z -
American Journal of Therapeutics
Topics: Male; Humans; Prostatism; Mirtazapine
PubMed: 35104061
DOI: 10.1097/MJT.0000000000001473 -
Radiologic Clinics of North America Jan 2024Prostate cancer is the most common malignancy diagnosed in men. MR imaging-guided therapies for prostate cancer have become an increasingly common treatment alternative... (Review)
Review
Prostate cancer is the most common malignancy diagnosed in men. MR imaging-guided therapies for prostate cancer have become an increasingly common treatment alternative to traditional whole-gland therapies, such as radical prostatectomy or radiation therapy. This is especially true in men with localized, low- to intermediate-risk prostate cancer. Although long-term oncologic data remain limited, the authors describe several MR imaging-guided therapeutic options for the treatment of prostate cancer, including cryoablation, laser ablation, transrectal high-intensity focused ultrasound, and transurethral ultrasound ablation.
Topics: Male; Humans; Prostatic Neoplasms; Prostate; Magnetic Resonance Imaging; Treatment Outcome
PubMed: 37973238
DOI: 10.1016/j.rcl.2023.06.012 -
The Journal of Clinical Investigation Dec 2023Cell lineage plasticity is one of the major causes for the failure of targeted therapies in various cancers. However, the driver and actionable drug targets in promoting...
Cell lineage plasticity is one of the major causes for the failure of targeted therapies in various cancers. However, the driver and actionable drug targets in promoting cancer cell lineage plasticity are scarcely identified. Here, we found that a G protein-coupled receptor, ADORA2A, is specifically upregulated during neuroendocrine differentiation, a common form of lineage plasticity in prostate cancer and lung cancer following targeted therapies. Activation of the ADORA2A signaling rewires the proline metabolism via an ERK/MYC/PYCR cascade. Increased proline synthesis promotes deacetylases SIRT6/7-mediated deacetylation of histone H3 at lysine 27 (H3K27), and thereby biases a global transcriptional output toward a neuroendocrine lineage profile. Ablation of Adora2a in genetically engineered mouse models inhibits the development and progression of neuroendocrine prostate and lung cancers, and, intriguingly, prevents the adenocarcinoma-to-neuroendocrine phenotypic transition. Importantly, pharmacological blockade of ADORA2A profoundly represses neuroendocrine prostate and lung cancer growth in vivo. Therefore, we believe that ADORA2A can be used as a promising therapeutic target to govern the epigenetic reprogramming in neuroendocrine malignancies.
Topics: Animals; Humans; Male; Mice; Cell Line, Tumor; Epigenesis, Genetic; Lung Neoplasms; Proline; Prostate; Prostatic Neoplasms; Sirtuins
PubMed: 38099497
DOI: 10.1172/JCI168670 -
BMJ (Clinical Research Ed.) Nov 2023
Topics: Male; Humans; Prostatitis; Chronic Disease; Pelvic Pain; Chronic Pain
PubMed: 37977592
DOI: 10.1136/bmj-2023-073908 -
Scientific Reports Feb 2024According to previous observational researches and clinical trials, the gut microbiota is related to prostate diseases. However, the potential association between gut...
According to previous observational researches and clinical trials, the gut microbiota is related to prostate diseases. However, the potential association between gut microbiota and prostate disorders is still uncertain. We first identified groups of gut microbiota based on the phylum, class, order, family, and genus levels from consortium MiBioGen. And we acquired prostate diseases statistics from the FINNGEN study and PRACTICAL consortium. Next, two-sample Mendelian randomization was used to investigate the potential associations between three prevalent prostate disease and gut microbiota. In addition, we performed a reverse MR analysis and Benjamini-Hochberg (BH) test for further research. We investigated the connection between 196 gut microbiota and three prevalent prostate diseases. We identified 42 nominally significant associations and 2 robust causative links. Upon correction for multiple comparisons using the Benjamini-Hochberg procedure, our analysis revealed a positive correlation between the risk of prostatitis and the presence of the taxonomic order Gastranaerophilales. Conversely, the risk of prostate cancer exhibited an inverse correlation with the presence of the taxonomic class Alphaproteobacteria. Our study revealed the potential association between gut microbiota and prostate diseases. The results may be useful in providing new insights for further mechanistic and clinical studies of prostate diseases.
Topics: Male; Humans; Gastrointestinal Microbiome; Mendelian Randomization Analysis; Prostate; Prostatic Diseases; Prostatic Neoplasms; Alphaproteobacteria; Genome-Wide Association Study
PubMed: 38369514
DOI: 10.1038/s41598-024-54293-5 -
Nature Reviews. Urology Nov 2023The role of the prostatic middle lobe in the presentation and management of benign prostatic hyperplasia (BPH) is under-appreciated. Middle lobe enlargement is... (Review)
Review
The role of the prostatic middle lobe in the presentation and management of benign prostatic hyperplasia (BPH) is under-appreciated. Middle lobe enlargement is associated with intravesical prostatic protrusion (IPP), which causes a unique type of bladder outlet obstruction (BOO) via a 'ball-valve' mechanism. IPP is a reliable predictor of BOO and the strongest independent factor for failure of medical therapy necessitating conversion to surgical intervention. Men with middle lobe enlargement tend to exhibit mixed symptoms of both the storage and the voiding types, but symptomatology will vary depending on the degree of IPP present. Initial assessments such as uroflowmetry and post-void residual volumes are inadequate to detect IPP and could confound the clinical picture. Radiological evaluation of prostate morphology is key to assessment as it provides important prognostic information and can help with operative planning. Treatment strategies employed for BPH should consider the shape and morphology of prostate adenomata, specifically the presence of middle lobe enlargement and the degree of associated IPP.
Topics: Male; Humans; Prostate; Prostatic Hyperplasia; Clinical Relevance; Ultrasonography; Urinary Bladder Neck Obstruction; Hypertrophy
PubMed: 37188789
DOI: 10.1038/s41585-023-00774-7 -
The Journal of Clinical Investigation Dec 2023Strategies for patient stratification and early intervention are required to improve clinical benefits for patients with prostate cancer. Here, we found that active DHEA...
Strategies for patient stratification and early intervention are required to improve clinical benefits for patients with prostate cancer. Here, we found that active DHEA utilization in the prostate gland correlated with tumor aggressiveness at early disease stages, and 3βHSD1 inhibitors were promising for early intervention. [3H]-labeled DHEA consumption was traced in fresh prostatic biopsies ex vivo. Active DHEA utilization was more frequently found in patients with metastatic disease or therapy-resistant disease. Genetic and transcriptomic features associated with the potency of prostatic DHEA utilization were analyzed to generate clinically accessible approaches for patient stratification. UBE3D, by regulating 3βHSD1 homeostasis, was discovered to be a regulator of patient metabolic heterogeneity. Equilin suppressed DHEA utilization and inhibited tumor growth as a potent 3βHSD1 antagonist, providing a promising strategy for the early treatment of aggressive prostate cancer. Overall, our findings indicate that patients with active prostatic DHEA utilization might benefit from 3βHSD1 inhibitors as early intervention.
Topics: Male; Humans; Prostate; Dehydroepiandrosterone; Prostatic Neoplasms
PubMed: 38099500
DOI: 10.1172/JCI171199 -
Archives of Pathology & Laboratory... Sep 2023It is important to recognize high-grade foamy gland prostatic adenocarcinoma with desmoplastic stroma given its aggressive clinical course with frequent metastases and...
CONTEXT.—
It is important to recognize high-grade foamy gland prostatic adenocarcinoma with desmoplastic stroma given its aggressive clinical course with frequent metastases and death.
OBJECTIVE.—
To review the morphology, immunohistochemistry, and prognosis for this rare subtype of prostate adenocarcinoma.
DESIGN.—
Twenty-four cases received for consultation from 2010 to 2021 were analyzed including needle biopsy (n = 21), transurethral resection (n = 2), and a cystoprostatectomy (n = 1).
RESULTS.—
Patients ranged in age from 40 to 89 years (mean, 67 years). On average, 8 cores per case were involved (mean 67% core involvement). Extraprostatic extension and seminal vesicle invasion were observed in 6 of 21 (29%) and 3 of 21 (14%) needle biopsy cases, respectively. Twenty of the 24 cases (83%) were Grade Group (GG) 5 with 4 of 24 (17%) being GG4. Tumor necrosis as a component of Gleason pattern 5 was observed in 21 of 24 cases (88%). Associated intraductal adenocarcinoma (IDC) was observed in 22 of 24 cases (92%), with 4 of 24 cases (17%) demonstrating extensive IDC. Diagnostic challenges were as follows: (1) sparse isolated cancer glands embedded in the dense desmoplastic stroma; (2) fragmented glands; and (3) aberrant staining for high-molecular-weight cytokeratin in a nonbasal cell pattern in all cases. PTEN loss was observed in 9 cases, and p53 nuclear accumulation was observed in 8 cases. Three patients were lost to follow-up. Overall, of the 16 patients with meaningful follow-up, 12 (75%) either had metastases or died from prostate cancer.
CONCLUSIONS.—
High-grade desmoplastic foamy gland adenocarcinoma is difficult to diagnose and grade and has a poor prognosis.
Topics: Male; Humans; Adult; Middle Aged; Aged; Aged, 80 and over; Prostate; Prostatic Neoplasms; Adenocarcinoma; Prostatectomy; Biopsy, Needle
PubMed: 36399606
DOI: 10.5858/arpa.2022-0165-OA -
Annual Review of Medicine Jan 2024Prostate-specific membrane antigen (PSMA) as a transmembrane protein is overexpressed by prostate cancer (PC) cells and is accessible for binding antibodies or... (Review)
Review
Prostate-specific membrane antigen (PSMA) as a transmembrane protein is overexpressed by prostate cancer (PC) cells and is accessible for binding antibodies or low-molecular-weight radioligands due to its extracellular portion. Successful targeting of PSMA began with the development of humanized J591 antibody. Due to their faster clearance compared to antibodies, small-molecule radioligands for targeted imaging and therapy of PC have been favored in recent development efforts. PSMA positron emission tomography (PET) imaging has higher diagnostic performance than conventional imaging for initial staging of high-risk PC and biochemical recurrence detection/localization. However, it remains to be demonstrated how to integrate PSMA PET imaging for therapy response assessment and as an outcome endpoint measure in clinical trials. With the recent approval of Lu-PSMA-617 by the US Food and Drug Administration for metastatic castration-resistant PC progressing after chemotherapy, the high value of PSMA-targeted therapy was confirmed. Compared to standard of care, PSMA-based radioligand therapy led to a better outcome and a higher quality of life. This review, focusing on the advanced PC setting, provides an overview of different approved and nonapproved PSMA-targeted imaging and therapeutic modalities and discusses the future of PSMA-targeted theranostics, also with an outlook on non-radiopharmaceutical-based PSMA-targeted therapies.
Topics: United States; Male; Humans; Quality of Life; Prostate; Prostatic Neoplasms; Positron-Emission Tomography; Precision Medicine
PubMed: 38285513
DOI: 10.1146/annurev-med-081522-031439