Novel drugs, drug sequences and combinations have improved the outcome of prostate cancer in recent years. The latest approvals include abiraterone acetate, enzalutamide and apalutamide which target ...androgen receptor (AR) signaling, radium-223 dichloride for reduction of bone metastases, sipuleucel-T immunotherapy and taxane-based chemotherapy. Adding abiraterone acetate to androgen deprivation therapy (ADT) in order to achieve complete androgen blockade has proven highly beneficial for treatment of locally advanced prostate cancer and metastatic hormone-sensitive prostate cancer (mHSPC). Also, ADT together with docetaxel treatment showed significant benefit in mHSPC. Ongoing clinical trials for different subgroups of prostate cancer patients include the evaluation of the second-generation AR antagonists enzalutamide, apalutamide and darolutamide, of inhibitors of the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) pathway, of inhibitors of DNA damage response, of targeted alpha therapy and of prostate-specific membrane antigen (PSMA) targeting approaches. Advanced clinical studies with immune checkpoint inhibitors have shown limited benefits in prostate cancer and more trials are needed to demonstrate efficacy. The identification of improved, personalized treatments will be much supported by the major progress recently made in the molecular characterization of early- and late-stage prostate cancer using "omics" technologies. This has already led to novel classifications of prostate tumors based on gene expression profiles and mutation status, and should greatly help in the choice of novel targeted therapies best tailored to the needs of patients.
Prostate cancer affects an increasing number of men worldwide and is a leading cause of cancer-associated deaths. Beside genetic mutations, many epigenetic alterations including DNA and histone ...modifications have been identified in clinical prostate tumor samples. They have been linked to aberrant activity of enzymes and reader proteins involved in these epigenetic processes, leading to the search for dedicated inhibitory compounds. In the wake of encouraging anti-tumor efficacy results in preclinical models, epigenetic modulators addressing different targets are now being tested in prostate cancer patients. In addition, the assessment of microRNAs as stratification biomarkers, and early clinical trials evaluating suppressor microRNAs as potential prostate cancer treatment are being discussed.
Recent advances in whole-genome and transcriptome sequencing of prostate cancer at different stages indicate that a large number of mutations found in tumors are present in non-protein coding regions ...of the genome and lead to dysregulated gene expression. Single nucleotide variations and small mutations affecting the recruitment of transcription factor complexes to DNA regulatory elements are observed in an increasing number of cases. Genomic rearrangements may position coding regions under the novel control of regulatory elements, as exemplified by the
fusion and the amplified enhancer identified upstream of the
(
) gene. Super-enhancers are increasingly found to play important roles in aberrant oncogenic transcription. Several players involved in these processes are currently being evaluated as drug targets and may represent new vulnerabilities that can be exploited for prostate cancer treatment. They include factors involved in enhancer and super-enhancer function such as bromodomain proteins and cyclin-dependent kinases. In addition, non-coding RNAs with an important gene regulatory role are being explored. The rapid progress made in understanding the influence of the non-coding part of the genome and of transcription dysregulation in prostate cancer could pave the way for the identification of novel treatment paradigms for the benefit of patients.
The CHD1 gene, encoding the chromo‐domain helicase DNA‐binding protein‐1, is one of the most frequently deleted genes in prostate cancer. Here, we examined the role of CHD1 in DNA double‐strand break ...(DSB) repair in prostate cancer cells. We show that CHD1 is required for the recruitment of CtIP to chromatin and subsequent end resection during DNA DSB repair. Our data support a role for CHD1 in opening the chromatin around the DSB to facilitate the recruitment of homologous recombination (HR) proteins. Consequently, depletion of CHD1 specifically affects HR‐mediated DNA repair but not non‐homologous end joining. Together, we provide evidence for a previously unknown role of CHD1 in DNA DSB repair via HR and show that CHD1 depletion sensitizes cells to PARP inhibitors, which has potential therapeutic relevance. Our findings suggest that CHD1 deletion, like BRCA1/2 mutation in ovarian cancer, may serve as a marker for prostate cancer patient stratification and the utilization of targeted therapies such as PARP inhibitors, which specifically target tumors with HR defects.
Synopsis
Chromo‐domain helicase DNA‐binding protein‐1 (CHD1) promotes HR‐mediated DSB repair. The depletion of CHD1 enhances cellular sensitivity to PARP inhibitors, which has potential therapeutic implications for CHD1‐depleted prostate cancers.
CHD1 is required for the recruitment of CtIP and efficient DNA DSB repair.
CHD1 facilitates the opening of chromatin at DSB and promotes HR repair.
CHD1 depletion elicits cellular sensitivity to PARP inhibition.
Chromo‐domain helicase DNA‐binding protein‐1 (CHD1) promotes HR‐mediated DSB repair. The depletion of CHD1 enhances cellular sensitivity to PARP inhibitors, which has potential therapeutic implications for CHD1‐depleted prostate cancers.
Background
Extrahepatic manifestation of hepatocellular carcinoma (HCC) is rare and primarily affects lung, lymph nodes and bone. Metastases to the adrenal glands are relatively infrequent. This ...25-year institutional experience aimed for an analysis of factors influencing survival in patients undergoing surgery for HCC adrenal metastasis.
Methods
A retrospective analysis of the institutional database of the Clinic for General-, Visceral- and Transplantation Surgery of the University Medical Center Mainz, Germany, was performed. Patients who underwent surgery for HCC adrenal metastases from January 1995 to June 2020 were included. Pre-, peri- and postoperative factors with potential influence on survival were assessed.
Results
In 16 patients (14 males, two females), one bilateral and 15 unilateral adrenalectomies were performed (13 metachronous, three synchronous). Thirteen operations were carried out via laparotomy, and three adrenalectomies were minimally invasive (two laparoscopic, one retroperitoneoscopic). Median overall survival (after HCC diagnosis) was 35 months, range: 5–198. Median post-resection survival (after adrenalectomy) was 15 months, range: 0–75. Overall survival was longer in patients with the primary HCC treatment being liver transplantation (median 66 months) or liver resection (median 51 months), compared to only palliative intended treatment of the primary with chemotherapy (median 35 months) or local ablation (median 23 months).
Conclusions
Surgery is a feasible treatment option for patients with adrenal metastases originating from HCC. In patients who underwent adrenalectomy for HCC adrenal metastasis, overall survival was superior, if primary HCC treatment was potentially curative (liver transplantation or resection).
Prostate cancer (PCa) is one of the most frequent tumor types in the male Western population. Early‐stage PCa and late‐stage PCa are dependent on androgen signaling, and inhibitors of the androgen ...receptor (AR) axis represent the standard therapy. Here, we studied in detail the global impact of darolutamide, a newly approved AR antagonist, on the transcriptome and AR‐bound cistrome in two PCa cell models. Darolutamide strongly depleted the AR from gene regulatory regions and abolished AR‐driven transcriptional signaling. Enhancer activation was blocked at the chromatin level as evaluated by H3K27 acetylation (H3K27ac), H3K4 monomethylation (H3K4me1), and FOXA1, MED1, and BRD4 binding. We identified genomic regions with high affinities for the AR in androgen‐stimulated, but also in androgen‐depleted conditions. A similar AR affinity pattern was observed in healthy and PCa tissue samples. High FOXA1, BRD4, H3K27ac, and H3K4me1 levels were found to mark regions showing AR binding in the hormone‐depleted setting. Conversely, low FOXA1, BRD4, and H3K27ac levels were observed at regulatory sites that responded strongly to androgen stimulation, and AR interactions at these sites were blocked by darolutamide. Beside marked loss of AR occupancy, FOXA1 recruitment to chromatin was also clearly reduced after darolutamide treatment. We furthermore identified numerous androgen‐regulated super‐enhancers (SEs) that were associated with hallmark androgen and cell proliferation‐associated gene sets. Importantly, these SEs are also active in PCa tissues and sensitive to darolutamide treatment in our models. Our findings demonstrate that darolutamide is a potent AR antagonist blocking genome‐wide AR enhancer and SE activation, and downstream transcription. We also show the existence of a dynamic AR cistrome that depends on the androgen levels and on high AR affinity regions present in PCa cell lines and also in tissue samples.
Schematic model showing how darolutamide blocks androgen (R1881)‐mediated AR signaling by inhibiting the function of normal enhancers and super‐enhancers, and impairing downstream gene transcription.
Several inhibitors of androgen receptor (AR) function are approved for prostate cancer treatment, and their impact on gene transcription has been described. However, the ensuing effects at the ...protein level are far less well understood. We focused on the AR signaling inhibitor darolutamide and confirmed its strong AR binding and antagonistic activity using the high throughput cellular thermal shift assay (CETSA HT). Then, we generated comprehensive, quantitative proteomic data from the androgen-sensitive prostate cancer cell line VCaP and compared them to transcriptomic data. Following treatment with the synthetic androgen R1881 and darolutamide, global mass spectrometry-based proteomics and label-free quantification were performed. We found a generally good agreement between proteomic and transcriptomic data upon androgen stimulation and darolutamide inhibition. Similar effects were found both for the detected expressed genes and their protein products as well as for the corresponding biological programs. However, in a few instances there was a discrepancy in the magnitude of changes induced on gene expression levels compared to the corresponding protein levels, indicating post-transcriptional regulation of protein abundance. Chromatin immunoprecipitation DNA sequencing (ChIP-seq) and Hi-C chromatin immunoprecipitation (HiChIP) revealed the presence of androgen-activated AR-binding regions and long-distance AR-mediated loops at these genes.
Color has been shown to facilitate both visual search and recognition tasks. It was our purpose to examine the impact of a color-coding algorithm on the interpretation of 2D-DSA acquisitions by ...experienced and inexperienced observers.
Twenty-six 2D-DSA acquisitions obtained as part of routine clinical care from subjects with a variety of cerebrovascular disease processes were selected from an internal data base so as to include a variety of disease states (aneurysms, AVMs, fistulas, stenosis, occlusions, dissections, and tumors). Three experienced and 3 less experienced observers were each shown the acquisitions on a prerelease version of a commercially available double-monitor workstation (XWP, Siemens Healthcare). Acquisitions were presented first as a subtracted image series and then as a single composite color-coded image of the entire acquisition. Observers were then asked a series of questions designed to assess the value of the color-coded images for the following purposes: 1) to enhance their ability to make a diagnosis, 2) to have confidence in their diagnosis, 3) to plan a treatment, and 4) to judge the effect of a treatment. The results were analyzed by using 1-sample Wilcoxon tests.
Color-coded images enhanced the ease of evaluating treatment success in >40% of cases (P < .0001). They also had a statistically significant impact on treatment planning, making planning easier in >20% of the cases (P = .0069). In >20% of the examples, color-coding made diagnosis and treatment planning easier for all readers (P < .0001). Color-coding also increased the confidence of diagnosis compared with the use of DSA alone (P = .056). The impact of this was greater for the naïve readers than for the expert readers.
At no additional cost in x-ray dose or contrast medium, color-coding of DSA enhanced the conspicuity of findings on DSA images. It was particularly useful in situations in which there was a complex flow pattern and in evaluation of pre- and posttreatment acquisitions. Its full potential remains to be defined.
During the 2022 Winter Paralympic Games in Beijing, the Para snow-sport events will be held at high altitudes and in possibly cold conditions while also requiring adjustment to several time zones. ...Furthermore, the ongoing COVID-19 pandemic may lead to suboptimal preparations. Another concern is the high rate of injuries that have been reported in the Para alpine and snowboard events. In addition to these challenges, Para athletes various impairments may affect both sports-specific demands and athlete health. However, the group of Para snow-sport athletes is an understudied population. Accordingly, this perspective paper summarises current knowledge to consider when preparing for the Paralympic Games in Beijing and point out important unanswered questions. We here focus specifically on how sport-specific demands and impairment-related considerations are influenced by altitude acclimatisation, cold conditions, travel fatigue and jetlag, complications due to the COVID-19 pandemic, and injury prevention and sports safety considerations. As Para athletes with spinal cord injury, limb deficiency, cerebral palsy and visual impairment account for the majority of the Para snow-sport athletes, the focus is mainly on these impairment groups. In brief, we highlight the extra caution required to ensure athlete health, performance and sports safety among Para athletes participating in the snow-sport events in the 2022 Beijing Paralympic Games. Although there is an urgent need for more high-quality research focusing on Para winter athletes, we hope these non-consensus recommendations will help prepare for the 2022 Beijing Paralympic Winter Games.
Prostate cancer is a frequent malignancy in older men and has a very high 5‐year survival rate if diagnosed early. The prognosis is much less promising if the tumor has already spread outside the ...prostate gland. Targeted treatments mainly aim at blocking androgen receptor (AR) signaling and initially show good efficacy. However, tumor progression due to AR‐dependent and AR‐independent mechanisms is often observed after some time, and novel treatment strategies are urgently needed. Dysregulation of the PI3K/AKT/mTOR pathway in advanced prostate cancer and its implication in treatment resistance has been reported. We compared the impact of PI3K/AKT/mTOR pathway inhibitors with different selectivity profiles on in vitro cell proliferation and on caspase 3/7 activation as a marker for apoptosis induction, and observed the strongest effects in the androgen‐sensitive prostate cancer cell lines VCaP and LNCaP. Combination treatment with the AR inhibitor darolutamide led to enhanced apoptosis in these cell lines, the effects being most pronounced upon cotreatment with the pan‐PI3K inhibitor copanlisib. A subsequent transcriptomic analysis performed in VCaP cells revealed that combining darolutamide with copanlisib impacted gene expression much more than individual treatment. A comprehensive reversal of the androgen response and the mTORC1 transcriptional programs as well as a marked induction of DNA damage was observed. Next, an in vivo efficacy study was performed using the androgen‐sensitive patient‐derived prostate cancer (PDX) model LuCaP 35 and a superior efficacy was observed after the combined treatment with copanlisib and darolutamide. Importantly, immunohistochemistry analysis of these treated tumors showed increased apoptosis, as revealed by elevated levels of cleaved caspase 3 and Bcl‐2‐binding component 3 (BBC3). In conclusion, these data demonstrate that concurrent blockade of the PI3K/AKT/mTOR and AR pathways has superior antitumor efficacy and induces apoptosis in androgen‐sensitive prostate cancer cell lines and PDX models.
Crosstalk between the androgen receptor (AR) and the PI3K/AKT/mTOR pathways plays an essential role in prostate cancer growth and therapy resistance. Treatment with the AR inhibitor darolutamide and the pan‐PI3K inhibitor copanlisib strongly reduces survival and growth of prostate cancer models.
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