Malignant Prostate Cancer Research Articles

Abstract 6268: TT125-802 is a potent and highly selective CBP/p300 bromodomain inhibitor for the treatment of castration resistant prostate cancer and haematological malignancies

Abstract The paralogous lysine acetyltransferases CREB-binding protein (CBP) and p300 are key epigenetic regulators involved in diverse signaling pathways in cancer. The bromodomain (BRD) of CBP/p300 serves as an acetyl-lysine “reader” that allows CBP/p300 to bind chromatin at acetylated histone and non-histone proteins leading to the regulation of gene transcription. Indeed, CBP/p300 are critical co-activators of nuclear receptors, including the androgen receptor (AR) in castration resistant prostate cancer (CRPC). Thus, inhibition of CBP and p300 is an emerging therapeutic strategy to block the transactivation activity of the AR in CRPC. In addition, inhibition of the CBP/p300 BRD has been described as a potential therapeutic strategy to treat multiple myeloma (MM) through transcriptional suppression of interferon regulatory factor 4 (IRF4) and concomitant repression of its target genes MYC and MYB. TT125-802 is a highly selective and potent, oral small molecule inhibitor of the BRD of CBP/p300. In a BROMOscan assay against a panel of 40 BRD-containing proteins, TT125-802 revealed the unique selectivity to the BRD of CBP/p300 with a minimal off-target binding to all other BRDs, including BET proteins.TT125-802 shows selective anti-proliferative activity in AR-dependent prostate cancer cell lines (22Rv-1, C4-2, and LNCaP) and inhibits AR target gene expression (KLK2, KLK3, TMPRSS2, and MYC) in a dose-dependent manner (IC50 of 2 to 33 nM). AR-negative prostate cancer cell lines (DU-145 and PC-3) are insensitive to TT125-802 in vitro, pointing to an AR-selective mode of action. In an in vivo model of CRPC, TT125-802 inhibited tumor growth when administered orally to human C4-2 xenograft-bearing mice. Daily dosing of TT125-802 was well tolerated with stable bodyweights and platelet counts. In addition, preclinical studies in CRPC patient-derived xenograft (PDX)-bearing mice showed that the combination treatment of TT125-802 and enzalutamide had a synergistic effect on tumor growth inhibition compared to single agent treatments. TT125-802 reduced mRNA expression of the AR-target genes in tumor samples and decreased plasma PSA levels compared to enzalutamide alone, and the combination reduced levels even further. In a preclinical model of MM (OPM2), TT125-802 had a dose-dependent effect on tumor growth, inducing tumor regressions at the highest dose. Target genes such as MYC, MYB, and IRF4 were potently downregulated in tumors. We conclude that TT125-802 is a novel, highly selective inhibitor of the BRD of CBP/P300. It has therapeutic potential as monotherapy in prostate cancer and multiple myeloma and in combination with next-generation AR inhibitors for patients with lethal prostate cancer. A FIH study of TT125-802 in cancer patients is on track to start in 2023. Citation Format: Sara Laudato, Dorothea Gruber, Thomas Bohnacker, Martin Schwill, Charles-Henry Fabritius, Raquel Herrador, Katrin Westritschnig, Thushara Pattupara, Vikram Ayinampudi, Stefanie Flückiger-Mangual. TT125-802 is a potent and highly selective CBP/p300 bromodomain inhibitor for the treatment of castration resistant prostate cancer and haematological malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6268.

Abstract 3605: Peroxiredoxin IV promotes prostate cancer malignancy through the activation of NF-kB signaling

Abstract Background: The peroxiredoxin (Prx) family of proteins functions as major cellular antioxidants to maintain redox homeostasis as well as mediate oxidative signaling in both physiological and pathological conditions. Our previous studies show that Prx4 is highly expressed in prostate cancer and promotes tumor growth in vitro and in vivo. But how Prx4 contributes to prostate cancer cell invasion and metastasis remains to be elucidated. The purpose of this study is to understand the oncogenic signaling pathways that are mediated by Prx4 in prostate cancer cells. Methods: Bioinformatic analysis of existing database were used to examine the expression of Prx4 in primary and metastatic prostate cancer samples. CRISPR/Cas9 technique was used to establish Prx4 knockout in cultured human prostate cancer cell lines. Matrigel invasion assays were performed to evaluate cell migration and invasion. RNAseq was performed to examine the differences of gene expression between control and Prx4KO cells. Gene Set Enrichment Analysis (GSEA) and Gene Oncology (GO) enrichment analysis were performed using RNAseq results. RT-PCR and immunoblotting were used to validate findings from RNAseq and enrichment analysis. Results: Compared with normal prostate, transcript levels of PRDX4 are found to be upregulated in specimens of patients with prostate cancer, and those with bone metastasis show even higher levels. Knockout of Prx4 in cultured human prostate cancer cells leads to significantly reduced ability of cell migration and invasion. Gene expression profiling reveals that loss of Prx4 leads to the upregulation of epithelial as well as downregulation of mesenchymal markers, and multiple signaling pathway changes including the inhibition of cellular response to inflammatory factors such as tumor necrosis factors and interleukins. These changes are also associated with variety of cellular activities such as wound healing, interferon signaling, and antigen processing & presentation. Among known target genes downstream of NF-κB signaling, E-cadherin, vimentin and matrix metalloproteinase 14 (MMP14) were found to be significantly affected by the loss of Prx4. Therefore, Prx4 plays a critical role in human prostate cancer cell malignancy through regulation of intracellular cell signaling pathways. Conclusions: A combination of bioinformatic, cellular and molecular methods reveals that Prx4 plays a critical role in promoting prostate cancer metastasis. Prx4 is a potential therapeutic target to reduce prostate cancer metastasis. Citation Format: Na Ding, Hong Jiang, Pratik Thapa, Yanning Hao, Aziza Alshahrani, Vivek Rangnekar, Xiaoqi Liu, Qiou Wei. Peroxiredoxin IV promotes prostate cancer malignancy through the activation of NF-kB signaling. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3605.

NUSAP1 Binds ILF2 to Modulate R-Loop Accumulation and DNA Damage in Prostate Cancer.

Increased expression of NUSAP1 has been identified as a robust prognostic biomarker in prostate cancer and other malignancies. We have previously shown that NUSAP1 is positively regulated by E2F1 and promotes cancer invasion and metastasis. To further understand the biological function of NUSAP1, we used affinity purification and mass spectrometry proteomic analysis to identify NUSAP1 interactors. We identified 85 unique proteins in the NUSAP1 interactome, including ILF2, DHX9, and other RNA-binding proteins. Using proteomic approaches, we uncovered a function for NUSAP1 in maintaining R-loops and in DNA damage response through its interaction with ILF2. Co-immunoprecipitation and colocalization using confocal microscopy verified the interactions of NUSAP1 with ILF2 and DHX9, and RNA/DNA hybrids. We showed that the microtubule and charged helical domains of NUSAP1 were necessary for the protein-protein interactions. Depletion of ILF2 alone further increased camptothecin-induced R-loop accumulation and DNA damage, and NUSAP1 depletion abolished this effect. In human prostate adenocarcinoma, NUSAP1 and ILF2 mRNA expression levels are positively correlated, elevated, and associated with poor clinical outcomes. Our study identifies a novel role for NUSAP1 in regulating R-loop formation and accumulation in response to DNA damage through its interactions with ILF2 and hence provides a potential therapeutic target.

A Multi-Level Systems Biology Analysis of Aldrin’s Metabolic Effects on Prostate Cancer Cells

Although numerous studies support a dose-effect relationship between Endocrine disruptors (EDs) and the progression and malignancy of tumors, the impact of a chronic exposure to non-lethal concentrations of EDs in cancer remains unknown. More specifically, a number of studies have reported the impact of Aldrin on a variety of cancer types, including prostate cancer. In previous studies, we demonstrated the induction of the malignant phenotype in DU145 prostate cancer (PCa) cells after a chronic exposure to Aldrin (an ED). Proteins are pivotal in the regulation and control of a variety of cellular processes. However, the mechanisms responsible for the impact of ED on PCa and the role of proteins in this process are not yet well understood. Here, two complementary computational approaches have been employed to investigate the molecular processes underlying the acquisition of malignancy in prostate cancer. First, the metabolic reprogramming associated with the chronic exposure to Aldrin in DU145 cells was studied by integrating transcriptomics and metabolomics via constraint-based metabolic modeling. Second, gene set enrichment analysis was applied to determine (i) altered regulatory pathways and (ii) the correlation between changes in the transcriptomic profile of Aldrin-exposed cells and tumor progression in various types of cancer. Experimental validation confirmed predictions revealing a disruption in metabolic and regulatory pathways. This alteration results in the modification of protein levels crucial in regulating triacylglyceride/cholesterol, linked to the malignant phenotype observed in Aldrin-exposed cells.

Treatment of Prostate Cancer with CD46-targeted 225Ac Alpha Particle Radioimmunotherapy.

Radiopharmaceutical therapy is changing the standard of care in prostate cancer and other malignancies. We previously reported high CD46 expression in prostate cancer and developed an antibody-drug conjugate and immunoPET agent based on the YS5 antibody, which targets a tumor-selective CD46 epitope. Here, we present the preparation, preclinical efficacy, and toxicity evaluation of [225Ac]DOTA-YS5, a radioimmunotherapy agent based on the YS5 antibody. [225Ac]DOTA-YS5 was developed, and its therapeutic efficiency was tested on cell-derived (22Rv1, DU145), and patient-derived (LTL-545, LTL484) prostate cancer xenograft models. Biodistribution studies were carried out on 22Rv1 tumor xenograft models to confirm the targeting efficacy. Toxicity analysis of the [225Ac]DOTA-YS5 was carried out on nu/nu mice to study short-term (acute) and long-term (chronic) toxicity. Biodistribution study shows that [225Ac]DOTA-YS5 agent delivers high levels of radiation to the tumor tissue (11.64% ± 1.37%ID/g, 28.58% ± 10.88%ID/g, 29.35% ± 7.76%ID/g, and 31.78% ± 5.89%ID/g at 24, 96, 168, and 408 hours, respectively), compared with the healthy organs. [225Ac]DOTA-YS5 suppressed tumor size and prolonged survival in cell line-derived and patient-derived xenograft models. Toxicity analysis revealed that the 0.5 μCi activity levels showed toxicity to the kidneys, likely due to redistribution of daughter isotope 213Bi. [225Ac]DOTA-YS5 suppressed the growth of cell-derived and patient-derived xenografts, including prostate-specific membrane antigen-positive and prostate-specific membrane antigen-deficient models. Overall, this preclinical study confirms that [225Ac]DOTA-YS5 is a highly effective treatment and suggests feasibility for clinical translation of CD46-targeted radioligand therapy in prostate cancer.

Tropical Pyomyositis of Atypical Etiology: A Case Report

Introduction: Tropical pyomyositis is a bacterial infection of the skeletal muscle caused by Staphylococcus aureus in 90% of cases. The most predisposed patients are those who are immunocompromised. Case Report: A 58-year-old male patient with a history of malignant prostate cancer undergoing treatment with hormonal therapy and radiotherapy, went to the emergency room for presenting, 1 week prior to admission, fever of 39°C associated with pain of progressive appearance located in the supracondylar region of the right lower limb, radiating to the inguinal region, of moderate to strong intensity, of an oppressive nature, which limited the movement of the entire right lower limb. After multiple negative tests, an MRI of the abdomen, pelvis, and lower limbs reported myositis of infectious etiology. From there, the relevant antibiotic treatment was indicated, and an ultrasound-guided biopsy of the iliopsoas muscle was performed, which reported Streptococcus agalactiae resistant to ampicillin and penicillin as the responsible pathogen. The evolution of the patient was favorable. Conclusions: Tropical pyomyositis is a disease little known by the medical community, which makes early diagnosis difficult. Immunosuppression plays an important role in its pathogenesis, so a thorough investigation must be carried out to exclude multiple predisposing conditions.

Prostate Cancer Morphologies: Cribriform Pattern and Intraductal Carcinoma Relations to Adverse Pathological and Clinical Outcomes—Systematic Review and Meta-Analysis

The present study aimed to assess the association between the cribriform pattern (CP)/intraductal carcinoma (IDC) and the adverse pathological and clinical outcomes in the radical prostatectomy (RP) cohort. A systematic search was performed according to the Preferred Reporting Items for Systematic Review and Meta-Analysis statement (PRISMA). The protocol from this review was registered on the PROSPERO platform. We searched PubMed®, the Cochrane Library and EM-BASE® up to the 30th of April 2022. The outcomes of interest were the extraprostatic extension (EPE), seminal vesicle invasion (SVI), lymph node metastasis (LNS met), risk of biochemical recurrence (BCR), distant metastasis (MET) and disease-specific death (DSD). As a result, we identified 16 studies with 164 296 patients. A total of 13 studies containing 3254 RP patients were eligible for the meta-analysis. The CP/IDC was associated with adverse outcomes, including EPE (pooled OR = 2.55, 95%CI 1.23-5.26), SVI (pooled OR = 4.27, 95%CI 1.90-9.64), LNs met (pooled OR = 6.47, 95%CI 3.76-11.14), BCR (pooled OR = 5.09, 95%CI 2.23-11.62) and MET/DSD (pooled OR = 9.84, 95%CI 2.75-35.20, p < 0.001). In conclusion, the CP/IDC belong to highly malignant prostate cancer patterns which have a negative impact on both the pathological and clinical outcomes. The presence of the CP/IDC should be included in the surgical planning and postoperative treatment guidance.

Impact of umbilical cord mesenchymal stromal/stem cell secretome and cord blood serum in prostate cancer progression

Prostate cancer (PCa) is the second most common malignancy in men, and the fifth leading cause of death worldwide. Mesenchymal stromal/stem cells (MSC) have been identified in PCa, although contradictory effects in malignant transformation and tumor progression have been described. Since umbilical cord (UC) MSC and cord blood serum (CBS) are rich in numerous growth and anti-inflammatory factors, UC-MSC secretome and CBS are able to modulate tumor cell proliferation and survival as well as immunity and angiogenesis. In the present study, we address this relationship and investigate the influence of UC-MSC secretome and CBS on two human PCa cell lines (PC3 and LNCaP) and a normal epithelial prostate cell line (HPEpiC). Our results disclosed that upon exposure to UC-MSC-conditioned medium or CBS, both PC3 and LNCaP cells exhibited reduced viability, proliferation, and motility while non-malignant epithelial prostate cells were unaffected. These findings were corroborated by expression analysis of AKT/PI3K signaling pathway, p53 and interleukin genes. UC-MSC and CBS factors decreased the expression of growth-stimulating AKT and PI3K effectors and simultaneously up-regulated the expression of tumor-suppressor p53. Moreover, a more anti-inflammatory expression profile was found in both malignant PCa cell lines. Altogether, these results shed light into possible mechanisms by which UC-MSC and CBS reduce PCa progression, further reinforcing their potential use as novel therapeutic agents in PCa.Graphical abstract

Hypoxia promotes conversion to a stem cell phenotype in prostate cancer cells by activating HIF-1α/Notch1 signaling pathway.

The hypoxic tumor microenvironment and the maintenance of stem cells are relevant to the malignancy of prostate cancer (PCa). However, whether HIF-1α in the hypoxic microenvironment mediates the transformation of prostate cancer to a stem cell phenotype and the mechanism have not been elucidated. Prostate cancer stem cells (PCSCs) from PC-3 cell lines were examined for the expression of CD44, CD133, ALDH1, HIF-1α, Notch1, and HES1. We observed the effect of knockdown HIF-1α in vitro and mice models and evaluated the impact of HIF-1α on the Notch1 pathway as well as stem cell dedifferentiation. The effects on sphere formation, cell proliferation, apoptosis, cell cycle, and invasive metastasis were evaluated. In our study, hypoxia upregulated HIF-1α expression and induced a stem cell phenotype through activation of the Notch1 pathway, leading to enhanced proliferation, invasion, and migration of PCa PC-3 cells. The knockdown of HIF-1α significantly inhibited cell dedifferentiation and the ability to proliferate, invade and metastasize. However, the inhibitory effect of knocking down HIF-1α was reversed by Jagged1, an activator of the Notch1 pathway. These findings were further confirmed in vivo, where hypoxia could enhance the tumorigenicity of xenograft tumors by upregulating the expression of HIF-1α to activate the Notch1 pathway. In addition, the expression of HIF-1α and Notch1 was significantly increased in human PCa tissues, and high expression of HIF-1α correlated with the malignancy of PCa. In a hypoxic environment, HIF-1α promotes PCa cell dedifferentiation to stem-like cell phenotypes by activating the Notch1 pathway and enhancing the proliferation and invasive capacity of PC-3 cells.

Ongoing phase II study of EZH2 inhibitor CPI-0209 in patients with advanced solid tumors including metastatic castration-resistant prostate cancer (mCRPC) or hematologic malignancies

Ongoing phase II study of EZH2 inhibitor CPI-0209 in patients with advanced solid tumors including metastatic castration-resistant prostate cancer (mCRPC) or hematologic malignancies

Immunological analysis of Interleukin-10 (IL-10), tumor necrosis factor-a (TNF-a), and Prostate-specific antigen (PSA) in benign and malignant prostate cancer.

Among the cancers that impacts men, prostate cancer considerably raises deaths for males around the world. Persons with tumours can have a localized or advanced form of the illness. The present study aimed to determining the relationship between the level of cytokines (IL-10 and TNF-a) and PSA in the sera of patients and compared it with healthy. A case control study consist of three group included was in this study. The first group involves 50 patients with PC were observation in Al-Amal Oncology Hospital in the period from April 2021 to April 2022 under the supervision of oncology specialists was included in this study. Second group consist of 30 patients. They have benign hyper plaisa (BHP), this group has been collected from urosergical department . Third group was include 20 healthy volunteers (non prostate cancer and non BHP). Prostate specific antigen (PSA) was measured by mini- VIDAS device using kit supplied by Biomerieux- France. IL-10 and TNF-a levels were measured by ELISA technique using kit supplied by CAUSABIO- China. Results of the present study showed the 60-69 years age group scored highest percentage in benign (56.7%), malignant (54.0%), compared to control (healthy) (50.0%), while > 69 years scored least percentage in these groups (3.3%, 14.0%, and 25.0%) respectively with significant different (p< 0.05). Additionally, the IL-10 and PSA scored highest mean levels in the malignant group (1.22 ± 0.23 and 27.66 ± 6.31), while TNF-a scored highest mean levels in a benign group (0.30 ± 0.11). The least mean level of IL-10 was in healthy (0.42 ± 0.15), TNF-a in malignant (0.23 ± 0.03), and PSA in benign (6.73 ± 1.36). Finally, there is a significant difference among age groups and PSA, IL-10, and TNF-parameters. We concluded the PSA, TNF-a and IL-10 parameters are play important roles in pathogenesis patients with prostate cancer. PCa is high prevalence in elderly population.

MiR-182 Is Upregulated in Prostate Cancer and Contributes to Tumor Progression by Targeting MITF.

Altered expression of microRNA-182-5p (miR-182) has been consistently linked with many cancers, but its specific role in prostate cancer remains unclear. In particular, its contribution to epithelial-to-mesenchymal transition (EMT) in this setting has not been well studied. Therefore, this paper profiles the expression of miR-182 in prostate cancer and investigates how it may contribute to progression of this disease. In vitro experiments on prostate cancer cell lines and in silico analyses of The Cancer Genome Atlas (TCGA) prostate adenocarcinoma (PRAD) datasets were performed. PCR revealed miR-182 expression was significantly increased in prostate cancer cell lines compared to normal prostate cells. Bioinformatic analysis of TCGA PRAD data similarly showed upregulation of miR-182 was significantly associated with prostate cancer and clinical markers of disease progression. Functional enrichment analysis confirmed a significant association of miR-182 and its target genes with EMT. The EMT-linked gene MITF (melanocyte inducing transcription factor) was subsequently shown to be a novel target of miR-182 in prostate cancer cells. Further TCGA analysis suggested miR-182 expression can be an indicator of patient outcomes and disease progression following therapy. In summary, this is the first study to report that miR-182 over-expression in prostate cancer may contribute to EMT by targeting MITF expression. We propose miR-182 as a potentially useful diagnostic and prognostic biomarker for prostate cancer and other malignancies.

METCAM Is a Potential Biomarker for Predicting the Malignant Propensity of and as a Therapeutic Target for Prostate Cancer.

Prostate cancer is the second leading cause of cancer-related death worldwide. This is because it is still unknown why indolent prostate cancer becomes an aggressive one, though many risk factors for this type of cancer have been suggested. Currently, many diagnostic markers have been suggested for predicting malignant prostatic carcinoma cancer; however, only a few, such as PSA (prostate-specific antigen), Prostate Health Index (PHI), and PCA3, have been approved by the FDA. However, each biomarker has its merits as well as shortcomings. The serum PSA test is incapable of differentiating prostate cancer from BPH and also has an about 25% false-positive prediction rate for the malignant status of cancer. The PHI test has the potential to replace the PSA test for the discrimination of BPH from prostate cancer and for the prediction of high-grade cancer avoiding unnecessary biopsies; however, the free form of PSA is unstable and expensive. PCA3 is not associated with locally advanced disease and is limited in terms of its prediction of aggressive cancer. Currently, several urine biomarkers have shown high potential in terms of being used to replace circulating biomarkers, which require a more invasive method of sample collection, such as via serum. Currently, the combined multiple tumor biomarkers may turn out to be a major trend in the diagnosis and assessment of the treatment effectiveness of prostate cancer. Thus, there is still a need to search for more novel biomarkers to develop a perfect cocktail, which consists of multiple biomarkers, in order to predict malignant prostate cancer and follow the efficacy of the treatment. We have discovered that METCAM, a cell adhesion molecule in the Ig-like superfamily, has great potential regarding its use as a biomarker for differentiating prostate cancer from BPH, predicting the malignant propensity of prostate cancer at the early premalignant stage, and differentiating indolent prostate cancers from aggressive cancers. Since METCAM has also been shown to be able to initiate the spread of prostate cancer cell lines to multiple organs, we suggest that it may be used as a therapeutic target for the clinical treatment of patients with malignant prostate cancer.

Over-expression of Long Non-coding RNA Urothelial Cancer-associated 1 as a Predictive Marker for Prostate Cancer.

To determine the expression of long non-coding RNA urothelial cancer-associated 1 (UCA1) by performing array-based quantitative polymerase chain reaction (PCR) and to identify the clinicopathological significance of UCA1 expression in prostate cancer using in situ hybridization (ISH) of surgically resected specimens. Array-based quantitative PCR was performed using 10 pairs of fresh malignant (prostate cancer) and normal tissue samples to determine UCA1 expression. Single-color RNA ISH of surgically resected prostate cancer specimens was performed using 70 formalin-fixed, paraffin-embedded tissue specimens to examine the clinicopathological significance of UCA1. Prostate cancer tissues exhibited higher levels of UCA1 expression than paired benign tissues. Furthermore, a correlation between high UCA1 expression and unfavourable clinicopathological characteristics, including advanced pathologic T stage, extraprostatic extension, presence of Gleason pattern 5, and involvement of the resection margins was observed. Notably, increased UCA1 expression significantly correlated with high- or very-high-risk patients, as defined by the 2023 National Comprehensive Cancer Network guidelines. UCA1 could be used as a novel diagnostic and prognostic biomarker for establishing an effective treatment protocol for prostate cancer.

POLYAMINES IN PROSTATE CANCER: THE RELATIONSHIP WITH THE AGGRESSIVENESS OF TUMORS AND THE RISK OF DISEASE PROGRESSION

Summary. Altered metabolism is one of the key molecular characteristics of prostate cancer (PCa). The search for new tissue biomarkers that could be used for diagnosis, assessment of aggressiveness and risk of progression of PCa is an urgent problem. In this regard, polyamines (PA) — spermine (Spn), spermidine, putrescine — substances necessary for cell proliferation and growth deserve special attention. Aim: to investigate PA levels in postoperative and biopsy specimens of benign and malignant human prostate tumors to determine the potential for their use for more accurate differential diagnosis, assessment of the aggressiveness of PCa and the risk of disease progression. Object and methods: the study was conducted on 120 postoperative samples from patients with PCa (n = 100) and with benign prostatic hyperplasia (BHP, n = 20), as well as on 40 samples obtained in multifocal trepanbiopsy of prostate (20 samples of malignant tissue and 20 samples of benign tumor tissue). The method of highperformance liquid chromatography (HPLC) was used to determine PA. Statistical processing of the results was carried out by the methods of variational statistics using standard licensed computer programs STATISTICA 6.0, Microsoft Excel. The significance of the differences between indicators in different groups was assessed using the Student’s t-test. Differences were considered significant at p &lt; 0.05. Spearman’s correlation coefficients were calculated to identify correlative relationships between the studied indicators. Results: it was established that in prostatic hyperplasia, PA levels are significantly higher than those in malignant tumors of the prostate. The most significant difference between PCa and BHP was observed for Spn. The relationship between the level of Spn and the histological evaluation of the differentiation of the PCa according to the Gleason Score and the risk of disease progression was established. Conclusions: the inverse relationship of Spn levels with the degree of differentiation of tumors according to the Gleason Score and the risk of disease progression indicate the participation of spermine in the formation of the aggressiveness of prostate cancer and demonstrate the perspective of its use as an additional tissue marker for the differential diagnosis of prostate tumors, assessment of the malignancy of prostate cancer and the risk of disease progression.

BLM promotes malignancy in PCa by inducing KRAS expression and RhoA suppression via its interaction with HDGF and activation of MAPK/ERK pathway.

Prostate cancer (PCa) has long been the leading cause of cancer-associated deaths among male worldwide. Our previous studies have shown that Bloom syndrome protein (BLM) plays a vital role in PCa proliferation, yet the underlying molecular mechanism remains largely obscure. Mechanistically, BLM directly interacted with hepatoma-derived growth factor (HDGF). Functionally, BLM and HDGF knockdown resulted in the higher impairment of PC3 proliferation, clonogenicity, migration and invasion than that their counterpart with either BLM or HDGF knockdown exclusively. Of note, HDGF overexpression expedited, whereas its knockdown suppressed, PC3 proliferation, clonogenicity, migration and invasion. Additionally, the potentiation or attenuation was partially antagonized upon BLM depletion or overexpression. In line with the vitro data, the impact of BLM and HDGF on tumor growth was investigated in mouse xenograft models. ChIP-seq, dual-luciferase reporter and western blotting assays were employed to expound the regulatory network in PC3 cells. The results unveiled that HDGF activated KRAS and suppressed RhoA transcription, and that the function of HDGF was mediated, in part, by interaction with BLM. Accordingly, the MAPK/ERK pathway was activated. Moreover, the regulation of HDGF on KRAS and RhoA had a signal crosstalk. To recapitulate, BLM and HDGF may serve as novel prognostic markers and potential therapeutic targets in PCa.

Prostate cancer malignancy detection and localization from mpMRI using auto-deep learning as one step closer to clinical utilization

Automatic diagnosis of malignant prostate cancer patients from mpMRI has been studied heavily in the past years. Model interpretation and domain drift have been the main road blocks for clinical utilization. As an extension from our previous work we trained on a public cohort with 201 patients and the cropped 2.5D slices of the prostate glands were used as the input, and the optimal model were searched in the model space using autoKeras. As an innovative move, peripheral zone (PZ) and central gland (CG) were trained and tested separately, the PZ detector and CG detector were demonstrated effective in highlighting the most suspicious slices out of a sequence, hopefully to greatly ease the workload for the physicians.

Dual attention guided multiscale neural network trained with curriculum learning for noninvasive prediction of Gleason Grade Group from MRI.

The Gleason Grade Group (GG) is essential in assessing the malignancy of prostate cancer (PCa) and is typically obtained by invasive biopsy procedures in which sampling errors could lead to inaccurately scored GGs. With the gradually recognized value of bi-parametric magnetic resonance imaging (bpMRI) in PCa, it is beneficial to noninvasively predict GGs from bpMRI for early diagnosis and treatment planning of PCa. However, it is challenging to establish the connection between bpMRI features and GGs. In this study, we propose a dual attention-guided multiscale neural network (DAMS-Net) to predict the 5-scored GG from bpMRI and design a training curriculum to further improve the prediction performance. The proposed DAMS-Net incorporates a feature pyramid network (FPN) to fully extract the multiscale features for lesions of varying sizes and a dual attention module to focus on lesion and surrounding regions while avoiding the influence of irrelevant ones. Furthermore, to enhance the differential ability for lesions with the inter-grade similarity and intra-grade variation in bpMRI, the training process employs a specially designed curriculum based on the differences between the radiological evaluations and the ground truth GGs. Extensive experiments were conducted on a private dataset of 382 patients and the public PROSTATEx-2 dataset. For the private dataset, the experimental results showed that the proposed network performed better than the plain baseline model for GG prediction, achieving a mean quadratic weighted Kappa (Kw ) of 0.4902 and a mean positive predictive value of 0.9098 for predicting clinically significant cancer (PPVGG>1 ). With the application of curriculum learning, the mean Kw and PPVGG>1 further increased to 0.5144 and 0.9118, respectively. For the public dataset, the proposed method achieved state-of-the-art results of 0.5413 Kw and 0.9747 PPVGG>1 . The proposed DAMS-Net trained with curriculum learning can effectively predict GGs from bpMRI, which may assist clinicians in early diagnosis and treatment planning for PCa patients.

Identification of protein kinase C beta as a therapeutic target for neuroendocrine prostate cancer and development of a nanoparticle-based therapeutic strategy

Neuroendocrine prostate cancer (NEPC) is a highly aggressive subtype of malignant prostate cancer for which there is no effective treatment. Although protein kinases are the most attractive therapeutic targets for cancer treatment, there are no clear kinase-targeted drugs available for NEPC treatment. Herein, we showed that protein kinase C beta (PKCβ) is highly expressed in NEPC and can be transcriptionally activated by c-Myc through the E-box elements present in its promoter region. Furthermore, PKCβ can activate PIM1 kinase by phosphorylating Ser51 and Ser54, which in turn stabilizes and enhances c-Myc function. Three formed a PIM1-c-Myc-PKCβ positive feedback loop to promote the progression of NEPC. Enzastaurin, a specific inhibitor of PKCβ, significantly ameliorated NEPC. However, enzastaurin causes thrombus and other side effects in several clinical trials of other diseases, which greatly limits its clinical application. To address these problems, we developed a functional polymer nanoparticle modified with SSTR2-targeted octreotide and a thrombin-binding aptamer to deliver enzastaurin for NEPC treatment. The tailor-designed nanomedicine efficiently retards tumor growth and the incidence of coagulation abnormalities in vitro and in vivo. Collectively, our findings highlight the key role of PKCβ in NEPC and provide a promising nanoparticle-based therapeutic strategy for the treatment of NEPC.

Evaluation of a radiomics nomogram derived from Fluoride-18 PSMA-1007 PET/CT for risk stratification in newly diagnosed prostate cancer.

The aim of this study was to evaluate the performance of Fluoride-18 (18F)-PSMA-1007-PET/CT radiomics for the tumor malignancy and clinical risk stratification in primary prostate cancer (PCa). A total of 161 pathological proven PCa patients in a single center were retrospectively analyzed. Prostate-specific antigen (PSA), Gleason Score (GS) and PET/CT indexes (SUVmin, SUVmax, and SUVmean) were compared according to risk stratification. Radiomics features were extracted from PCa 18F-PSMA-1007-PET/CT imaging. The radiomics score integrating all selected parameters and clinicopathologic characteristics was used to construct a binary logistic regression and nomogram classifier. Predictors contained in the individualized prediction nomogram included radiomics score, PSA level and metastasis status. The radiomics signature, which consisted of 30 selected features, was significantly associated with PSA level and Gleason score (P < 0.001 for both primary and validation cohorts). Predictors contained in the individualized prediction nomogram included radiomics score, PSA level and metastasis status. The model showed good discrimination with an area under the ROC curve of 0.719 for the GS. Combined clinical-radiomic score nomogram had a similar benefit to utilizing the PET/CT radiomic features alone for GS discrimination. The 18F-PSMA-1007-PET/CT radiomics signature can be used to facilitate preoperative individualized prediction of GS; incorporating the radiomics signature, PSA level, and metastasis status had similar benefits to those of utilizing the PET/CT radiomics features alone.