Androgen Deprivation In Prostate Cancer Research Articles

Induction of double-strand breaks with the non-steroidal androgen receptor ligand flutamide in patients on androgen suppression: a study protocol for a randomized, double-blind prospective trial

BackgroundProstate cancer remains the most prevalent malignancy and the second-leading cause of cancer-related death in men in the USA. Radiation therapy, typically with androgen suppression, remains a mainstay in the treatment of intermediate- and high-risk, potentially lethal prostate cancers. However, local recurrence and treatment failure remain common. Basic and translational research has determined the potential for using androgen receptor (AR) ligands (e.g., dihydrotestosterone and flutamide) in the context of androgen-deprived prostate cancer to induce AR- and TOP2B-mediated DNA double-strand breaks (DSBs) and thereby synergistically enhance the effect of radiation therapy (RT). The primary aim of this study is to carry out pharmacodynamic translation of these findings to humans.MethodsPatients with newly diagnosed, biopsy-confirmed localized prostatic adenocarcinoma will be recruited. Flutamide, an oral non-steroidal androgen receptor ligand, will be administered orally 6–12 h prior to prostate biopsy (performed under anesthesia prior to brachytherapy seed implantation). Key study parameters will include the assessment of DNA double-strand breaks by γH2A.x foci and AR localization to the nucleus. The initial 6 patients will be treated in a single-arm run-in phase to assess futility by establishing whether at least 2 subjects from this group develop γH2A.x foci in prostate cancer cells. If this criterion is met, the study will advance to a two-arm, randomized controlled phase in which 24 participants will be randomized 2:1 to either flutamide intervention or placebo standard-of-care (with all patients receiving definitive brachytherapy). The key pharmacodynamic endpoint will be to assess whether the extent of γH2A.x foci (proportion of cancer cells positive and number of foci per cancer cell) is greater in patients receiving flutamide versus placebo. Secondary outcomes of this study include an optional, exploratory analysis that will (a) describe cancer-specific methylation patterns of cell-free DNA in plasma and urine and (b) assess the utility of serum and urine samples as a DNA-based biomarker for tracking therapeutic response.DiscussionThis study will confirm in humans the pharmacodynamic effect of AR ligands to induce transient double-strand breaks when administered in the context of androgen deprivation as a novel therapy for prostate cancer. The findings of this study will permit the development of a larger trial evaluating flutamide pulsed-dose sequencing in association with fractionated external beam RT (+/− brachytherapy). The study is ongoing, and preliminary data collection and recruitment are underway; analysis has yet to be performed.Trial registrationClinicalTrials.gov NCT03507608. Prospectively registered on 25 April 2018.

RNA-binding protein 14 promotes phase separation to sustain prostate specific antigen expression under androgen deprivation in human prostate cancer

Castration-resistant prostate cancer (CRPC) is a big challenge in managing prostate cancer patients. The androgen receptor (AR) pathway is a major driver even in CRPC under androgen deprivation. The mechanism in maintaining of the AR pathway under androgen deprivation remains elusive. The recent discovery of biomolecular condensate, a membrane-less intracellular construct formed by liquid-liquid phase separation (LLPS), that facilitate molecular assembly, encouraged the re-screening of our previous microarray data list. We selected Rbm14 as a target molecule for further analysis because it works as a coactivator of nuclear receptors as well as it facilitates formation of biomolecular condensates via its intrinsically disordered region. GFP-tagged Rbm14 transfected into HEK293T cells formed droplet-like puncta, which diminished following treatment with 1,6-hexanediol. Droplet-like structures were also observed in immunofluorescence for endogenous RBM14 of PC-3 and DU145 cells. Luciferase assay revealed that Rbm14 enhanced androgen-responsive element (ARE)-mediated reporter activity in all conditions with or without testosterone and AR. Co-immunoprecipitation confirmed the Rbm14–AR interaction. Long non-coding RNAs, including NEAT1, SRA1, and HOTAIR, were also interacted with Rbm14. Small interfering RNAs of NEAT1 reduced ARE-mediated reporter activity, while transfection of SRA1 and HOTAIR enhance the reporter activity. Treatment with 1,6-hexanediol as well as transfection with a dominant-negative splice variant of Rbm14 reduced expression of prostate specific antigen (PSA), a prototype of androgen-regulated gene, in LNCaP, PC-3, and DU145 cells under androgen deprivation. Immunohistochemically, RBM14 expression was substantially upregulated in prostate cancer tissues after androgen deprivation therapy than in untreated tumors. In conclusion, RBM14 is a novel factor involved in maintenance of PSA expression via phase separation under androgen deprivation in prostate cancer.

Ablative radiotherapy improves survival but does not cure autochthonous mouse models of prostate and colorectal cancer

BackgroundGenetically engineered mouse models (GEMMs) of cancer are powerful tools to study mechanisms of disease progression and therapy response, yet little is known about how these models respond to multimodality therapy used in patients. Radiation therapy (RT) is frequently used to treat localized cancers with curative intent, delay progression of oligometastases, and palliate symptoms of metastatic disease.MethodsHere we report the development, testing, and validation of a platform to immobilize and target tumors in mice with stereotactic ablative RT (SART). Xenograft and autochthonous tumor models were treated with hypofractionated ablative doses of radiotherapy.ResultsWe demonstrate that hypofractionated regimens used in clinical practice can be effectively delivered in mouse models. SART alters tumor stroma and the immune environment, improves survival in GEMMs of primary prostate and colorectal cancer, and synergizes with androgen deprivation in prostate cancer. Complete pathologic responses were achieved in xenograft models, but not in GEMMs.ConclusionsWhile SART is capable of fully ablating xenografts, it is unable to completely eradicate disease in GEMMs, arguing that resistance to potentially curative therapy can be modeled in GEMMs.

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...

Does Androgen Deprivation for Prostate Cancer Affect Normal Adaptation to Resistance Exercise?

Background: Loss of muscle mass and muscle function is a common side effect from androgen deprivation therapy (ADT) for prostate cancer (PCa). Here, we explored effects of heavy-load resistance training (RT) on lean body mass and muscle strength changes reported in randomized controlled trials (RCTs) among PCa patients on ADT and in healthy elderly men (HEM), by comparison of results in separate meta-analysis. Methods: RCTs were identified through databases and reference lists. Results: Seven RCTs in PCa patients (n = 449), and nine in HEM (n = 305) were included. The effects of RT in lean body mass change were similar among PCa patients (Standardized mean difference (SMD): 0.4, 95% CI: 0.2, 0.7) and HEM (SMD: 0.5, 95% CI: 0.2, 0.7). It is noteworthy that the within group changes showed different patterns in PCa patients (intervention: 0.2 kg; control: −0.6 kg) and HEM (intervention: 1.2 kg; control: 0.2 kg). The effects of RT on change in muscle strength (measured as 1 RM) were similar between PCa patients and HEM, both for lower body- (PCa: SMD: 1.9, 95% CI: 1.2, 2.5; HEM: SMD: 2.2, 95% CI: 1.0, 3.4), and for upper body exercises (PCa: SMD: 2.0, 95% CI: 1.3, 2.7; HEM: SMD: 1.9, 95% CI: 1.3, 2.6). Conclusions: The effects of RT on lean body mass and 1 RM were similar in PCa patients on ADT and HEM, but the mechanism for the intervention effect might differ between groups. It seems that RT counteracts loss of lean body mass during ADT in PCa patients, as opposed to increasing lean body mass in HEM.

CaV1.3 enhanced store operated calcium promotes resistance to androgen deprivation in prostate cancer

Androgen deprivation therapy (ADT) is the main treatment for advanced prostate cancer (PCa) but resistance results in progression to terminal castrate resistant PCa (CRPC), where there is an unmet therapeutic need. Aberrant intracellular calcium (Cai2+) is known to promote neoplastic transformation and treatment resistance. There is growing evidence that voltage gated calcium channel (VGCC) expression is increased in cancer, particularly CACNA1D/CaV1.3 in CRPC. The aim of this study was to investigate if increased CaV1.3 drives resistance to ADT and determine its associated impact on Cai2+ and cancer biology. Bioinformatic analysis revealed that CACNA1D gene expression is increased in ADT treated PCa patients. This was corroborated in both in vivo LNCaP xenograft mouse and in vitro PCa cell line models, which demonstrated a significant increase in CaV1.3 protein expression following ADT with bicalutamide. Expression was found to be of a shortened 170kDa CaV1.3 isoform associated with plasma and intracellular membranes, which failed to induce calcium influx following membrane depolarisation. Instead, under ADT CaV1.3 mediated a rise in basal cytosolic calcium and an increase in store operated calcium entry (SOCE). This mechanism was found to promote the proliferation and survival of ADT resistant CRPC cells. Overall, this study demonstrates for the first time in PCa that under ADT specific CaV1.3 isoforms promote an upregulation of SOCE which contributes to treatment resistance and CRPC biology. Thus, this novel oncochannel represents a target for therapeutic development to improve PCa patient outcomes.

Selected Articles from This Issue

Malignant pleural mesothelioma (MPM) is a highly aggressive cancer that lacks effective therapeutic options, owing to chemotherapeutic resistance and lack of currently targetable oncogenic mutations. However, mutations in histone modifiers documented in Mp. represent exciting potential therapeutic targets. Wirawan and colleagues used estrogen receptor sensitive Snail variant mesenchymal and sarcomatoid-like MPM cell lines to show that lysine-specific demethylase 1 (LSD1) drives a MPM mesenchymal phenotype, tumor cell migration, and cisplatin resistance. The authors integrated microarray, phospho-kinase array, and assay for transposase-accessible chromatin using sequencing (ATAC-seq) analyses to identify milk fat globulin protein E8 (MFGE8) as the LSD1-mediated driver of cisplatin resistance. Subsequent experiments demonstrated that MFGE8 interaction with integrin β3 drives FAK and AKT phosphorylation, initiating a positive feedback loop that upregulates Snail expression and promotes its associated mesenchymal phenotype. In sum, the work presented suggests that LSD1 may be a multifactorial therapeutic target for MPM.While androgen deprivation can provide at least temporary benefit for men with metastatic prostate cancer, most patients go on to develop lethal castration-resistant prostate cancer (CRPC). Speckle-type POZ protein (SPOP) mutations and Sonic hedgehog (SHH)-mediated androgen receptor (AR) signaling activation are prevalent in CRPC, making each therapeutic targets of interest for the disease. In their study, Burleson and colleagues demonstrate that a transcriptional activator of the SHH pathway, GLI3, enhances SHH signaling and cell proliferation in androgen-deprived prostate cancer cells. The authors show that GLI3 is post-translationally stabilized by somatic SPOP mutations, and that stabilized GLI3 partners with AR to induce a gene expression program that promotes tumor cell proliferation in vitro and in vivo. CRPC patients whose tumors expressed the GLI3 gene signature displayed higher biochemical relapse rates, suggesting that the signature may identify patients at high risk of disease progression. Overall, the presented data provide a novel mechanistic link between SPOP mutations and SHH-mediated AR signaling activation that could inform prognostic and therapeutic strategies for CRPC moving forward.The efficacy of antiangiogenic cancer therapies has been limited by side effects and therapeutic resistance, suggesting that targeting angiogenesis alongside other oncogenic processes may be more effective than targeting angiogenesis alone. Recent work linking low IQ motif-containing GTPase-activating protein 2 (IQGAP2) expression to breast tumor epithelial–mesenchymal transition (EMT), angiogenesis, and poor patient outcomes makes IQGAp. an intriguing therapeutic candidate. Kumar and colleagues used IQGAP2 ablation and overexpression in both estrogen receptor-positive and -negative breast cancer cell lines to demonstrate that IQGAP2 reduction in those cell lines increases endothelial cell proliferation and migration. Accordingly, IQGAP2 reduction increased vascular density in chick chorioallantoic membranes and wound healing assays, which supported the authors' observation that IQGAP2 expression inversely correlated with endothelial cell abundance in tumor cells from breast cancer patients. The authors mechanistically attributed their findings to increased ERK-VEGF-A signaling in tumor cells, which activated VEGFR2-AKT signaling in endothelial cells. Results from the study position IQGAP2 as a next-generation anti-angiogenic therapeutic target potentially capable of simultaneously inhibiting angiogenesis and EMT.Draining lymph node metastasis is often noted upon nasopharyngeal carcinoma (NPC) diagnosis, and can mark an initial stage of progressive metastatic dissemination. While Epstein-Barr virus (EBV) has long been associated with NPC, its role in initial metastatic processes has not been defined. In their study, Li and colleagues used EBV-infected and functional EBV knockout NPC cell lines to demonstrate that EBV-positive NPC induces lymphatic endothelial cell proliferation and migration. Gene expression analysis revealed elevated VEGF-C expression in NPC infected with EBV, and the authors showed that VEGF-C was responsible for EBV-induced lymphangiogenesis. Further work demonstrated that EBV miRNA BART15 targets PHLPP1 in NPC cells, resulting in increased AKT phosphorylation, HIF-1α activation, and VEGF-C production. Moreover, patients with EBV-positive NPC displayed higher levels of lymphangiogenesis and lymph node metastasis. Taken together, the presented work sheds light on how EBV induces early NPC progression and elucidates a molecular pathway that could be therapeutically targeted.

1682P Effects of a walking football program on muscle strength and balance of androgen deprived prostate cancer patients: The Prostata_Move trial

Prostate cancer (PrC) patients undergoing androgen deprivation therapy (ADT) may suffer from several adverse events, such as deterioration of physical fitness. The main aim of this work was to analyze the impact of walking football on muscle strength and balance in PrC survivors.

Reduction in prostate cancer hospitalizations in the COVID-19 pandemic epicenter of Latin America.

e18814 Background: The novel SARS-CoV-2 coronavirus disease 2019 (COVID-19) has disrupted health care systems worldwide since December 2019 causing atypical pneumonia and affecting multiple body organs. In Latin America, COVID-19 had its first case in the megacity of São Paulo, Brazil, thus being the starting point and epicenter of this disease. In this context, prostate cancer (PC) is the most common non-skin cancer among men and its preventive healthcare is substantial to public health surveillance. Additionally, PC raises particular interest during COVID-19 outbreak as PC androgen-deprivation therapies have shown to mitigate SARS-CoV-2 infection, which suggests an association between SARS-CoV-2 and PC cells. Thus, the consequences of the COVID-19 outbreak on male genital cancers care remain inconclusive and will probably be felt for decades. This study aimed to determine the impact of pandemic on the incidence of hospital admissions (HA) due to malignant neoplasms of male genital organs in the city of São Paulo, Brazil. Methods: This is a cross-sectional study of the HAs due to malignant neoplasms of male genital organs in the city of São Paulo comparing the outbreak period (January-June 2020) and a pre-pandemic corresponding period of the years 2017-2019. Data were obtained from the Brazilian Unified Health System - Hospital Information System database according to the chapter II of the International Classification of Diseases - 10th revision (ICD-10). Linear regression was used to analyze the relationship between the incidence of HAs and time (months). Results: A significant reduction in HAs due to malignant neoplasms of male genital organs was observed in PC, but not other malignant neoplasms of male genital organs during the outbreak period (January-June 2020). PC (-19, CI -36 to -1) showed to be remarkably affected while other male genital cancers (-1, CI -5 to 3) did not (Table). Conclusions: Our findings seem to be associated to delayed oncological care delivery to PC during the lockdown and health system disruption. Further studies are required to evaluate the impact of the ongoing pandemic in malignant neoplasm of male genital organs, particularly PC, in order to strategically corroborate public health actions for implications of COVID-19 pandemic. Linear regression of hospital admissions for the years 2017-2020 (January until June) due to malignant neoplasms of male genital organs (chapter II of the ICD-10). Municipality of São Paulo, São Paulo, Brazil.[Table: see text]

Androgen deprivation in prostate cancer: benefits of home-based resistance training

IntroductionAndrogen deprivation therapy (ADT) has detrimental effects on body composition, metabolic health, physical functioning, bone mineral density (BMD) and health-related quality of life (HRQOL) in men with prostate cancer. We investigated whether a 12-month home-based progressive resistance training (PRT) programme, instituted at the start of ADT, could prevent these adverse effects.MethodsTwenty-five patients scheduled to receive at least 12 months of ADT were randomly assigned to either usual care (UC) (n = 12) or PRT (n = 13) starting immediately after their first ADT injection. Body composition, body cell mass (BCM; a functional component of lean body mass), BMD, physical function, insulin sensitivity and HRQOL were measured at 6 weeks and 6 and 12 months. Data were analysed by a linear mixed model.ResultsADT had a negative impact on body composition, BMD, physical function, glucose metabolism and HRQOL. At 12 months, the PRT group had greater reductions in BCM by − 1.9 ± 0.8 % (p = 0.02) and higher gains in fat mass by 3.1 ± 1.0 % (p = 0.002), compared to the UC group. HRQOL domains were maintained or improved in the PRT versus UC group at 6 weeks (general health, p = 0.04), 6 months (vitality, p = 0.02; social functioning, p = 0.03) and 12 months (mental health, p = 0.01; vitality, p = 0.02). A significant increase in the Matsuda Index in the PRT versus UC group was noted at 6 weeks (p = 0.009) but this difference was not maintained at subsequent timepoints. Between-group differences favouring the PRT group were also noted for physical activity levels (step count) (p = 0.02). No differences in measures of BMD or physical function were detected at any time point.ConclusionA home-based PRT programme instituted at the start of ADT may counteract detrimental changes in body composition, improve physical activity and mental health over 12 months.Trial registrationAustralian and New Zealand Clinical Trials Registry, ACTRN12616001311448

This Month in Adult Urology

This Month in Adult Urology

Synthetic Lethal Metabolic Targeting of Androgen-Deprived Prostate Cancer Cells with Metformin.

The initiation of androgen-deprivation therapy (ADT) induces susceptibilities in prostate cancer cells that make them vulnerable to synergistic treatment and enhanced cell death. Senescence results in cell-cycle arrest, but cells remain viable. In this study, we investigated the mechanisms by which prostate cancer cells undergo senescence in response to ADT, and determined whether an FDA-approved antidiabetic drug metformin has a synergistic effect with ADT in prostate cancer both in vitro and in vivo Our results show that longer term exposure to ADT induced senescence associated with p16INK4a and/or p27kip2 induction. The activation of PI3K/AKT and inactivation of AMPK in senescent cells resulted in mTORC1 activation. In addition, the antiapoptotic protein XIAP expression was increased in response to ADT. The addition of metformin following ADT induced apoptosis, attenuated mTOR activation, reduced senescent cell number in vitro, and inhibited tumor growth in prostate cancer patient-derived xenograft models. This study suggests that combining ADT and metformin may be a feasible therapeutic approach to remove persistent prostate cancer cells after ADT.

Relative Timing of Radiotherapy and Androgen Deprivation for Prostate Cancer and Implications for Treatment During the COVID-19 Pandemic

This cohort study uses National Cancer Database data from 2004 to 2014 to examine the association between overall survival and timing of radiotherapy relative to androgen deprivation therapy in patients with prostate cancer.

Oral Relugolix for Androgen-Deprivation Therapy in Advanced Prostate Cancer

BackgroundInjectable luteinizing hormone–releasing hormone agonists (e.g., leuprolide) are the standard agents for achieving androgen deprivation for prostate cancer despite the initial testosterone surge and delay in therapeutic effect. The efficacy and safety of relugolix, an oral gonadotropin-releasing hormone antagonist, as compared with those of leuprolide are not known.MethodsIn this phase 3 trial, we randomly assigned patients with advanced prostate cancer, in a 2:1 ratio, to receive relugolix (120 mg orally once daily) or leuprolide (injections every 3 months) for 48 weeks. The primary end point was sustained testosterone suppression to castrate levels (<50 ng per deciliter) through 48 weeks. Secondary end points included noninferiority with respect to the primary end point, castrate levels of testosterone on day 4, and profound castrate levels (<20 ng per deciliter) on day 15. Testosterone recovery was evaluated in a subgroup of patients.ResultsA total of 622 patients received relugolix and 308 received leuprolide. Of men who received relugolix, 96.7% (95% confidence interval [CI], 94.9 to 97.9) maintained castration through 48 weeks, as compared with 88.8% (95% CI, 84.6 to 91.8) of men receiving leuprolide. The difference of 7.9 percentage points (95% CI, 4.1 to 11.8) showed noninferiority and superiority of relugolix (P<0.001 for superiority). All other key secondary end points showed superiority of relugolix over leuprolide (P<0.001). The percentage of patients with castrate levels of testosterone on day 4 was 56.0% with relugolix and 0% with leuprolide. In the subgroup of 184 patients followed for testosterone recovery, the mean testosterone levels 90 days after treatment discontinuation were 288.4 ng per deciliter in the relugolix group and 58.6 ng per deciliter in the leuprolide group. Among all the patients, the incidence of major adverse cardiovascular events was 2.9% in the relugolix group and 6.2% in the leuprolide group (hazard ratio, 0.46; 95% CI, 0.24 to 0.88).ConclusionsIn this trial involving men with advanced prostate cancer, relugolix achieved rapid, sustained suppression of testosterone levels that was superior to that with leuprolide, with a 54% lower risk of major adverse cardiovascular events. (Funded by Myovant Sciences; HERO ClinicalTrials.gov number, NCT03085095.)

CREB5 Promotes Resistance to Androgen-Receptor Antagonists and Androgen Deprivation in Prostate Cancer

SUMMARYAndrogen-receptor (AR) inhibitors, including enzalutamide, are used for treatment of all metastatic castration-resistant prostate cancers (mCRPCs). However, some patients develop resistance or never respond. We find that the transcription factor CREB5 confers enzalutamide resistance in an open reading frame (ORF) expression screen and in tumor xenografts. CREB5 overexpression is essential for an enzalutamide-resistant patient-derived organoid. In AR-expressing prostate cancer cells, CREB5 interactions enhance AR activity at a subset of promoters and enhancers upon enzalutamide treatment, including MYC and genes involved in the cell cycle. In mCRPC, we found recurrent amplification and overexpression of CREB5. Our observations identify CREB5 as one mechanism that drives resistance to AR antagonists in prostate cancers.

The clinical relevance of adiposity when assessing muscle health in men treated with androgen deprivation for prostate cancer.

BackgroundAndrogen deprivation therapy (ADT) for prostate cancer (PCa) may prospectively decrease absolute lean mass (LM) and increase absolute fat mass (FM). Given that estimates of LM by dual‐energy X‐ray absorptiometry may be overestimated in obese people, this study examined the influence of adiposity on muscle health in men treated with ADT for PCa.MethodsThis cross‐sectional study examined the influence of adiposity on total and appendicular LM (ALM), muscle cross‐sectional (CSA), and muscle strength in 70 men treated with ADT [mean (standard deviation) age, 71 (6) years] for PCa compared with age‐matched PCa (n = 52) and healthy controls (n = 70). Total body LM, FM and ALM, and 66% tibia and radius muscle CSA were quantified by dual‐energy X‐ray absorptiometry and peripheral quantitative computed tomography, respectively. ALM was further divided by height (m2) or body mass index, with muscle CSA expressed as a per cent of total limb CSA. Upper and lower body and back (three‐repetition maximum and dynamometry) muscle strength were expressed per kilogram of body weight.ResultsOn average, ADT‐treated men had 4.4–6.4 kg greater FM compared with controls (P ≤ 0.014) and there were no differences in total body or ALM. Total body per cent LM and ALMBMI were 3.8–5.4% (P ≤ 0.001) and 7.8–9.4% (P ≤ 0.001) lower, respectively, in ADT‐treated men compared with both controls. Percentage muscle CSA at both sites and muscle strength (except leg) were 3.0–6.0% (P ≤ 0.031) and 15–17% (P ≤ 0.010) lower, respectively, in ADT‐treated men compared with both controls.ConclusionsThe findings from this study indicate muscle mass, size, and strength are compromised in men treated with ADT after accounting for their increased adiposity or body size.

Engineering osteoblastic metastases to delineate the adaptive response of androgen-deprived prostate cancer in the bone metastatic microenvironment

While stromal interactions are essential in cancer adaptation to hormonal therapies, the effects of bone stroma and androgen deprivation on cancer progression in bone are poorly understood. Here, we tissue-engineered and validated an in vitro microtissue model of osteoblastic bone metastases, and used it to study the effects of androgen deprivation in this microenvironment. The model was established by culturing primary human osteoprogenitor cells on melt electrowritten polymer scaffolds, leading to a mineralized osteoblast-derived microtissue containing, in a 3D setting, viable osteoblastic cells, osteocytic cells, and appropriate expression of osteoblast/osteocyte-derived mRNA and proteins, and mineral content. Direct co-culture of androgen receptor-dependent/independent cell lines (LNCaP, C4-2B, and PC3) led cancer cells to display functional and molecular features as observed in vivo. Co-cultured cancer cells showed increased affinity to the microtissues, as a function of their bone metastatic potential. Co-cultures led to alkaline phosphatase and collagen-I upregulation and sclerostin downregulation, consistent with the clinical marker profile of osteoblastic bone metastases. LNCaP showed a significant adaptive response under androgen deprivation in the microtissues, with the notable appearance of neuroendocrine transdifferentiation features and increased expression of related markers (dopa decarboxylase, enolase 2). Androgen deprivation affected the biology of the metastatic microenvironment with stronger upregulation of androgen receptor, alkaline phosphatase, and dopa decarboxylase, as seen in the transition towards resistance. The unique microtissues engineered here represent a substantial asset to determine the involvement of the human bone microenvironment in prostate cancer progression and response to a therapeutic context in this microenvironment.

Exercise medicine across the cancer trajectory

Physical exercise is essential to maintaining human health and is now recognised by the American College of Sports Medicine and the American Heart Association as an essential component for both the prevention and management of chronic disease, injury and other illnesses. Previously, the recommendation for cancer treatment-related adverse effects had been rest; however, research on exercise has challenged this recommendation. It has become increasingly clear that exercise plays an important role in the management of many cancer patients and survivors across the disease trajectory (e.g. pre-, during and post-treatment). We have demonstrated clinical benefits of resistance training for improving physical and muscle function in prostate cancer survivors undergoing androgen deprivation therapy with significant improvements in muscle strength, physical function, balance, and cardiorespiratory fitness. We have also reported the rapid loss of bone and lean mass and increased total body fat due to androgen deprivation for prostate cancer and established the efficacy of exercise as medicine to reverse muscle loss, improve physical function and quality of life including general health, and reduce fatigue and low-grade systemic inflammation. This work has been further expanded in older cancer survivors who had completed primary therapy and in those with advanced bone disease. In addition, preliminary work indicates improved physical function post-surgery in patients with lung, colorectal and prostate cancer involved in prehabilitation programs. Exercise has also been shown to have numerous positive effects in breast cancer survivors during and following treatment including potential increase in chemotherapy completion. Evidence from large observational studies also suggests that regular exercise post-diagnosis is associated with increased survival in patients with breast, colorectal and prostate cancer. This presentation will cover clinical studies in exercise oncology across the cancer continuum from prehabilitation to long-term survivorship.

Androgen deprivation in prostate cancer and the long-term risk of fracture

ObjectivesTo determine the rate of bone mass loss and the risk of fracture induced by androgen deprivation therapy in patients with prostate cancer. Material and methodsProspective study in 2 phases. In the first phase, demographic variables, FRAX®, bone mineral density and clinical fractures were collected, before starting the therapy and up to 1 year after ending the therapy. In the second phase, we conducted a telephone interview a mean of 8.5 years after the start of the study to assess new fractures. ResultsWe included 150 patients with a mean age of 67 years and a mean therapy duration of 24 months. Before starting the treatment, 62 patients (41%) showed osteoporosis or low bone mass in the densitometry. After the first year of treatment, the bone mineral density decreased a mean of 3.7% and 2.1% in the lumbar spine and femoral neck, respectively. At the end of the second and third year, the loss rate was lower. During the first phase of the study, 4 patients (2.7%) experienced a fracture. In the telephone interviews with 80 patients (53%), only 1 had experienced a fracture. ConclusionsIn the patients with prostate cancer and androgen deprivation therapy, greater bone loss occurred during the first year. When the treatment did not exceed 2 years, the absolute risk of fracture was low, and clinical fractures were uncommon in the short and long term.

Androgen deprivation in prostate cancer: first do no harm

Androgen deprivation in prostate cancer: first do no harm