Androgen Prostate Cancer Research Articles

Abstract 7525: Investigating B7-H3 as a checkpoint and antibody drug conjugate target across prostate cancer variants- both androgen receptor dependent and independent

Abstract Background: CD276 (B7-H3) has recently emerged as a promising presumptive immune checkpoint inhibitor (ICI) and antibody-drug conjugate (ADC) target for PCa. Unfortunately, current immunotherapy trials have yielded few objective responses in PCa and hormonal therapy seldom cures necessitating the need to develop new immunotherapy or targeted antibody-drug conjugate (ADC) treatment options for PCa, including B7-H3 targeted approaches. Method: In this work, we evaluated important ADC targets and immune checkpoints (PD-1, PD-L1, PD-L2, LAG3, TIGIT, OX40, 4-1BB, CTLA4, STEAP1, STEAP2, PSMA, NECTIN1, TROP-2, DLL3 and B7-H3) in various PCa cell lines and multiple patients spanning various subtypes of PCa using publicly available bulk RNA sequencing data and single-cell RNA sequencing (scRNA-seq) data respectively. The results were validated at RNA and protein levels in listed cell lines. Further, the impact of androgen receptor (AR) signaling on B7-H3 expression was quantified using charcoal stripped media, AR agonist (R1881) and antagonist (enzalutamide) using real-time PCR and flow cytometry at RNA and protein levels respectively. Results: We found that B7-H3 shows high expression and very low variability compared to other ADC targets and immune checkpoints in AR-positive (LnCAP), hormone-refractory (VCAP), Castrate resistant (22RVI), AR negative (PC3, DU145), and neuroendocrine (H660) cell lines, as well as in—PCa cells and tumor microenvironment (TME) myeloid cells—of multiple patients spanning various subtypes of PCa. Western blotting confirms the ubiquitous presence of B7-H3 in all these cell lines, even when PSMA is absent. Furthermore, B7-H3 expression was modifiable via androgen depletion, R1881 supplementation, or addition of the AR antagonist enzalutamide. These changes were significant in AR-positive LnCAP cells compared to AR-negative DU145 cells further endorsing the crosstalk between AR and B7-H3 signaling pathways, which will be presented in greater detail. Conclusion: This work explores the therapeutic relevance of important ADC targets and immune checkpoints for Prostate Cancer (PCa), highlighting B7-H3 as a unique therapeutic ADC and ICI candidate across the continuum of PCa—androgen sensitive, castration resistant, and neuroendocrine—due to its stable expression across various subtypes and on TME myeloid cells. The relationship between AR and B7-H3 opens the possibility of future combination therapies based on this interaction. Citation Format: Nikita Mundhara, Shivang Sharma, Emirhan Tekoglu, Ezra G. Baraban, Nathan A. Lack, Eugene Shenderov. Investigating B7-H3 as a checkpoint and antibody drug conjugate target across prostate cancer variants- both androgen receptor dependent and independent [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7525.

Nutrition services during prostate cancer androgen deprivation therapy

ObjectiveDietary interventions are effective strategies to mitigate multiple side effects from androgen deprivation therapy (ADT) in prostate cancer, however the perception of, and access to, nutrition services is relatively unknown.MethodsA...

Abstract 1996: Prostate cancer androgen receptor signaling inhibition via romidepsin encapsulated lipid-polymer hybrid nanoparticle with PSMA617 targeting

Abstract Purpose/Objective(s): Androgen deprivation therapy (ADT) has been a clinical standard of care for the treatment of castration sensitive prostate cancer (CSPC). However, it is not curative, and ADT has significant systemic effects including hot flashes, osteoporosis, anemia, etc. We sought to identify agents that would inhibit AR signaling without causing these systemic effects. Histone deacetylase inhibitors (HDACis) are attractive agents because they impede AR signaling and DNA damage repair in PCa and show epigenetic modifications in prostate cancer (PCa) development and progression. This study demonstrated romidepsin as an alternative to ADT and the development of a romidepsin encapsulated CSPC PCa targeted nanoparticle for PCa cell killing and growth inhibition without the toxicity associated with free romidepsin or ADT. Materials/Methods: Three PCa cell lines, LNCaP, 22Rv1 and PC3 that express different androgen receptor (AR) levels were used for this study. Cell viability was tested by real-time cell analysis (RTCA), protein expression by western blot analysis, and quantification of γ-H2AX double stranded DNA (dsDNA) breaks by immunofluorescent microscopy. We developed a poly (D,L-lactide-co-glycolide) (PLGA) and 1, 2-Distearoyl-sn-glycero-3-phosphoethanolamine-polyethylene glycol (DSPE-PEG) polymer-lipid nanoparticle coated with vipivotide tetraxetan(PSMA-617) for prostate specific membrane antigen (PSMA) targeting. Nanoparticles were characterized by transmission electron microscope (TEM), dynamic light scattering (DLS) analysis, and nanoparticle tracking analysis (NTA). Romidepsin encapsulation efficiency was quantified by high-performance liquid chromatography(HPLC). Results: RTCA showed free romidepsin inhibited cell growth in all three PCa cell lines in a dose dependent manner. The addition of ADT exhibited an additive effect with low romidepsin doses, but did not significantly improve cell growth inhibition when combined with high doses of romidepsin. Western blot and γ-H2AX foci staining confirmed that romidepsin inhibited AR signaling and increased dsDNA damage, respectively. HPLC showed nanoparticle encapsulated romidepsin of 0.7%wt and TEM/DLS/NTA showed a size of 130 ±20nm. Furthermore, PSMA-617 coated nanoparticles exhibited enhanced uptake in LNCaP cells compared to non-coated nanoparticles. Conclusion: Our study showed that the romidepsin has a dual effect on inhibiting AR signaling as well as downregulating DNA damage repair genes. Additionally, we developed a PCa targeted nanoparticle for specific PCa delivery of romidepsin. PSMA-targeted, romidepsin-encapsulated nanoparticles would reduce the systemic effects of free romidepsin and a potential replacement for ADT. Citation Format: Wendi Ma, Daiki Hara, Yu-Ping Yang, Olivia Yolande Bosquet, Wei Zhang, Emre Dikici, Huayang Feng, Tim Horton, Wensi Tao, Jessi Hersh, Junwei Shi, Sylvia Daunert, Sapna Deo, Alan Pollack. Prostate cancer androgen receptor signaling inhibition via romidepsin encapsulated lipid-polymer hybrid nanoparticle with PSMA617 targeting [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 1996.

The role of 11-oxygenated androgens in prostate cancer.

11-oxygenated androgens are a class of steroids capable of activating the androgen receptor (AR) at physiologically relevant concentrations. In view of the AR as a key driver of prostate cancer (PC), these steroids are potential drivers of disease and progression. The 11-oxygenated androgens are adrenal-derived, and persist after androgen deprivation therapy (ADT), the mainstay treatment for advanced PC. Consequently, these steroids are of particular interest in the castration-resistant prostate cancer (CRPC) setting. The principal androgen of the pathway, 11-ketotestosterone (11KT), is a potent AR agonist and the predominant circulating active androgen in CRPC patients. Additionally, several precursor steroids are present in the circulation which can be converted into active androgens by steroidogenic enzymes present in PC cells. In vitro evidence suggests that adaptations frequently observed in CRPC favour the intratumoral accumulation of 11-oxygenated androgens in particular. Still, apparent gaps in our understanding of the physiology and role of the 11-oxygenated androgens remain. In particular, in vivo and clinical evidence supporting these in vitro findings is limited. Despite recent advances, a comprehensive assessment of intratumoral concentrations has not yet been performed. The exact contribution of the 11-oxygenated androgens to CRPC progression therefore remains unclear. This review will focus on the current evidence linking the 11-oxygenated androgens to PC, will highlight current gaps in our knowledge, and will provide insight into the potential clinical importance of the 11-oxygenated androgens in the CRPC setting based on the current evidence.

The Prostate Cancer Androgen Receptor Cistrome in African American Men Associates with Upregulation of Lipid Metabolism and Immune Response.

With immunotherapies and inhibitors of metabolic enzymes in clinical development, the altered lipid metabolism and immune response in African-American men provides potential therapeutic opportunities to attenuate racial disparities in prostate cancer.

Abstract 122: Hypoxia-reoxygenation couples enzyme and cofactor upregulation to quicken prostate cancer androgen biosynthesis and hormone therapy resistance

Abstract Androgen deprivation therapy depletes circulating testosterone and is the mainstay treatment for advanced prostate cancer by suppressing tumor androgen receptor signaling. Despite initial treatment response, castration-resistant prostate cancer nearly always develops and remains driven primarily by the androgen axis. We investigated how changes in oxygenation affect androgen synthesis. Our study indicates that when chronic hypoxia is coupled to reoxygenation, prostate cancer cells efficiently metabolize androgen precursors to produce androgens and activate AR. Hypoxia induces 3βHSD1, the rate-limiting androgen synthesis regulator, and reoxygenation replenishes necessary cofactors. Therefore, hypoxia and reoxygenation are both essential for potent androgen synthesis. The EGLN1/VHL/HIF2α pathway promoted transcription of HSD3B1 by directly binding the 5’ regulatory region of HSD3B1. HIF2α overexpression facilitated prostate cancer progression, which largely depends on 3βHSD1. PT2399, a specific HIF2α inhibitor, prevented prostate cancer cell proliferation. Our study indicates HIF2α is a potential therapeutic target in prostate cancer. Citation Format: Liang Qin, Yoon-Mi Chung, Michael Berk, Bryan Naelitz, Eric Klein, Abhishek A Chakraborty, Nima Sharifi. Hypoxia-reoxygenation couples enzyme and cofactor upregulation to quicken prostate cancer androgen biosynthesis and hormone therapy resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 122.

Chronic IL-1 Exposed AR+ PCa Cell Lines Show Conserved Loss of IL-1 Sensitivity and Evolve Both Conserved and Unique Differential Gene Expression Profiles

Inflammation drives prostate cancer (PCa) progression. While inflammation is a cancer hallmark, the underlying mechanisms mediating inflammation-induced PCa are still under investigation. Interleukin-1 (IL-1) is an inflammatory cytokine that promotes cancer progression, including PCa metastasis and castration resistance. We previously found that acute IL-1 exposure represses PCa androgen receptor (AR) expression concomitant with the upregulation of pro-survival proteins, causing de novo accumulation of castration-resistant PCa cells. However, acute inflammation is primarily anti-tumorigenic, while chronic inflammation is pro-tumorigenic. Thus, using the LNCaP PCa cell line as model, we found that PCa cells can evolve insensitivity to chronic IL-1 exposure, restoring AR and AR activity and acquiring castration resistance. In this paper we expanded our chronic IL-1 model to include the MDA-PCa-2b PCa cell line to investigate the response to acute versus chronic IL-1 exposure and to compare the gene expression patterns that evolve in the LNCaP and MDA-PCa-2b cells chronically exposed to IL-1. We chronically exposed MDA-PCa-2b cells to IL-1α or IL-1β for several months to establish sublines. Once established, we determined subline sensitivity to exogenous IL-1 using cell viability assay, RT-qPCR and western blot. RNA sequencing was performed for parental and subline cells and over representation analysis (ORA) for geneset enrichment of biological process/pathway was performed. MDA-PCa-2b cells repress AR and AR activity in response to acute IL-1 exposure and evolve insensitivity to chronic IL-1 exposure. While cell biological and molecular response to acute IL-1 signaling is primarily conserved in LNCaP and MDA-PCa-2b cells, including upregulation of NF-κB signaling and downregulation of cell proliferation, the LNCaP and MDA-PCa-2b cells evolve conserved and unique molecular responses to chronic IL-1 signaling that may promote or support tumor progression. Our chronic IL-1 subline models can be used to identify underlying molecular mechanisms that mediate IL-1-induced PCa progression.

Use of FVB Myc-CaP cells as an immune competent, androgen receptor positive, mouse model of prostate cancer bone metastasis

Prostate cancer (PCa) metastasis research has been hamstrung by lack of animal models that closely resemble the disease present in most patients – that metastasize to bone, are dependent on the androgen receptor (AR), and grow in an immune competent host. Here, we adapt the Myc-CaP cell line for use as a PCa androgen dependent, immune competent bone metastases model and characterize the metastases. After injection into the left cardiac ventricle of syngeneic FVB/NJ mice, these cells formed bone metastases in the majority of animals; easily visible on H&E sections and confirmed by immunohistochemistry for Ar and epithelial cell adhesion molecule. Mediastinal tumors were also observed. We also labeled Myc-CaP cells with tdTomato, and confirmed the presence of cancer cells in bone by flow cytometry. To adapt the model to a bone predominant metastasis pattern and further examine the bone phenotype, we labeled the cells with luciferase, injected in the tibia and observed tumor formation only in tibia with a mixed osteolytic/osteoblastic phenotype. The presence of Myc-CaP tumors significantly increased tibia bone volume as compared to sham injected controls. The osteoclast marker, TRAcP-5b was not significantly changed in plasma from tibial tumor bearing animals vs. sham animals. However, conditioned media from Myc-CaP cells stimulated osteoclast formation in vitro from FVB/NJ mouse bone marrow. Overall, Myc-CaP cells injected in the left ventricle or tibia of syngeneic mice recapitulate key aspects of human metastatic PCa.

Selective androgen receptor modulators activate the canonical prostate cancer androgen receptor program and repress cancer growth.

Prostate cancer (PC) is driven by androgen receptor (AR) activity, a master regulator of prostate development and homeostasis. Frontline therapies for metastatic PC deprive the AR of the activating ligands testosterone (T) and dihydrotestosterone (DHT) by limiting their biosynthesis or blocking AR binding. Notably, AR signaling is dichotomous, inducing growth at lower activity levels, while suppressing growth at higher levels. Recent clinical studies have exploited this effect by administration of supraphysiological concentrations of T, resulting in clinical responses and improvements in quality of life. However, the use of T as a therapeutic agent in oncology is limited by poor drug-like properties as well as rapid and variable metabolism. Here, we investigated the antitumor effects of selective AR modulators (SARMs), which are small-molecule nonsteroidal AR agonists developed to treat muscle wasting and cachexia. Several orally administered SARMs activated the AR program in PC models. AR cistromes regulated by steroidal androgens and SARMs were superimposable. Coregulatory proteins including HOXB13 and GRHL2 comprised AR complexes assembled by both androgens and SARMs. At bioavailable concentrations, SARMs repressed MYC oncoprotein expression and inhibited the growth of castration-sensitive and castration-resistant PC in vitro and in vivo. These results support further clinical investigation of SARMs for treating advanced PC.

Androgens in prostate cancer: A tale that never ends.

Androgens play an essential role in prostate cancer. Clinical treatments that target steroidogenesis and the androgen receptor (AR) successfully postpone disease progression. Abiraterone and enzalutamide, the next-generation androgen receptor pathway inhibitors (ARPI), emphasize the function of the androgen-AR axis even in castration-resistant prostate cancer (CRPC). However, with the increased incidence in neuroendocrine prostate cancer (NEPC) showing resistance to ARPI, the importance of androgen-AR axis in further disease management remains elusive. Herein we review the steroidogenic pathways associated with different disease stages and discuss the potential targets for disease management after manifesting resistance to abiraterone and enzalutamide.

Selective androgen receptor modulators activate the canonical prostate cancer androgen receptor program and repress cancer growth.

Prostate cancer (PC) is driven by androgen receptor (AR) activity, a master regulator of prostate development and homeostasis. Frontline therapies for metastatic PC deprive the AR of the activating ligands testosterone (T) and dihydrotestosterone (DHT) by limiting their biosynthesis or blocking AR binding. Notably, AR signaling is dichotomous, inducing growth at lower activity levels, while suppressing growth at higher levels. Recent clinical studies have exploited this effect by administration of supraphysiological concentrations of T, resulting in clinical responses and improvements in quality of life. However, the use of T as a therapeutic agent in oncology is limited by poor drug-like properties as well as rapid and variable metabolism. Here, we investigated the antitumor effects of selective AR modulators (SARMs), which are small-molecule nonsteroidal AR agonists developed to treat muscle wasting and cachexia. Several orally administered SARMs activated the AR program in PC models. AR cistromes regulated by steroidal androgens and SARMs were superimposable. Coregulatory proteins including HOXB13 and GRHL2 comprised AR complexes assembled by both androgens and SARMs. At bioavailable concentrations, SARMs repressed MYC oncoprotein expression and inhibited the growth of castration-sensitive and castration-resistant PC in vitro and in vivo. These results support further clinical investigation of SARMs for treating advanced PC.

The Correlation between PSCA Expression and Neuroendocrine Differentiation in Prostate Cancer.

The prostate stem cell antigen (PSCA), as a predominantly prostate-specific marker, is overexpressed in most prostate cancer specimens, is positively correlated with prostate cancer androgen independence, and has the potential to be treated with castration-resistant prostate cancer (CRPC) as a gene therapy target. Using the typical androgen deprivation therapy, most tumors will progress to CRPC, as well as develop into neuroendocrine prostate cancer (NEPC) characterized by the expression of neuroendocrine markers such as enolase 2 (NSE). Our study was aimed at investigating the expressions of PSCA and NSE and the relationship between the two markers, as well as the correlation between the PSCA and NSE expressions and the clinicopathological parameters in prostate cancer specimens from 118 patients by using immunohistochemistry. Our results demonstrated that the PSCA and NSE protein expressions did not correlate with the prostate cancer patients' age or the hormone therapy but showed a significant correlation with the pathological tumor stage of prostate cancer, the Gleason score, and the presence of metastasis. There is a positive association between PSCA and NSE but a negative one between the prostate-specific antigen (PSA) and PSCA or between PSA and NSE. High PSCA and NSE expressions correlated with a poor prognosis in prostate cancer patients. PSCA may play an important role in the progression of neuroendocrine prostate cancer (NEPC).

Mechanistic targets for BPH and prostate cancer-a review.

All men, almost, suffer from prostatic disorders in average life expectancy. In the year of 1950s, the first autopsy of prostate gland discovered the link between Benign prostatic hyperplasia (BPH) and Prostate Cancer (PCa). After that, many histology, biochemistry, epidemiology studies explained the association and associated risk factor for the same. From the various scientific evidence, it is proved that both diseases share some common transcription factors and signalling pathways. Still, BPH cannot be considered as the first step of PCa progression. To define, the relationship between both of the diseases, a well-defined large epidemiological study is needed. Along with androgen signalling, imbalanced apoptosis, oxidative stress, and microbial infection also crucial factors that significantly affect the pathogenesis of BPH. Various signalling pathways are involved in the progression of BPH. Androgen signalling is the driving force for the progress of PCa. In PCa androgen signalling is upregulated as compared to a healthy prostate. Some dominant Androgen-regulated genes and their functions have been discussed in this work.

PSA secretion and cell proliferation are affected by NCoR1 silencing in prostate cancer cells

The androgen receptor (AR) plays an important role in normal prostate gland development as well as in prostatic neoplasms. Transcriptional regulation by AR is modulated by its interaction with co-activators or co-repressors, such as NCoR1 (nuclear receptor co-repressor 1), which is involved in the reduction of AR activity over the target gene transcription. To identify the role of NCoR1 in the prostate cancer androgen independence in a cell line model, we aimed to evaluate the effects of silencing NCoR1 on prostate-specific antigen ( PSA) gene expression, the proliferative response and PSA secretion on the supernatant of C4-2B and LNCaP cells that were submitted to small interfering RNAs (siRNAs) transfection and to treatments with different androgen dosages. In LNCaP and C4-2B cells with no dihydrotestosterone (DHT) treatment, a decrease of PSA mRNA expression was observed 48 hours and 72 hours after gene silencing in the siNCoR group when compared to the control and siNC groups. LNCaP and C4-2B cells showed a biphasic pattern in response to dihydrotestosterone treatment in transfected groups (siNCoR and siNC) as well as in the control condition (no transfection). The secretion of PSA in cell supernatant of LNCaP and C4-2B cells was higher in the siNCoR group, and, regarding the hormonal treatment, higher in the 10 -8 M DHT group. A reduction in the levels of NCoR1 seems to have a double influence on the activity of AR in PCa cells. These results suggest that NCoR can act as AR a co-repressor depending upon hormonal stimulation.

Assessment of testosterone and its fraction in patients with locally advanced prostate cancer and in patients with primary metastatic disease

Introduction: The assessment of serum concentration testosterone in patients with localized prostate cancer in the aspect of the development of aggressive features raises a number of controversies, remains still an unresolved research area with the results of studies trying to assess the importance of circulating androgens in prostate cancer are still not clear. The aim of the study was to determine whether preoperative levels of circulating androgens (testosterone and its free and bioavailable fractions) are correlated with tumor aggressiveness in patients with localized prostate cancer and metastatic disease Materials and Methods: The study involved 40 asymptomatic men, 98 men with benign prostatic hyperplasia and 129 male patients diagnosed with prostate cancer (PCa) (T1 – T2, irrespective of N and M). All patients had total PSA (tPSA), free PSA (fPSA), testosterone (TEST), SHBG and albumin levels measured before the treatment begun. For each of the subjects, the percentage of free PSA (f/tPSA), free (fTEST) and bioavailable testosterone (bioTEST) concentration, percentage of free (% fTEST) and bioavailable (% bioTEST) testosterone were calculated. Results: In patients with prostate cancer the significantly higher tPSA levels (p = 0.0001 and p = 0.0001), significantly lower albumin concentration (p = 0.0001 and p = 0.0001), and levels f/tPSA (p = 0.0001 and p = 0.0001) were found, compared to the group of asymptomatic men and BPH . In addition, in the group of patients with PCa, the lower levels of fTEST (p = 0.0004) and bioTEST (p = 0.0001), and their percentages (p = 0.0013 and p = 0.0001), as well as higher SHBG concentration (p = 0.0002) were observed compared to the asymptomatic males. Significantly higher fTEST (p = 0.0377) and bioTEST (p = 0.0447) concentration were found in patients with cT2c stage as compared to the cT2b stage. There were no significant differences in the levels of the parameters studied depending on the grade of malignancy according to Gleason score. The presence of distant and / or regional node metastases is associated with the significantly higher tPSA (p = 0.0001), and SHBG (p = 0.0039) concentrations and significantly lower levels of %fTEST (p = 0.0346) and %bioTEST (p = 0.0030). Patients who died within the five years (since diagnosis) had significantly higher tPSA (p = 0.0001) and SHBG (p = 0.0002), and significantly lower levels of %fTEST (p = 0.0018) and %bioTEST (p = 0.0003). The percentages of free and bioavailable testosterone and the bioTEST concentration showed a statistically significant downward trend and the SHBG concentration significantly increased with the increase of tPSA concentration in PCa patients. In patients in the cT2a + cT2b group, tPSA concentrations inversely correlated with %bioTEST (r = – 0.2633). There were no significant correlations between the studied hormones and tPSA in the group of patients with the worse prognosis (cT2c). Patients with GS < 7 presented also a significant correlation between tPSA concentration and the %bioTEST levels (r = – 0.2548). Conclusions: Significantly lower percentages of free and bioavailable testosterone are observed in prostate cancer patients with PSA concentration higher than 100 ng/ml, distant and/or regional node metastases and shorter overall survival. Lower percentages of free and bioavailable testosterone are associated with the elevated serum hormone binding globulin (SHBG) levels (up to 5 years).

How Does Androgen Deprivation Therapy Affect Mental Health including Cognitive Dysfunction in Patients with Prostate Cancer?

Androgen deprivation therapy (ADT) is used to block the release of androgen in prostate cancer to promote the regression of cancer cells, and hence, disease progression. Its indication has been widened from the metastatic setting to the localized setting in prostate cancer. Long-term ADT for suppressing androgen release leads to a rapid decrease in androgen, termed as andropause, resulting in several dose and duration dependent adverse effects, including cognitive dysfunction such as dementia. Many retrospective and prospective studies, as well as meta-analyses, have attempted to confirm the crucial relationship between ADT and cognitive dysfunction, but pro and contrary opinions regarding this issue are ongoing owing to the absence of randomized controlled trials. Additionally, several recent studies have suggested the negative effects of dose- and duration-dependent ADT on cognitive dysfunction, especially in 40–65-year-old patients with prostate cancer, who are currently active workers in the society. This review article discusses several studies examining the influence of ADT on mental health based on diverse significant perspectives, especially cognitive dysfunction.

Prostate cancer androgen receptor splice variant 7 biomarker study - a multicentre randomised feasibility trial of biomarker-guided personalised treatment in patients with advanced prostate cancer (the VARIANT trial) study protocol

IntroductionProstate cancer is the most common male cancer with one in four developing non-curable metastatic disease. Initial treatment responses to hormonal therapies are transient and further management options lie between...

Preclinical study using androgen receptor (AR) degradation enhancer to increase radiotherapy efficacy via targeting radiation-increased AR to better suppress prostate cancer progression.

BackgroundWhile androgen deprivation therapy (ADT) and radiotherapy (RT) are currently used together to treat locally advanced prostate cancer (PCa), RT might have the adverse effect of increasing the PCa androgen receptor (AR) protein expression, which might then increase the resistance to continued RT.MethodsWe used multiple assays for RT sensitivity, protein and RNA expression of AR and related DDR genes, ROS level, DNA damage/repair level, cell cycle and apoptosis. All statistical comparisons were analyzed with t-test or one-way ANOVA.FindingsWe demonstrated that RT induced AR expression in C4-2 and CWR22Rv-1 cells. We found that combining RT and ASC-J9®, but not the antiandrogen, Enzalutamide, could increase radiosensitivity via inducing DNA damage, altering the AR mediated and DNA repair pathways, and activating apoptosis. ASC-J9® had little effects on normal bladder cells.InterpretationTargeting ionizing radiation (IR)-increased AR with the AR degradation enhancer, ASC-J9®, could increase the radiosensitivity while sparing adjacent normal tissue. Mechanism dissection revealed that ASC-J9®, but not Enzalutamide, treatment could increase radiosensitivity via inducing DNA damage, altering DNA repair pathways, as well as activating the IR-induced apoptosis via suppressing the pATR-CHK1 signals. Importantly, results from preclinical studies using an in vivo mouse model also demonstrated that combining RT with ASC-J9® to target AR led to better therapeutic efficacy to suppress PCa progression.

Isolation and Structural Characterization of Bioactive Molecules on Prostate Cancer from Mayan Traditional Medicinal Plants.

Prostate cancer is the most common cancer in men around the world. It is a complex and heterogeneous disease in which androgens and their receptors play a crucial role in the progression and development. The current treatment for prostate cancer is a combination of surgery, hormone therapy, radiation and chemotherapy. Therapeutic agents commonly used in the clinic include steroidal and non-steroidal anti-androgens, such as cyproterone acetate, bicalutamide and enzalutamide. These few agents have multiple adverse effects and are not 100% effective. Several plant compounds and mixtures, including grape seed polyphenol extracts, lycopene and tomato preparations, soy isoflavones, and green tea extracts, have been shown to be effective against prostate cancer cell growth. In vivo activity of some isolated compounds like capsaicin and curcumin was reported in prostate cancer murine models. We prepared a library of plant extracts from traditional Mayan medicine. These plants were selected for their use in the contemporaneous Mayan communities for the treatment of different diseases. The extracts were assessed in a phenotypic screening using LNCaP prostate cancer androgen sensitive cell line, with a fixed dose of 25 μg/mL. MTT assay identified seven out of ten plants with interesting anti-neoplastic activity. Extracts from these plants were subjected to a bioguided fractionation to study their major components. We identified three compounds with anti-neoplastic effects against LNCaP cells, one of which shows selectivity for neoplastic compared to benign cells.

Abstract A078: Towards understanding noncanonical phosphatidylinositol kinases in the maintenance of prostate metabolism

Abstract An estimated 1 in 7 men will develop prostate cancer (PCa) with many progressing to advanced castrate-resistant disease. Unlike other tissue types, normal prostate cell growth and development is heavily dependent on the androgen receptor (AR) signaling pathway. While the introduction of novel AR antagonists for clinical treatment has improved outcomes, most castration-resistant prostate cancer (CRPC) patients ultimately develop resistance to these therapies. A need exists to better understand the mechanisms that control the transition of prostate cells from a hormone-dependent to castrate-resistant state. Androgens strongly influence the metabolic state of PCa cells to favor sustained cellular growth. We hypothesize there are effectors working in conjunction with AR to coordinate alterations to androgen-dependent metabolism that are linchpins in the orchestration of the transition to CRPC. Leading candidates are members of phosphoinositol (PI) pathways, which have a high frequency of alteration in PCa (i.e phosphoinositide 3-kinase (PI3K)). Herein we explore a family of poorly understood lipid kinases called the type II phosphatidylinositol-5-phosphate 4-kinases (PI5P4Ks) and predict them to be critical regulators of cancer cell survival. PI5P4Ks are druggable targets that act by phosphorylating the lipid phosphatidylinositol-5-phosphate (PI 5-P) at the 4 position of the inositol ring to generate phosphatidylinositol-4,5-bisphosphate (PI-4,5-P2; PIP2). We implicate the three PI5P4K isoforms (PI5P4Kα, PI5P4Kβ, and PI5P4Kγ) encoded by the genes PIP4K2A, B, and C, to be important regulators of cancer metabolism that play a role in the maintenance of prostate biology and oncogenesis. Analysis of transcript data revealed expression of PIP4K2A, B, and C in primary PCa patient samples, which was correlated with an AR activation gene signature and hotspot tumor suppressor deletion. As well, isoform expression was assessed for differential expression in relation to an integrated neuroendocrine prostate cancer mRNA score (TCGA; n=333). PI5P4Kα and PI5P4Kβ protein was detected in primary and advanced prostate cancer using optimized antibodies of patient tissue TMAs (n= 72). Using in vitro LNCaP cell models, siRNA knockdown systems were tested to evaluate the molecular consequence of targeting PIP4K2A and PIP4K2B in androgen-dependent systems. Stable knockdown using fluorescently labeled lentiviral shRNA constructs significantly reduced proliferation of shPIP4K2 treated cells. As well, we have produced a prostate-specific PI5P4K knockout mouse model by expressing probasin-driven Cre in a homozygous 129/SvEv Pip4k2aflx/flx murine strain. Finally, implementation of a discovery-based metabolomic platform (Metabolon HD4) was used to profile the overall shift in metabolite species that results from downregulating the expression of PIP4K2A in androgen-dependent cell models. In summary, we have developed novel insights into the role of a family of noncanonical PI kinases in prostate biology. There are a growing number of PI3K/AKT inhibitors being tested in combination with androgen deprivation therapy in clinical trials, but there is still almost nothing known about the potential crosstalk of the greater PI kinase network. These data convincingly implicate a fundamental role for PI5P4Ks in PCa androgen signaling and metabolism, as well as lay the foundation of phenotypic understanding of what PI5P4K is responsible for in the prostate. Citation Format: Joanna Triscott, Matteo Benelli, Verena Sailer, Davide Prandi, Brooke Emerling, Francesca Demichelis, Lewis Cantley, Mark A. Rubin. Towards understanding noncanonical phosphatidylinositol kinases in the maintenance of prostate metabolism [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A078.