Hormone-resistant Prostate Cancer Research Articles

Inhibition of the sterol regulatory element binding protein (SREB-P) SREBF-1 overcomes docetaxel resistance in advanced prostate cancer.

Resistance to anti-androgens and chemotherapy (Cx) limits therapeutic options for patients with hormone-sensitive (mHSPC) and hormone-resistant prostate cancer (mCRPC). In this context, upregulation of the glucocorticoid receptor (GR) has been identified as a potential bypass mechanism in mCRPC, and a combination of docetaxel and mifepristone (Doc + RU-486), an inhibitor of GR, re-sensitized docetaxel-resistant cell models to Cx. This study was designed to elucidate the molecular mechanisms responsible for this phenomenon. RNA sequencing (RNA-seq) in docetaxel-resistant PCa cell models after Doc + RU-486 treatment with consecutive functional assays were performed. Expression of selected proteins was verified in prostatic tissue from prostate cancer (PCa) patients with progressive disease. Treatment with Doc + RU-486 significantly reduced cancer cell viability and RNA-Seq. revealed sterol regulatory element of binding transcription factor 1 (SREBF-1), a transcription factor of cholesterol and lipid biosynthesis, as a significantly downregulated target. Functional assays confirmed that SREBF-1 downregulation is partially responsible for this observation. In concordance, SREBF-1 knockdown and pharmacological SREBP inhibition, together with other key enzymes in the cholesterol pathway, showed similar results. Furthermore, SREBF-1 expression is significantly elevated in advanced PCa tissues, demonstrating its potential involvement in tumor progression and emerging therapy resistance. Therefore, specific inhibition of cholesterol and lipid biosynthesis might also target Cx-resistant cancer cells and represent a potential additive future therapeutic option to improve mCRPC therapy.

Comparative efficacy of radical prostatectomy and radiotherapy in the treatment of high-risk prostate cancer.

Both radical prostatectomy and radiation therapy are effective in controlling the condition of patients with hormone-resistant prostate cancer (HRPCa). However, there is limited research on the prognosis and quality of life of HRPCa patients after different treatment modalities. To explore the efficacy of radical prostatectomy (RP) and radiotherapy (RT), when treating high-risk prostate cancer (HRPCa). Overall 103 HRPCa patients were included and were divided into RP group and RT group according to different treatment methods. The propensity score matching method (PSM) was used to balance the baseline data of the two groups and match 34 patients in each group. The prognosis, quality of life, and basic efficacy of patients were compared. After intervention, the disease-free survival rate of the RT group was higher than that of the RP group (79.41% vs. 55.88%, p= 0.038). Quality of life scores between the two treatment methods had no difference before intervention (p> 0.05), but higher in RT group than that of the RP group after intervention (p< 0.05). After treatment, there was no statistically significant difference in total effective rate of treatment between two groups (44.12% vs. 58.82%, p> 0.05), but the disease control rate was significantly higher in RT group (94.12% vs. 76.47%, p= 0.040). Radical radiotherapy is effective in the clinical treatment of HRPCa patients, with a higher disease-free survival rate and improved quality of life after treatment, and is worth promoting.

Novel TROP2-targeted CAR T cells with high specificity and sustained efficacy for solid tumors in animal models.

e14563 Background: CAR T cell therapy, successful in hematological malignancies, encounters challenges against solid tumors due to immune exhaustion and senescence within the tumor microenvironment. The imperative need for an optimal tumor target antigen is evident in advancing CAR T therapy. TROP2, a membrane-associated glycoprotein, is highly expressed in diverse cancers, including cervical, bladder, esophageal, ovarian, and endometrial cancers. TROP2 overexpression, approaching 100% in cervical and hormone-resistant prostate cancer, correlates inversely with prognosis and survival, presenting TROP2 as a promising CAR T therapy target. This study engineered the novel TROP2 antibody R4702, featuring a distinct binding epitope from Sacituzumab and Datopotamab, to develop TROP2-specific CAR T cells and evaluated their efficacy against a spectrum of solid tumors. Methods: Expansion of CAR T Cells and Cytotoxicity: CAR T cells were created through lentivirus-mediated genetic engineering with the TROP2 antibody, followed by 10 days of expansion. T cell differentiation was evaluated, and luciferase-encoding target cells incubated with varying CAR T cell ratios overnight were quantified luciferase activity. In Vivo Efficacy and Persistence: CAR T cells were adoptively transferred into ASID mice with tumors. In vivo tumor imaging used luciferase activity, and calipers monitored tumor size weekly. CAR T cell persistence assessed their ability to suppress rechallenged tumor growth. Results: R4702, a novel TROP2-specific antibody, displayed high binding affinity to a distinct epitope. Post- ex vivo expansion, R4702 CAR T cells showed a substantial increase (100 to 200-fold) over 10 days, with a high expression level (50~80%) of R4702 CAR on T cells. Over 60% of R4702 CAR T cells displayed a less differentiated status, characterized by a CD62L+ population comprising TSCM and TCM. In vitro cytotoxicity revealed potent and specific efficacy against various TROP2-positive cancer cell lines, with no observed killing activity against TROP2-negative cells. In vivo efficacy of R4702 CAR T cells demonstrated 100% tumor growth inhibition within 30 days post-treatment across diverse xenograft models. Importantly, R4702 CAR T cells exhibited enduring anti-tumor efficacy against successive tumor challenges in xenograft models of pancreatic, gastric, NSCLC, TNBC, and ovarian cancers. In a head-to-head comparison with Sacituzumab and Datopotamab CAR T, R4702 demonstrated superior anti-tumor efficacy to Sacituzumab and comparable efficacy with Datopotamab in the BxPC-3 CDX model of pancreatic cancer. Conclusions: A novel TROP2-specific R4702 CAR T cell, developed, showcased robust tumor-killing capabilities. The anti-tumor activity persisted upon repeated tumor challenges across various xenograft models, underscoring the potential of R4702 CAR T cells as a promising therapeutic strategy.

EFFECT OF SPERMININE AND ITS COMBINATION WITH SPERMINOXIDASE INHIBITORS ON THE PROFILE OF POLYAMINE AND SURVIVAL OF HUMAN PROSTATE CANCER CELLS

Summary. Aim: to investigate the effect of spermine (Spn) and spermine oxidase inhibitors (SMO) and their effect in combination on the polyamine profile in human PCa cell lines and to compare the nature of polyamine changes with tumor cell viability. Object and methods: the study was performed on cell cultures of hormone-sensitive (LNCaP) and hormone-resistant (DU-145) cell lines. The profile of polyamines in tumor cells and the activities of spermine oxidase and polyamine oxidase (PAO) were determined by high-performance liquid chromatography. Results: the addition of Spn to the culture medium causes a significant accumulation of this polyamine in cells, a decrease in putrescine (Put) and spermidine (Spd). The use of SMO inhibitors (chlorhexidine and MDL-72527) is accompanied by a decrease in Spd levels and accumulation of acetylated spermidine (AcSpd). The use of Spn leads to a decrease in the proliferation rate — the molar ratio of spermidine/spermine (Spd/Spn). Particularly low values of the Spd/Spn ratio were observed when spermine was used in combination with SMO inhibitors. When Spn was used in combination with SMO inhibitors, the lowest cell viability rates were also observed, indicating a more effective inhibition of cell growth with the combined use of these factors compared to their use separately, even in significantly higher concentrations. The use of chlorhexidine and chlorhexidine together with spermine led to a decrease in the activity of SMO and PAO. Conclusions: the use of spermine and spermine in combination with SMO inhibitors leads to changes in the polyamine profile in tumor cells characteristic of growth inhibition (decrease in Spd, Put and increase in Spn) and a decrease in the molar ratio Spd/Spn. These changes are accompanied by a decrease in the survival of cells of hormone-sensitive (LNCaP) and hormone-resistant (DU-145) human prostate cancer lines. The obtained results show the prospects for further study of spermine and its combination with SMO inhibitors as potential agents for the treatment of prostate cancer.

Calcium Activation of the Androgen Receptor in Prostate Cells.

Although prostate cancer patients initially respond to androgen deprivation therapy, most patients progress to a resistant phenotype. Castration resistance is due, in part, to intratumoral and/or adrenal synthesis of androgens, overexpression or mutation of the androgen receptor (AR), stabilization of AR by chaperones, and ligand-independent activation of AR. Increasing evidence also links disruption of calcium homeostasis to progression of prostate cancer. Our previous study shows that heavy metal cadmium activates the AR through a ligand-independent mechanism. Cadmium mimics calcium in biological systems due to their similar ionic charge and radius. This study determines whether calcium activates AR and whether first- and second-generation antiandrogens block the ability of calcium to activate the receptor. The expression of androgen-responsive genes and calcium channels was measured in prostate cells using a quantitative real-time polymerase chain reaction assay. Cell growth was measured. To ask whether calcium activates AR, prostate cells were treated with calcium in the absence and presence of the first-generation antiandrogens hydroxyflutamide and bicalutamide and the second-generation antiandrogen enzalutamide, and the expression of androgen-responsive genes and cell growth was measured. In the normal PWR-1E cells and HEK293T cells transiently expressing AR, treatment with calcium increased the expression of androgen-responsive genes by approximately 3-fold. The increase was blocked by enzalutamide but was not consistently blocked by the first-generation antiandrogens. In LNCaP cells which contain a mutant AR, treatment with calcium also increased the expression of androgen-responsive genes by approximately 3-fold, and the increase was more effectively blocked by enzalutamide than by hydroxyflutamide or bicalutamide. Treatment with calcium also increased cell growth that was blocked by enzalutamide. To ask whether dysregulation of calcium channels is associated with castration resistance, calcium channels were measured in the normal PWR-1E prostate cells, the hormone-responsive LNCaP cells, and the castration-resistant VCaP and 22RV1 cells. Compared to normal prostate cells, the hormone-responsive and hormone-resistant cells overexpressed several calcium channels. The results of this study show that calcium activates AR and increases cell growth and that calcium channels are overexpressed in hormone-responsive and hormone-resistant prostate cancer cells. Taken together, the results suggest a novel role of calcium in the castration-resistant phenotype.

SURVIVAL ANALYSIS OF PATIENTS DIAGNOSED WITH METASTATIC PROSTATE CANCER IN 2008-2016

Background and objectives. Prostate cancer is the second most common cancer diagnosis made in men. Given that 2,293,818 new cases are expected worldwide by 2040, it is important to conceptualize the disease and primary stage of cancer, distant metastases, testosterone concen­tration, and previous treatments help to understand and predict this disease. The aim of the study is to determine the impact of pro­gnostic factors, comorbidities and systematic treatment on the survival of patients with metastatic prostate cancer. Material and Methods. It is a retrospective analysis of data from 76 patients treated for metastatic prostate cancer (C61) at the Afiliate of Lithuanian University of Health Sciences Kaunas Oncology Hospital between 2008 and 2016. The following data were collected: age of patients, date of diagnosis, clinical stage of diagno­sis (cTNM), baseline PSA level (at diagnosis), Gleason score, treatment method used, localization of metastases, the period during which resistance to hormonal therapy developed, date of death. The date of diagnosis was con­sidered to be the date on which the prostate carcinoma was confirmed by histological examination. The data obtained in the study were analyzed using the programs IBM SPSS v28.0. Results. A statistically significant correlation was found between the dependence of patient survival time and tumor differentiation grade (p=0.041) , the Charlson Comorbidity Index (p&lt;0,001), treatment method used in prostate cancer unresponsive to hormone therapy (p=0.049), location of metastases (p=0.021), the time during which resistance to hormone therapy developed (p&lt;0.001). Conclusions. The risk of dying from prostate cancer de­pends on the period during which resistance to hormone therapy has developed and the Charlson comorbidity index. The higher the Charlson comorbidity index, the lower the survival rate. In patients with hormone-sen­sitive prostate cancer, the choice of treatment does not affect survival, and in patients with hormone-resistant prostate cancer, survival is prolonged by treatment with abiraterone acetate.

Cholesterol biogenesis is a PTEN-dependent actionable node for the treatment of endocrine therapy-refractory cancers.

PTEN and PIK3CA mutations are the most prevalent PI3K pathway alterations in prostate, breast, colorectal, and endometrial cancers. p110β becomes the prominent PI3K isoform upon PTEN loss. In this study, we aimed to understand the molecular mechanisms of PI3K dependence in the absence of PTEN. Using online bioinformatical tools, we examined two publicly available microarray datasets with aberrant PI3K activation. We found that the rate-limiting enzyme of cholesterol biogenesis, SQLE, was significantly upregulated in p110β-hyperactivated or PTEN-deficient mouse prostate tumors. Concomitantly, the expression of cholesterol biosynthesis pathway enzymes was directly correlated with PI3K activation status in microarray datasets and diminished upon PTEN re-expression in PTEN-null prostate cancer cells. Particularly, PTEN re-expression decreased SQLE protein levels in PTEN-deficient prostate cancer cells. We performed targeted metabolomics and detected reduced levels of cholesteryl esters as well as free cholesterol upon PTEN re-expression. Notably, PTEN-null prostate and breast cancer cell lines were more sensitive to pharmacological intervention with the cholesterol pathway than PTEN-replete cancer cells. Since steroid hormones use sterols as structural precursors, we studied whether cholesterol biosynthesis may be a metabolic vulnerability that enhances antihormone therapy in PTEN-null castration-resistant prostate cancer cells. Coinhibition of cholesterol biosynthesis and the androgen receptor enhanced their sensitivity. Moreover, PTEN suppression in endocrine therapy-resistant luminal-A breast cancer cells leads to an increase in SQLE expression and a corresponding sensitization to the inhibition of cholesterol synthesis. According to our data, targeting cholesterol biosynthesis in combination with the hormone receptor signaling axis can potentially treat hormone-resistant prostate and breast cancers.

Narirutin. A flavonoid found in citrus fruits modulates cell cycle phases and inhibits the proliferation of hormone-refractory prostate cancer cells by targeting hyaluronidase.

Narirutin is a dietary flavanone found in lemons, oranges, passion fruit, bergamot and grapefruit. It possesses anti-allergic, cardioprotective, neuroprotective, hepatoprotective potential, and its enriched fraction suppresses the growth of prostate cancer cells; however, there is currently no information on the chemopreventive potential of narirutin alone against hormone-refractory prostate cancer cells (PC-3) and its mode of action. Thus, the chemopreventive possibility of narirutin was investigated in PC-3cells by utilising cytotoxicity assays. Further, a mechanism was deduced targeting hyaluronidase, an early-stage diagnosis marker, by cell-free, cell-based and in silico studies. The results indicate that narirutin reduced the viability of PC-3cells with the inhibitory concentration range of 66.87-59.80μM. It induced G0/G1 phase arrest with a fold change of 1.12. Besides, it increased the generation of reactive oxygen species (ROS) with a fold change of 1.34at 100μM. Narirutin inhibited hyaluronidase's activity in cell-free (11.17μM) and cell-based assays (67.23μM) and showed a strong binding interaction with hyaluronidase. Finally, the MD simulation analysis supported the idea that narirutin binding enhanced compactness and stability and created a stable complex with hyaluronidase. In addition, ADMET prediction indicates that it is a non-toxic, non-CYPs inhibitor and thus didn't alter the metabolism. The results reveal that narirutin may be a potential chemopreventive agent for hormone-resistant prostate cancer cells in addition to offering data for supporting diet-based nutraceutical agents to prevent prostate cancer.

The Case | Hematuria, proteinuria, and renal insufficiency in metastatic prostate cancer

A 75-year-old man with metastatic hormone-resistant prostate cancer and well-controlled hypertension on amlodipine presented with lower limb swelling for 2 weeks. Two years before presentation, he had surgical resection of a destructive bony metastasis in the right innominate bone, followed by stereotactic whole-body radiation therapy and anti-androgen and gonadotropin-releasing hormone antagonists. Despite an 8-month course of prostate-specific membrane antigen (PSMA)–targeted radioligand therapy with 177Lu-PSMA (total 1154 mCi over 6 doses) that was completed 2 months before presentation, the cancer remained progressive.

Glucose-Functionalized Silver Nanoparticles as a Potential New Therapy Agent Targeting Hormone-Resistant Prostate Cancer cells.

PurposeSilver nanoparticles (AgNPs) have shown great potential as anticancer agents, namely in therapies’ resistant forms of cancer. The progression of prostate cancer (PCa) to resistant forms of the disease (castration-resistant PCa, CRPC) is associated with poor prognosis and life quality, with current limited therapeutic options. CRPC is characterized by a high glucose consumption, which poses as an opportunity to direct AgNPs to these cancer cells. Thus, this study explores the effect of glucose functionalization of AgNPs in PCa and CRPC cell lines (LNCaP, Du-145 and PC-3).MethodsAgNPs were synthesized, further functionalized, and their physical and chemical composition was characterized both in water and in culture medium, through UV-visible spectrum, dynamic light scattering (DLS), transmission electron microscopy (TEM) and Fourier-transform infrared spectroscopy (FTIR). Their effect was assessed in the cell lines regarding AgNPs’ entering pathway, cellular proliferation capacity, ROS production, mitochondrial membrane depolarization, cell cycle analysis and apoptosis evaluation.ResultsAgNPs displayed an average size of 61nm and moderate monodispersity with a slight increase after functionalization, and a round shape. These characteristics remained stable when redispersed in culture medium. Both AgNPs and G-AgNPs were cytotoxic only to CRPC cells and not to hormone-sensitive ones and their effect was higher after functionalization showing the potential of glucose to favor AgNPs’ uptake by cancer cells. Entering through endocytosis and being encapsulated in lysosomes, the NPs increased the ROS, inducing mitochondrial damage, and arresting cell cycle in S Phase, therefore blocking proliferation, and inducing apoptosis.ConclusionThe nanoparticles synthesized in the present study revealed good characteristics and stability for administration to cancer cells. Their uptake through endocytosis leads to promising cytotoxic effects towards CRPC cells, revealing the potential of G-AgNPs as a future therapeutic approach to improve the management of patients with PCa resistant to hormone therapy or metastatic disease.

Comparison of Weekly Low Dose Docetaxel with the Standard Protocol in Hormone-resistant Metastatic Prostate Cancer.

To evaluate and compare the effects and toxicity of weekly low dose with three weekly standard doses of docetaxel in hormone-resistant metastatic prostate cancer. Descriptive study. University of Health Sciences, Ankara Training and Research Hospital, Ankara, Turkey, from January 2013 to July 2021. The study was conducted on 79 patients with refractory prostate cancer. Patients were assessed in 2 groups. One group was treated with the classical standard Docetaxel dose 75 mg/m2/day (every 3-week) + Prednisolone 10 mg/day (daily), whereas the second group consisting of elderly and poor performance status received a low dose Docetaxel 25 mg/m2/day (weekly, 1-week interval) + Prednisolone 10 mg/day (daily). The overall survival and toxicity profile differences between the low dose protocol in this study and the standard treatment protocol were compared. Survival times in both groups were found as 44.3 months and 35.5 months in 1-week and 3-week interval groups, respectively (p = 0.09). The rate of hematologic toxicity associated with systemic treatment was 10% in the 1-week interval treatment group and 41% in the 3-week group (p = 0.002). In particular, the febrile neutropenia was 30.8% in the 3-week interval group and 2.5% (p = 0.001) in the 1-week interval group. The study showed that instead of using docetaxel in the standard dose and range, it is more tolerated in elderly and poor performance patients when administered in the revised dose. The disrupting effects of chemotherapy are overperforming, especially in such patients. Metastatic prostate cancer, Hormone resistant prostate cancer, Weekly docetaxel.

Role of monocarboxylate transporters and glucose transporters in prostate cancer.

Currently, research of new diagnostic approaches to detect clinically significant prostate cancer is relevant because of the importance of early detection of aggressive forms of the disease, often challenging, even when using modern diagnostic tools. The aim of this review is to present the current knowledge regarding monocarboxylate transporters' and glucose transporters' expression as a component of glycolytic phenotype definition in prostate cancer cells. We searched PubMed and Scopus databases. Twenty-six articles from 2003 to 2022 were included. Literature research and selection were carried out based on the recommendations of the PRISMA statement. The presence of "lactate shuttle" in the tumor tissue is associated with a worse prognosis. Increased expression of MCT2, MCT4, GLUT1, and down-regulation of GLUT3 are associated with prostate adenocarcinoma. MCT4 expression level correlates with the grade of tumor malignancy and disease prognosis. Up-regulation of GLUT1 and MCT4 is typical for hormone-resistant prostate cancer. Inhibition of MCT1 and MCT4 and GLUT1 in prostate cancer cells reduces their metabolic activity and growth rate, a suitable novel approach for targeted therapy. Review of the current studies showed that expression of certain MCTs and GLUTs types are associated with prostate cancer and some of them correlate with high malignancy and poor prognosis. Detection by immunohistochemistry of these transporters could represent a new diagnostic tool to identify aggressive forms of prostate cancer, and a novel therapeutic target for selective drugs.

Development of Abiraterone Acetate Nanocrystal Tablets to Enhance Oral Bioavailability: Formulation Optimization, Characterization, In Vitro Dissolution and Pharmacokinetic Evaluation.

Abiraterone acetate is a prodrug of abiraterone used in combination with prednisone as a standard therapeutic strategy for hormone-resistant prostate cancer (mCRPC). Due to the poor solubility and permeability, the release and absorption of abiraterone acetate are low and reduce its bioavailability. In this project, abiraterone acetate tablets prepared using nanocrystal technology were developed to overcome the drawbacks of normal tablets by enhancing in vitro dissolution rate and oral bioavailability. The abiraterone acetate nanocrystal suspensions were prepared by top-down wet milling method using a planetary ball mill with the mixture of Poloxamer 407 and Poloxamer 188 as the optimized stabilizer at a ratio of 7:1. The optimized nanocrystals were freeze-dried and characterized using DLS, TEM, DSC, and XRD. The abiraterone acetate nanocrystal tablets significantly improve the in vitro dissolution rate of abiraterone acetate compared to raw materials. Although exhibiting a similar dissolution rate compared to the Zytiga® tablets, the nanocrystal tablets significantly improve the oral bioavailability with Cmax and AUC0–t being 3.51-fold and 2.80-fold higher, respectively, in the pharmacokinetic study. The present data indicate that nanocrystal is a promising strategy for improving the dissolution and bioavailability of abiraterone acetate.

Oligoprogression in Metastatic, Castrate-Resistant Prostate Cancer-Prevalence and Current Clinical Practice.

AimsOligoprogression is poorly defined in current literature. Little is known about the natural history and significance of oligoprogression in patients with hormone-resistant prostate cancer on abiraterone or enzalutamide treatment [termed androgen receptor-targeted therapy (ARTT)]. The aim of this study was to determine the prevalence of oligoprogression, describe the characteristics of oligoprogression in a cohort of patients from a single center, and identify the number of patients potentially treatable with stereotactic body radiotherapy (SBRT).MethodsCastration-resistant prostate cancer (CRPC) patients who radiologically progressed while on ARTT were included. Patients with oligoprogressive disease (OPD) (≤3 lesions) on any imaging were identified in a retrospective analysis of electronic patient records. Kaplan–Meier method and log-rank test were used to calculate progression-free and overall survival.ResultsA total of 102 patients with metastatic CRPC on ARTT were included. Thirty (29%) patients presented with oligoprogression (46 lesions in total); 21 (21% of total) patients had lesions suitable for SBRT. The majority of lesions were in the bone (21, 46%) or lymph nodes (15, 33%). Patients with oligoprogression while on ARTT had a significantly better prostate-specific antigen (PSA) response on commencing ARTT as compared to patients who later developed polyprogression. However, PSA doubling time immediately prior to progression did not predict OPD. Median progression-free survival to oligoprogression versus polyprogression was 16.8 vs. 11.7 months. Time to further progression after oligoprogression was 13.6 months in those treated with radiotherapy (RT) for oligoprogression vs. 5.7 months in those treated with the continuation of ARTT alone.ConclusionsIn this study, nearly a third of patients on ARTT for CRPC were found to have OPD. OPD patients had a better PSA response on ART and a longer duration on ARTT before developing OPD as compared to those developing polyprogressive disease (Poly-PD). The majority of patients (70%) with OPD had lesions suitable for SBRT treatment. Prospective randomized control trials are needed to establish if there is a survival benefit of SBRT in oligoprogressive prostate cancer and to determine predictive indicators.

PGC1 alpha coactivates ERG fusion to drive antioxidant target genes under metabolic stress

The presence of ERG gene fusion; from developing prostatic intraepithelial neoplasia (PIN) lesions to hormone resistant high grade prostate cancer (PCa) dictates disease progression, altered androgen metabolism, proliferation and metastasis1–3. ERG driven transcriptional landscape may provide pro-tumorigenic cues in overcoming various strains like hypoxia, nutrient deprivation, inflammation and oxidative stress. However, insights on the androgen independent regulation and function of ERG during stress are limited. Here, we identify PGC1α as a coactivator of ERG fusion under various metabolic stress. Deacetylase SIRT1 is necessary for PGC1α-ERG interaction and function. We reveal that ERG drives the expression of antioxidant genes; SOD1 and TXN, benefitting PCa growth. We observe increased expression of these antioxidant genes in patients with high ERG expression correlates with poor survival. Inhibition of PGC1α-ERG axis driven transcriptional program results in apoptosis and reduction in PCa xenografts. Here we report a function of ERG under metabolic stress which warrants further studies as a therapeutic target for ERG fusion positive PCa.

Fucoidan Independently Enhances Activity in Human Immune Cells and Has a Cytostatic Effect on Prostate Cancer Cells in the Presence of Nivolumab.

Fucoidan compounds may increase immune activity and are known to have cancer inhibitory effects in vitro and in vivo. In this study, we aimed to investigate the effect of fucoidan compounds on ex vivo human peripheral blood mononuclear cells (PBMCs), and to determine their cancer cell killing activity both solely, and in combination with an immune-checkpoint inhibitor drug, Nivolumab. Proliferation of PBMCs and interferon gamma (IFNγ) release were assessed in the presence of fucoidan compounds extracted from Fucus vesiculosus, Undaria pinnatifida and Macrocystis pyrifera. Total cell numbers and cell killing activity were assessed using a hormone resistant prostate cancer cell line, PC3. All fucoidan compounds activated PBMCs, and increased the effects of Nivolumab. All fucoidan compounds had significant direct cytostatic effects on PC3 cells, reducing cancer cell numbers, and PBMCs exhibited cell killing activity as measured by apoptosis. However, there was no fucoidan mediated increase in the cell killing activity. In conclusion, fucoidan compounds promoted proliferation and activity of PBMCs and added to the effects of Nivolumab. Fucoidan compounds all had a direct cytostatic effect on PC3 cells, as shown through their proliferation reduction, while their killing was not increased.

Lovastatin enhances chemosensitivity of paclitaxel-resistant prostate cancer cells through inhibition of CYP2C8

Chemotherapy is the mainstay of treatment for prostate cancer, with paclitaxel being commonly used for hormone-resistant prostate cancer. However, drug resistance often develops and leads to treatment failure in a variety of prostate cancer patients. Therefore, it is necessary to enhance the sensitivity of prostate cancer to chemotherapy. Lovastatin (LV) is a natural compound extracted from Monascus-fermented foods and is an inhibitor of HMG-CoA reductase (HMGCR), which has been approved by the FDA for hyperlipidemia treatment. We have previously found that LV could inhibit the proliferation of refractory cancer cells. Up to now, the effect of LV on chemosensitization and the mechanisms involved have not been evaluated in drug-resistant prostate cancer. In this study, we used prostate cancer cell line PC3 and its paclitaxel-resistant counterpart PC3-TxR as the cell model. Alamar Blue cell viability assay showed that LV and paclitaxel each conferred concentration-dependent inhibition of PC3-TxR cells. When paclitaxel was combined with LV, the proliferation of PC3-TxR cells was synergistically inhibited, as demonstrated by combination index <1. Moreover, colony formation decreased while apoptosis increased in paclitaxel plus LV group compared with paclitaxel alone group. Quantitative RT-PCR showed that the combination of paclitaxel and LV could significantly reduce the expression of CYP2C8, an important drug-metabolizing enzyme. Bioinformatics analysis from the TCGA database showed that CYP2C8 expression was negatively correlated with progression-free survival (PFS) in prostate cancer patients. Our results suggest that LV might increase the sensitivity of resistant prostate cancer cells to paclitaxel through inhibition of CYP2C8 and could be utilized as a chemosensitizer for paclitaxel-resistant prostate cancer cells.

Abstract 228: A precision dosing application for patients treated with docetaxel and G-CSF

Abstract Purpose Produce a precision dosing application for clinicians to control neutropenia in patients treated with both docetaxel and G-CSF. Context Chemotherapy induced neutropenia (CIN) poses serious harm to patients due to the heightened risk of severe infection. Accordingly, chemotherapy dose is assessed at the beginning of each cycle. The therapeutic window of chemotherapy is determined from population studies, with an individual's dose often scaled by their body surface area. This leads to a large number of patients being over- or under- dosed. We previously developed an application [1] which uses weekly neutrophil counts from the first cycle of docetaxel treatment to predict the level of neutropoenia in subsequent cycles for a given dose of docetaxel. However, in the original app the administration of G-CSF, used as a prophylactic treatment for neutropenia, was not considered. G-CSF administration lacks standardisation and the COVID-19 pandemic has created a highly risk averse environment to infections, raising the prospects that a clinician will administer G-CSF. MethodsAiming to predict the level of neutropenia after the first cycle we draw from models in the literature of CIN for G-CSF treated patients [2,3,4]. We adapt the G-CSF induced feedback effect on neutrophil development in these models to account for features specific to docetaxel patients; notably the rebound in neutrophils above baseline seen after nadir [5], and the apparent short maturation time of neutrophils [4]. Using data in the public domain from the comparator arm of a phase III clinical trial for metastatic hormone-resistant prostate cancer (clinical trial number NCT00617669), we identify 27 patients treated with docetaxel and G-CSF with weekly blood tests in the first and second cycle. We calibrate our model by minimising a Bayesian objective function to establish a model that predicts the neutrophil count in the second docetaxel cycle from the first. We then simulate the effect of different combinations of docetaxel, G-CSF, and the timing of G-CSF administration. Conclusions Current progress includes a model which captures the rebound above baseline in neutrophil count seen in docetaxel patients. We will show that our model captures the effect of filgrastim and pegfilgrastim on neutrophil counts, and can determine how a docetaxel patient may best benefit from G-CSF treatment and/or a change in dose of docetaxel.

68Ga-PSMA-11 PET imaging in patients with ongoing androgen deprivation therapy for advanced prostate cancer

PurposeProstate-specific membrane antigen (PSMA) targeted positron emission tomography (PET) imaging significantly improved the detection of recurrent prostate cancer (PCa). However, the value of PSMA PET imaging in patients with advanced hormone-sensitive or hormone-resistant PCa is still largely unknown. The aim of this study was to analyze the detection rate and distribution of lesions using PSMA PET imaging in patients with advanced PCa and ongoing androgen deprivation therapy (ADT).MethodsA total of 84 patients diagnosed with hormone-sensitive or hormone-resistant PCa who underwent 68Ga-PSMA-11 PET/magnetic resonance imaging (MRI) or computer tomography (CT) under ongoing ADT were retrospectively analyzed. We assessed the detection of PSMA-positive lesions overall and for three PSA subgroups (0 to < 1 ng/mL, 1 to < 20 ng/mL and > 20 ng/mL). In addition, PSMA-positive findings were stratified by localization (prostatic fossa, pelvic, para-aortic, mediastinal/supraclavicular and axillary lymph nodes, bone lesions and visceral lesions) and hormone status (hormone-sensitive vs. hormone-resistant). Furthermore, we assessed how many patients would be classified as having oligometastatic disease (≤ 3 lesions) and theoretically qualify for metastasis-directed radiotherapy (MDRT) in a personalized patient management.ResultsWe detected PSMA-positive lesions in 94.0% (79 of 84) of all patients. In the three PSA subgroups detection rates of 85.2% (0 to < 1 ng/mL, n = 27), 97.3% (1 to < 20 ng/mL, n = 37) and 100% (> 20 ng/mL, n = 20) were observed, respectively. PSMA-positive visceral metastases were observed only in patients with a PSA > 1 ng/mL. Detection of PSMA-positive lesions did not significantly differ between patients with hormone-sensitive and hormone-resistant PCa. Oligometastatic PCa was detected in 19 of 84 patients (22.6%). Almost all patients, 94.7% (n = 18) would have been eligible for MDRT.ConclusionsIn this study, we observed an overall very high detection rate of 94% using PSMA PET imaging in patients with advanced PCa and ongoing ADT. Even in a majority of patients with very low PSA values < 1 ng/ml PSMA-positive lesions were found.

A precision dosing application for prostate cancer patients treated with docetaxel and G-CSF.

e13585 Background: The aim of this study is to produce a precision dosing application for clinicians to control neutropenia in prostate cancer patients treated with both docetaxel and G-CSF. Chemotherapy-induced neutropenia (CIN) poses serious harm to patients due to the heightened risk of severe infection. Accordingly, chemotherapy dose is assessed at the beginning of each cycle. The therapeutic window of chemotherapy is determined from population studies, with an individual’s dose often scaled by their body surface area. This leads to a large number of patients being over- or under- dosed. We previously developed an application [1] which uses weekly neutrophil counts from the first cycle of docetaxel treatment to predict the level of neutropoenia in subsequent cycles for a given dose of docetaxel. However, in the original app the administration of G-CSF, used as a prophylactic treatment for neutropenia, was not considered. G-CSF administration lacks standardisation and the COVID-19 pandemic has created a highly risk adverse environment to infections, raising the prospects that a clinician will administer G-CSF. Methods: We adapted and combined representations of endogenous and exogenous G-CSF action on CIN from the literature [2,3,4] to capture the inherent feedback effect of circulating neutrophils on progenitor proliferation as well as the stimulatory action of G-CSF injection on proliferation and maturation of progenitor cells. Using data in the public domain from the comparator arm of a phase III clinical trial for metastatic hormone-resistant prostate cancer (NCT00617669), we identified 134 patients treated with docetaxel with recorded weekly blood tests in the first and second cycle, including 27 also receiving G-CSF. We calibrated individualised patient models against neutrophil counts measured in the first cycle by minimising a Bayesian objective function and evaluated their ability to predict the levels observed in the second cycle. Results: The model was able to capture the main features of endogenous and exogenous G-CSF action on neutrophil count described in the literature, including endogenous-G-CSF-mediated rebound above baseline after chemotherapy-induced depletion [4], rapid rise in neutrophil count following exogenous G-CSF administration [5], as well as reduced chemotherapy-induced depletion and earlier recovery under G-CSF treatment compared to chemotherapy alone [5]. Conclusions: This tool has the potential to help determine how a docetaxel patient may best benefit from G-CSF treatment and/or a change in dose of docetaxel.