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At least 37 records · Page 2Linked to original sources
PubMed2026

SPEN inactivation drives resistance to androgen receptor pathway inhibitors in metastatic prostate cancer.

PURPOSE: Treatment intensification with androgen receptor pathway inhibitors (ARPIs) has become the standard of care for patients with metastatic prostate cancer. However, there remains an unmet need to identify biomarkers for treatment resistance. Here, we identify SPEN inactivation as a driver of ARPI resistance. EXPERIMENTAL DESIGN: Pre-clinical studies were performed in LNCaP and VCaP cell lines. Data from a nationwide prostate cancer clinico-genomic database were extracted. Log-rank test and Cox proportional hazards models were used to compare time to next treatment (TTNT) on ARPI with/without SPEN mutations. SPEN immunohistochemistry was performed on a rapid autopsy metastatic tissue microarray. RESULTS: SPEN was identified as a top enzalutamide resistance hit in an unbiased genome-wide loss-of-function screen. SPEN inactivation results in upregulation of cell cycle proliferation and basal/stem cell activity as well as increased translation of pro-oncogenic genes. In a large patient cohort (N=6828), SPEN mutations are enriched following treatment with ARPIs (2.1% to 3.6%, p=0.001) and correlate with shorter TTNT on ARPI in patients with metastatic hormone-sensitive prostate cancer (6.4 vs 29.7 months, HR 2.67, p=0.02). In a metastatic rapid autopsy cohort (N=181), low SPEN H-score is associated with shorter time on abiraterone (5.0 vs 7.9 months, p=0.023) in metastatic castration-resistant prostate cancer. CONCLUSIONS: In real-world cohorts, loss of SPEN function across genomic, transcriptomic, and protein levels is associated with reduced benefit from ARPI therapy in metastatic prostate cancer. These findings identify SPEN inactivation as a clinically relevant biomarker of ARPI resistance that warrants prospective evaluation to guide treatment selection.

Journal Article↗
PubMed2025

A double-negative prostate cancer subtype is vulnerable to SWI/SNF-targeting degrader molecules.

Proteolysis targeting chimera (PROTAC) therapies degrading SWI/SNF ATPases offer a novel approach to interfere with androgen receptor (AR) signaling in AR-dependent castration-resistant prostate cancer (CRPC-AR). To explore the utility of SWI/SNF therapy beyond AR-sensitive CRPC, we investigated SWI/SNF-targeting agents in AR-negative CRPC. SWI/SNF targeting PROTAC treatment of cell lines and organoid models reduced the viability of not only CRPC-AR but also WNT-signaling dependent AR-negative CRPC (CRPC-WNT). The CRPC-WNT subgroup represents 11% of around 400,000 cases of CRPC worldwide who die yearly of CRPC. We discovered that SWI/SNF ATPase SMARCA4 depletion interfered with the master transcriptional regulator TCF7L2 (TCF4) in CRPC-WNT. Functionally, TCF7L2 maintains proliferation via the MAPK signaling axis in this subtype of CRPC. These data suggest a mechanistic rationale for interventions that perturb the DNA binding of the pro-proliferative TCF7L2 transcription factor (TF) and/or direct MAPK signaling inhibition in the CRPC-WNT subclass of advanced prostate cancer.

Journal Article↗
PubMed2026

Polyamine Metabolism as a Metabolic Vulnerability in Prostate Cancer Treated with Supraphysiological Androgens.

Prostate cancer progression is predominantly driven by androgen receptor (AR) signaling, and despite initial benefits of androgen deprivation therapy (ADT), most patients eventually develop lethal castration-resistant disease. Cyclic administration of supraphysiologic androgen (SPA) with ADT paradoxically suppresses tumor growth; however, responses are heterogeneous, and the mechanisms underlying the antitumor effects of SPA remain incompletely understood. In this issue of Cancer Research, Kumar and colleagues demonstrate that SPA induces a distinct metabolic response, characterized by AR-dependent induction of polyamine biosynthesis via ODC1 and AMD1. This metabolic rewiring elevates polyamine synthesis while concurrently depleting the methyl donor S-adenosylmethionine (SAM). Although increased polyamine metabolism by SPA may promote adaptive resistance, genetic or pharmacologic inhibition of ODC1 using difluoromethylornithine (DFMO) enhances SPA-induced growth suppression by disrupting protective polyamine pools and further exacerbating SAM depletion, revealing a metabolic vulnerability in SPA-treated prostate cancer cells. Supporting these findings, a clinical trial combining DFMO with bipolar androgen therapy (BAT) demonstrated reduced circulating polyamines in patients, confirming polyamine pathway suppression in patients with different genomic features. Together, this study uncovers a mechanistic link among androgen signaling, polyamine metabolism, and therapeutic response, providing a rationale for targeting metabolic dependencies to improve SPA efficacy. See related article by Kumar et al., p. 1148.

Male↗
PubMed2026

Ubiquitination-Androgen Receptor Coupling in Prostate Cancer Therapeutics.

Prostate cancer is one of the most frequently diagnosed malignancies in men and a leading cause of cancer-related mortality worldwide. The androgen receptor (AR) remains the principal driver of prostate cancer progression and castration-resistant prostate cancer (CRPC), with its stability, localization, and transcriptional activity being tightly regulated by the ubiquitin-proteasome system (UPS). E3 ubiquitin ligases and deubiquitinases (DUBs) critically govern AR turnover and signalling output, thereby influencing tumour growth, therapeutic resistance, and disease progression. Emerging evidence further highlights a complex interplay between ubiquitination, DNA damage response (DDR) pathways, and ADP-ribosylation (ADPr) signalling, collectively shaping genomic stability and treatment responsiveness in prostate cancer. This review is organized into four major themes: (i) ubiquitin-mediated regulation of AR signalling, (ii) ubiquitination and DNA damage response in AR-driven prostate cancer, (iii) crosstalk between ubiquitination, ADPr, and AR-associated signalling pathways, and (iv) therapeutic strategies targeting the UPS and AR axis. This study also discusses recent advances in targeted protein degradation, modulation of E3 ligases, inhibition of deubiquitinases, and PARP-based therapeutic approaches. These emerging insights into the interconnected regulation of ubiquitination, AR signalling, DDR pathways, and ADP-ribosylation may facilitate the development of next-generation therapeutic approaches for advanced prostate cancer.

ADP-ribosylation (ADPr)↗
PubMed2026

Tumor-Intrinsic Blood and Imaging Correlatives in Advanced Prostate Cancer Treated with Combination Radiopharmaceutical Therapy and Immunotherapy.

The PRINCE trial showed the clinical activity for 177Lu-PSMA-617 in combination with pembrolizumab for metastatic castration-resistant prostate cancer. To refine patient selection and improve response monitoring strategies to this combination, we investigated candidate tumor-intrinsic biomarkers of treatment response and resistance. Methods: We performed circulating tumor DNA (ctDNA), circulating tumor cell (CTC), and PET imaging analyses at baseline, 12 wk on-treatment, and disease progression in participants enrolled in PRINCE (n = 37). We performed targeted sequencing for ctDNA quantification and genomic analysis of more than 70 prostate cancer genes. CTC enumeration was performed on the EpicSciences platform and was combined with selective single-cell whole-genome sequencing. PET imaging included serial PSMA PET as well as 18F-FDG PET imaging at baseline. Results: A low baseline ctDNA fraction and high PSMA avidity in metastatic lesions were linked to superior treatment responses and may have composite biomarker value. Genomic alterations in tumor suppressor genes TP53, RB1, or PTEN were associated with higher 18F-FDG avidity and metabolic tumor volume on 18F-FDG PET imaging and worse prognosis. At 12-wk on-treatment, both ctDNA detection and PSMA PET imaging were strong indicators of response depth and durability. At disease progression, PSMA expression on PET imaging was lower compared with baseline and supported by subclonal remodeling of ctDNA and CTC copy number profiles and by clonal expansions of tumor suppressor gene mutations. Conclusion: We provide the first integrated molecular and imaging insights into determinants of response and resistance to combined radiopharmaceutical therapy and immunotherapy in prostate cancer and propose biomarker strategies to inform future clinical development.

177Lu-PSMA-617↗
PubMed2026

Profibrogenic Gremlin-1 expression in prostate cancer and the clinicopathologic association.

BACKGROUND: Gremlin-1 (GREM1) is a profibrogenic molecule involved in TGF-&#x3b2; signaling. Recent studies have implicated GREM1 in androgen receptor (AR)-independent signaling and castration resistance in advanced prostate cancer. However, its compartment expression patterns and clinicopathologic significance in primary prostate cancer remain unclear. METHODS: GREM1 mRNA expression and clinicopathologic associations were analyzed in the Cancer Genome Atlas (TCGA) prostate adenocarcinoma (TCGA-PRAD), the Memorial Sloan Kettering Cancer Center (MSKCC), and the German Cancer Research Center (DKFZ) primary prostate cancer cohorts. Correlations between GREM1 and genes related to TGF-&#x3b2; signaling, extracellular matrix organization, fibroblast activation, and AR signaling were evaluated by Spearman analysis. GREM1 protein expression was examined by immunohistochemistry in commercial human prostate cancer tissue microarrays (TMAs) using compartment-specific QuPath-based H-scores. RESULTS: GREM1 expression was relatively elevated in prostate and bladder cancers. Across the three prostate cancer cohorts, higher GREM1 expression was associated with adverse pathologic features and was most consistently correlated with FAP. Inverse correlations were observed with selected AR-related genes, whereas no significant correlation was found with AR itself. Higher GREM1 expression was associated with shorter disease-free survival only in MSKCC but was not an independent prognostic factor after clinicopathologic adjustment. Quantitative immunohistochemistry in 43 patients showed higher epithelial than stromal GREM1 H-scores (median, 3.10 vs 1.41; P < 0.0001), with heterogeneous staining in both compartments. Neither epithelial nor stromal H-scores were associated with Gleason score or pathologic T stage. CONCLUSIONS: GREM1 mRNA expression in primary prostate cancer was associated with adverse clinicopathologic features, and a fibroblast-associated transcriptional context but did not demonstrate independent prognostic value. At the protein-level, GREM1 expression was heterogeneous in both epithelial and stromal compartments, with higher epithelial H-scores on average. These findings support further investigation of the biological significance of GREM1 expression in primary prostate cancer.

TCGA↗
PubMedDate not supplied

[Treatment with 32P of carcinoma of the prostate (author's transl)].

Twenty-eight patients affected with disseminated prostate cancer, which proved hormone resistant (after castration and oestrogen administration), have undergone combined treatment with Testosterone (for 13 days) and 32P (for the last 7 days of the Testosterone treatment). During the initial fase of the treatment (Testosterone only), 14 patients experienced pain exacerbation and/or fever and one experienced immediate improvement. The exacerbation quickly disappeared following 32P administration, and 26 of the patients had distinct improvement at some time during or after treatment, with a mean remission duration of 3 months and mean survival rate of 7 months. No lytic or soft part deposit showed improvement; improvement was noticeable only in the mixed type or osteo-sclerotic metastases. This observation suggests that the androgen stimulates uptake of the isotope not inside the tumor cells but in the bone matrix around the tumoral deposit. The patient who showed very early improvement had a subsequent relapse on oestrogens, but later responded to the androgen alone.

Humans↗
PubMed1977

Effect of aminoglutethimide on calcitonin sensitivity.

Studying the influence of aminoglutethimide treatment on calcitonin sensitivity, serum calcium levels were measured in normal rats, aminoglutethimide treated rats, adrenalectomized and castrated rats, following i.v. injection of porcine calcitonin. The aminoglutethimide administration caused a more distinct calcitonin resistance than surgical sex hormone deprivation. It was found that castration in most of experiments failed to enhance calcitonin resistance in aminoglutethimide treated animals. The aminoglutethimide administration may influence the steroid synthesis of adrenals, accessory adrenals and testes too. Results obtained with castrated, aminoglutethimide plus dehydroepiandrosterone treated and castrated, aminoglutethimide plus epiandrosterone treated rats affirm the earlier observations, i.e. in state of sex hormone deficiency the exogeneous androgens have an enhancing or restoring effect on calcitonin sensitivity.

Adrenal Cortex Hormones↗
PubMed1975

The role of chemotherapy in the treatment of cancer of the breast.

Chemotherapy is of significant benefit to patients with advanced breast cancer, as measured by tumor regression and increased survival. Yet these tumor regressions are short-lived, and the patient survival benefit is measured in terms of months. This relative refractoriness is due either to drug resistance or to what is called "kinetic" resistance. Kinetic resistance implies large numbers of cells and long doubling times. Experimentally, surgery combined with chemotherapy offers the best chance of cure of several solid tumors in animals. Several clinical trials in combined surgery and chemotherapy indicating a markedly favorable effect of this approach are in progress. This suggests that, as in the animal systems, kinetic resistance can be overcome by the combined-modality approach. The response to endocrine manipulation can be predicted by estrogen receptors. Clinical trials to combine chemotherapy, surgery and hormonal treatment are under way.

Breast Neoplasms↗
PubMed1977

Electrophysiological and contractile properties of the levator ani muscle after castration and testosterone administration.

Electrical and contractile properties of the levator ani muscle were studied in normal rats, in castrated rats and in castrated rats treated with testosterone. 2. No significant changes in the frequency of miniature end-plate potentials were found 6 months after castration. The frequency increased already 6 h after testosterone treatment; an increase of about 100% was observed after 7 days of testosterone treatment. 3. Castration led to a 2-fold increase of the input resistance of the muscle fibres. After 7 days of testosterone treatment the input resistance was only slightly higher than normal. 4. The weight of the muscle was decreased to 18% of the control value after 6 months castration. It increased to 46% after 7 days of testosterone treatment. 5. The muscles of castrated animals revealed a prolongation of contraction time and marked changes in maximal rate of tension development and half relaxation time. Partial recovery of these parameters was found after 7 days of testosterone treatment. 6. Long-term castration did not induce any denervation-like changes of action potential parameters, and no tetrodotoxin resistance was found in spite of marked muscle atrophy.

Anal Canal↗
PubMed1976

Age resistance of cattle to the nodular worm Oesophagostomum radiatum.

Two groups of seven castrated male calves, aged three and 13 months respectively, which had been reared worm-free, were infected with 5000 larvae of Oesophagostomun radiatum. At autopsy six weeks later a mean of 403 +/- 398 adult worms were recovered from the older animals and a mean of 1174 +/- 484 from the younger. This significant difference (P less than 0-01) indicates that the resistance of cattle to initial infection with O radiatum increases with age.

Age Factors↗
PubMed1975

Effects of hormonal pretreatment of cardiac necrosis in the Japanese quail.

Male Japanese quail castrated and treated with beta-estradiol-3-benzoate for 3 wk were more resistant than sham-operated males to the necrogenic effects of massive doses of isoproterenol. The estrogen-treated castrate also weighed significantly more and had significantly lower hematocrit ratios than either the sham-operated male or the intact male. These results indicate that there is a definite sex-related protective effect this type of cardiac necrosis which cannot be explained on the basis of differences in body weight.

Animals↗
PubMed1979

A rat prostatic adenocarcinoma as a model for the human disease.

A transplantable, metastasizing prostatic adenocarcinoma (Tumor I) in Lobund Wistar rats was examined for activity and distribution of five hydrolytic enzymes and for ability to accumulate radioactive zinc. The results suggest that the tumor had arisen in the ventral lobe of the prostate and that its growth was not affected by orchiectomy, adrenalectomy, or replacement treatment with exogenous androgen or corticosteroids. The androgen independency of the tumor was further shown by the low uptake of 3H-testosterone, in contrast to the high uptake in the ventral prostate. Tumor growth was retarded by Cytoxan but not by 5-fluorouracil, Estracyt, or streptozotocin, three agents clinically effective in the treatment of some patients with prostatic cancer resistant to endocrine therapy. It is concluded that this tumor in Lobund Wistar rats may be an adequate model for human prostatic cancers resistant to the agents mentioned above.

Acid Phosphatase↗
PubMed1979

Effects of pregnancy and progesterone and/or oestradiol on the insulin secretion and pancreatic insulin content in the perfused rat pancreas.

Progesterone and oestradiol treatment of ovariectomized rats was administered leading to plasma steroid concentrations comparable to those of the pregnant rat. In these experimental conditions oestradiol enhanced insulin secretion but progesterone had little effect on B cell response to glucose (0.8 g/l and 1.4 g/l) of the perfused pancreas. At low glucose concentration (0.8 g/l) neither of the two steroids, added to the perfusion medium, had any effect on insulin release of the pancreas of the castrated animals; oestradiol exerted a facilitating action on glucose stimulation (1.4 g/l); progesterone had no effect. During pregnancy biphasic insulin secretion was enhanced, but pancreatic hormonal content was only increased at term. Neither oestradiol nor progesterone treatment changed pancreatic insulin content. It is concluded that oestradiol acts on insulin release at pancreatic level directly, whereas progesterone influences insulin release by causing insulin resistance.

Animals↗
PubMed1978

Influence of methyl xanthine treatment on calcitonin effect.

The presented results clearly demonstrate that theophylline, caffeine and theobromine have a blocking action on calcitonin effect as determined by the elevation of serum calcium level, although different degree of potency was found with each drugs. There is no difference in respect of the serum calcium elevation after a single dose of methyl xanthines or after a 9-10 day lasting treatment. The castration had no additional enhancing effect of the calcitonin resistance of methyl xanthine treated animals. The administration of androgens simultaneously with the methyl xanthine treatment failed to produce improvement of calcitonin sensitivty preventing the elevation of serum calcium after calcitonin injection. So the calcitonin resistance of methyl xanthine treated animals appears to be different to the calcitonin resistance of sex hormone deprived conditions because the latter could be abolished by androgen administration. Theophylline treatment resulted in a slightly but significantly elevated serum calcium comparing to controls without exogeneous calcitonin. This magnitude of elevation remains between the normocalcaemic limits.

Androgens↗
PubMed1978

Castration effects on tumor-specific immunity.

Using 2 immunogenic (3-methylcholanthrene-induced fibrosarcomas in BALB/c x DBA/2 F1 (CD2F1) male mice, we observed initially that the rate of tumor growth might be enhanced by castration. For confirmation, tumor transplantation experiments with over 500 mice were done to compare tumor-specific transplantation immunity in castrate and in control male mice. Inbred mice bearing a 3-methylcholanthrene-induced fibrosarcoma transplant underwent surgical excision of the tumor; specific resistance to subsequent challenges with varying doses of that tumor cell line were compared in castrate and in noncastrate groups of mice. Although castration influenced the rate of tumor growth, it had no apparent effect on tumor-specific immunoresistance. Mechanisms of host-tumor immunorelationships are discussed as they might relate to endocrine therapy of prostate adenocarcinoma.

Adenocarcinoma↗
PubMed1977

Castration effects on tumor specific immunity.

Using two immunogenic methylcholanthrene-induced fibrosarcomas in CD2F1 male mice, initial observations suggested that the rate of tumor growth might be enhanced by castration. For confirmation, tumor transplantation experiments using more than 500 mice were carried out in order to compare tumor specific transplantation immunity in castrate and in control male mice. Inbred mice bearing a 3-methylcholanthrene-induced fibrosarcoma transplant underwent surgical excision of the tumor; and specific resistance to subsequent challenges using varying doses of that tumor cell line were compared in castrate and in noncastrate groups of mice. Although castration influenced the rate of tumor growth, castration had no apparent effect on tumor specific immunoresistance. Mechanisms of host-tumor immunorelationships are discussed.

Animals↗