Treatment Of Prostate Cancer Research Articles

Methylation-based immune deconvolution in prostate cancer patients before and after radical prostatectomy.

Surgery, an established short-term immunosuppressive event, may spur dissemination of circulating tumor cells and promote the growth of micrometastases. Whether surgical treatment for prostate cancer (i.e., radical prostatectomy) leads to long-term immune changes is unknown. We characterized intra-individual changes in circulating immune cell subsets across a six-month period using serial blood samples from prostate cancer patients pre- and post-radical prostatectomy (n = 11), and from a comparison group managed with active surveillance (n = 8). Immune cell subsets for each patient at each time point were deconvoluted using genome-wide methylation data. There were no statistically significant intra-individual changes in immune cell proportions from pre- to six months post-radical prostatectomy. There were also no intra-individual changes in immune cell proportions in the active surveillance group, and no differences between treatment groups in immune cell changes over time. We observed no meaningful changes in circulating immune cell subsets six months after radical prostatectomy, suggesting that surgery-induced immune changes may not be long-lasting.

How do Japanese patients really feel about losing potency after radical prostatectomy? (MAJI study).

To investigate actual patients' feelings about losing erectile function because of treatment for prostate cancer. The study participants were 20 patients who were going to receive robot-assisted laparoscopic radical prostatectomy without nerve sparing. Before surgery, we interviewed them using an original questionnaire. The questionnaire included inquiries concerning their feelings about losing sexual function, whether they were sad or not, wanted to preserve sexual function, wanted to receive treatment if there were one that would restore sexual function and how much they would be willing to pay to recover their sexual function. The median age of the participant was 67 years (range 60-73 years). Fourteen patients (70%) were sad about losing their sexual function and 17 (85%) wanted to preserve it if they could. Thirteen patients (65%) wanted to receive treatment that would restore their lost sexual function, and they thought that they would be willing to pay a median of 500 000 yen (range 0-1 000 000 yen) to recover it. Most of the patients felt sad about losing their potency just before radical prostatectomy without nerve sparing. Although almost all patients wanted to preserve their sexual function if they could, they did not want to spend a great deal of money for it.

Current status, evolution, and future perspectives in robotic platform systems for prostate cancer treatment: a narrative review.

Robotic surgery has contributed greatly to the shift from traditional surgery to minimally invasive surgery. Urology is the major field of application of robotic surgery. Several urological procedures, especially radical prostatectomy, benefit from the use of robotic surgery. Non-systematic research of the literature was performed using "Robot-assisted radical prostatectomy" and "Robotic platforms" as keywords to understand the actual situation and the future perspectives of this technology in prostate cancer treatment. The robotic platform landscape is constantly evolving. DaVinci has always been the mainstay in this field, particularly after the advent of the new single port platforms. New platforms are emerging, providing an alternative option to the well-known DaVinci system. Since in literature, few studies compare the use of different robotic platforms, their application in urological procedures is not yet widely used, for both oncological and non-oncological procedures. Furthermore, artificial intelligence begins to play a role in this landscape and could be useful for future developments. So further studies are warranted to give a full comprehension of the whole scenario. This review aims to analyze the current state of the use of robotic platforms in urology, particularly in radical prostatectomy, and to understand the evolution.

The Androgen Deprivation Therapy Landscape in 2024 – Co-navigating the Available Options with Prostate Cancer Patients

This symposium convened during the 2024 European Association of Urology (EAU) Congress in Paris, France, focusing on the multifaceted aspects of prostate cancer (PCa) treatment from the patient’s perspective. The session delved into the nuanced needs, expectations, and treatment experiences encountered by individuals diagnosed with this condition. A pivotal aspect of the discussion centred on the imperative of ensuring patient awareness and informed consent, particularly concerning androgen deprivation therapy (ADT), given its array of potential side effects. ADT, a cornerstone in advanced PCa management, encompasses a spectrum of side effects including both physical and psychological dimensions. These include, but are not limited to, body hair loss, weight fluctuations, mood alterations, decreased libido, cognitive impairments, muscle atrophy, and bone density loss. Effective management of these side effects requires comprehensive support to be provided to patients to mitigate complications and optimise quality of life. The options for ADT were discussed, with their comparative strengths and challenges. ADT strategies take effect over different time periods (from 12 hours up to 4 weeks), exert varying effects on testosterone levels, and carry different side effect profiles. Selecting the optimal course of treatment for localised or locally advanced PCa requires consideration of whether the patient is at intermediate-, high-, or very high-risk of biochemical recurrence, and whether the intermediate-risk disease is classified as favourable intermediate-risk (FIR) or unfavourable intermediate-risk (UIR). While continuous ADT is the standard of care, intermittent ADT has been associated with significantly better quality of life scores for hot flushes, desire for sexual activity, and urinary symptoms, with a trend toward improvement in the level of fatigue. Furthermore, the interplay between PCa, ADT, and cardiovascular disease (CVD) was discussed to underscore the imperative for clinicians to assess the cardiovascular risks associated with ADT, particularly in patients with heightened cardiovascular vulnerability. Mitigating the adverse skeletal effects of ADT mandates a multifaceted approach encompassing nutritional supplementation, exercise regimens, and lifestyle modifications including alcohol cessation and smoking cessation. Integrating a prehabilitation checklist into clinical practice emerges as a pragmatic strategy to facilitate informed discussions regarding the potential adverse effects of ADT, enabling proactive support provision to optimise patient outcomes.

Metformin in Overcoming Enzalutamide Resistance in Castration-Resistant Prostate Cancer.

Androgen deprivation is the standard treatment for prostate cancer (PCa) patients. However, the disease eventually progresses as castration-resistant PCa (CRPC). Enzalutamide, an AR inhibitor, is a typical drug to treating CRPC and due to continuous reliance on the drug, can lead to Enzalutamide-resistance (ENZ-r). This highlights the necessity for developing novel therapeutic targets to combat the gain of resistance. Metformin has been recently investigated for its potential anti-tumorigenic effects in many cancer types. In this study, we used enzalutamide and metformin in combination to explore the possible rescued efficacy of enzalutamide in the treatment of ENZ-r CRPC. We first tested the effects of this combination treatment on cell viability, drug synergy, and cell proliferation in ENZ-r CRPC cell lines. After combination treatment, we observed a decrease in cell proliferation and viability as well as a synergistic effect of both enzalutamide and metformin in vitro Following these results, we sought to explore how combination treatment effected mitochondrial fitness utilizing mitochondrial stress test analysis and mitochondrial membrane potential (MMP) shifts due to metformin's action in inhibiting Complex I of oxidative phosphorylation. We employed 2 different strategies of in vivo testing using 22Rv1 and LuCaP35CR xenograft models. Finally, RNA sequencing revealed a potential link in the downregulation of Ras/MAPK signaling following combination treatment. Significance Statement Increasing evidence suggests that oxidative phosphorylation might play a critical role in the development of resistance to cancer therapy. We showed that targeting oxidative phosphorylation with metformin can enhance the efficacy of enzalutamide in castration-resistant prostate cancer in vitro.

CACA guidelines for holistic integrative management of prostate cancer

Prostate cancer (PC) is an epithelial malignancy occurring in the prostate. PC ranks second in incidence among all male malignancies globally by the latest statistics from the World Health Organization. Notably, China has seen a more rapid increase in PC incidence compared to developed European and American nations. By 2022, the newly reported cases and deaths due to PC in China increased to 134,200 and 47,500, respectively. Thus, early diagnosis and standardized treatment for prostate cancer in China remain far-reaching objectives. Burgeoning research on advanced PC and castration-resistant prostate cancer in recent years have paved the way for a new era of integrated treatment methods including novel endocrine drugs, chemotherapy, targeted therapy, and immunotherapy. Future therapies involve precision treatment guided by genetic testing and individualized integrated treatment as part of a multidisciplinary integrated diagnosis and treatment model for PC. The Genitourinary Oncology Committee of the China Anti-Cancer Association (CACA-GU) has invited multidisciplinary experts across fields including surgery, oncology, pathology, radiology, herbal medicine, physiatry, and psychology to collaboratively write, discuss, and revise guidelines on managing PC. The CACA Guidelines for Holistic Integrative Management of Prostate Cancer includes epidemiology, screening and diagnosis, treatment for localized PC, diagnosis and treatment of PC recurrence after radical prostatectomy, management of metastatic PC, traditional Chinese medicine diagnosis and treatment of PC, and rehabilitation from PC. This guideline aims to standardize the clinical diagnosis and treatment management of PC in China. It is more aligned with China’s clinical practice, highlights Chinese characteristics, and bears significant clinical importance.

Comparative Transcriptomes of Canine and Human Prostate Cancers Identify Mediators of Castration Resistance.

Prostate cancer continues to be one of the most lethal cancers in men. While androgen deprivation therapy is initially effective in treating prostate cancer, most cases of advanced prostate cancer eventually progress to castration-resistant prostate cancer (CRPC), which is incurable. Similarly, the most aggressive form of prostatic carcinoma occurs in dogs that have been castrated. To identify molecular similarities between canine prostate cancer and human CRPC, we performed a comparative analysis of gene expression profiles. Through this transcriptomic analysis, we found that prostatic carcinoma in castrated dogs demonstrates an androgen-indifferent phenotype, characterised by low-androgen receptor and neuroendocrine-associated genes. Notably, we identified two genes, ISG15 and AZGP1, that were consistently up- and down-regulated, respectively, in both canine prostatic carcinoma and human CRPC. Additionally, we identified several other genes, including GPX3, S100P and IFITM1, that exhibited similar expression patterns in both species. Protein-protein interaction network analysis demonstrated that these five genes were part of a larger network of interferon-induced genes, suggesting that they may act together in signalling pathways that are disrupted in prostate cancer. Accordingly, our findings suggest that the interferon pathway may play a role in the development and progression of CRPC in both dogs and humans and chart a new therapeutic approach.

Plant-based diets and urological health.

Plant-based diets have grown in popularity owing to multiple health and environmental benefits. Some evidence suggests that plant-based diets are associated with benefits for urological health. In genitourinary oncology, most research has focused on prostate cancer. Clinical trial results suggest a favourable influence of healthy lifestyle modifications including plant-based diets before and after prostate cancer treatment. Epidemiological evidence shows that a diet higher in plant-based and lower in animal-based food is associated with a lower risk of aggressive prostate cancer and better quality-of-life scores than a diet with less plant-based and more animal-based food. Studies on bladder and kidney cancer are scarce, but limited data suggest that vegetarian or plant-forward dietary patterns (increased consumption of fruits and vegetables and minimizing meat) are associated with a lower risk of development of these cancers than dietary patterns with fewer fruits and vegetables and more meat. With respect to benign urological conditions, epidemiological studies suggest that plant-based dietary patterns are associated with a lower risk of benign prostatic hyperplasia and urinary tract infections than non-plant-based dietary patterns. Compared with diets high in animal-based foods and low in plant-based foods, a substantial body of epidemiological evidence also suggests that increased consumption of healthy plant-based food is associated with a lower risk of erectile dysfunction. Plant-based dietary patterns that are high in fruits and vegetables with normal calcium intake, while limiting animal protein and salt, are associated with a lower risk of kidney stone development than dietary patterns that do not follow these parameters. Overall, increasing consumption of plant-based foods and reducing intake of animal-based foods has favourable associations with multiple urological conditions.

PASS Assisted Prediction and Meta-analysis of Active Phytoconstituents of <i>Guggul</i> for the Treatment of Chronic Prostatitis: A Gateway to Cure Prostate Cancer

Background: Mostly men are particularly prone to prostate cancer as well as chronic prostatitis the underlying causes behind prostate cancer as well as chronic prostatitis are multifaceted as well as diverse a spike in serum prostate-specific antigen characterises both diseases. Chronic prostatitis is prostate inflammation independent of the source inflammation and is linked to a variety of malignancies in general along with prostate inflammatory reactions that are thought to have a contributing influence on the advancement and growth of prostate cancer. Aim: This study aims to identify different phytoconstituents of Guggulu for treating chronic prostatitis along with meta-analysis. Meta-analysis is used as an analytical technique to aggregate results of separate inferential statistics investigations of clinical data on chronic prostatitis. Methods: Phytochemical ingredients were analyzed using PASS estimates. Canonical SMILES were identified to determine Pa values. PASS software was then used to forecast activities. Doxycycline, a conventional drug for chronic prostatitis, was selected for comparison. Data was collected using the PASS online program to estimate physiological and biochemical parameters. The activities of all constituents were then compared against doxycycline. Results: The results indicate that Guggul sterone Z shows promise as a candidate for further investigation in medication therapy for chronic prostatitis. A meta-analysis aims to identify clinical trials for this phytoconstituent, which has yielded the highest number of results. PASS prediction findings reveal that Guggul sterone Z, followed by Mansumbinone, 16-dehydroprogesterone, and alpha-pinene, exhibit the most significant activities. Conclusion: The study forecasted that Guggul sterone Z, Mansumbinone, 16-dehydroprogesterone and alpha-pinene are the potential phytoconstituents that can play a vital role in the development of novel treatments for chronic prostatitis-induced prostate cancer.

The use of focal therapy for the treatment of prostate cancer in Canada: Where are we, how did we get here, and where are we going?

Focal therapy is an emerging treatment for localized prostate cancer. The objectives of this review were to: 1) review how focal therapies are regulated and approved; 2) summarize the scope and quality of the literature regarding safety, efficacy, and side-effects; and 3) outline ongoing clinical trials of focal therapy in Canada. Using the PRISMA framework for scoping reviews, we searched PubMed, Embase, and Cochrane from 2021-2024, complementing Hopstaken et al's search up functional and oncologic outcomes. Additionally, we examined the FDA database for regulatory details and ongoing trials in Canada via ClinicalTrial.gov. FDA approval for prostate tissue ablation was granted to high-intensity focused ultrasound (HIFU) in 2015 via the de novo pathway; other therapies followed the 510(k) route, citing equivalence to predicate devices. Most studies are in early stages, primarily single-arm, prospective cohort designs. Oncologic outcomes like cancer detection and survival rates, alongside functional data, such as adverse events and erectile function, were assessed. Recurrence-free survival at 48 months ranged from 58-92%, pad-free rates were greater than 95%, and rates of new-onset erectile dysfunction were variable, ranging from no change to 50%. Rates of serious adverse events (SAEs) were low, ranging from 0-14%. Three Canadian clinical trials are actively enrolling participants, and five private clinics were found offering private HIFU, irreversible electroporation (IRE), or transurethral ultrasound ablation (TULSA). Focal therapy technologies have gained regulatory approval for prostate tissue ablation, and, aside from provincial support for cryoablation in Alberta, are available to Canadians through private payment or clinical trials. Many studies demonstrate promising cancer control and impressive functional outcomes but are limited by their short followup and lack of comparator group. Clinical trial or registry participation should be prioritized to ensure an evidence-based integration into current prostate cancer treatment approaches.

Advancements in prostate zone segmentation: integrating attention mechanisms into the nnU-Net framework

Abstract Prostate cancer is one of the most lethal cancers in the world. Early diagnosis is essential for successful treatment of prostate cancer. Segmentation of prostate zones in magnetic resonance images is an important task in the diagnosis of prostate cancer. Currently, the state-of-the-art method for this task is no-new U-Net. In this paper, a method to incorporate the attention U-Net architecture into no-new U-Net is proposed and compared with a classical U-net architecture as research. The experimental results indicate that there is no significant statistical difference between the proposed modification of no-new U-Net with the generalizability of the attention mechanism or the ability to achieve more accurate results. Moreover, two novel workflows are proposed for prostate segmentation, transitional zone segmentation and peripheral zone calculation workflow, and separate models for peripheral zone and transitional zone segmentation workflow. These workflows are compared with a baseline single peripheral zone and transitional zone segmentation model workflow. The experimental results indicate that separate models for peripheral zone and transitional zone segmentation workflow generalizes better than the baseline between data sets of different sources. In peripheral zone segmentation separate models for peripheral zone and transitional zone segmentation workflow achieves 1.9% higher median Dice score coefficient than the baseline workflow when using the attention U-Net architecture and 5.6% higher median Dice score coefficient when using U-Net architecture. Moreover, in transitional zone segmentation separate models for peripheral zone and transitional zone segmentation workflow achieves 0.4% higher median Dice score coefficient than the baseline workflow when using the attention U-Net architecture and 0.7% higher median Dice score coefficient when using U-Net architecture. Meanwhile, prostate segmentation, transitional zone segmentation and peripheral zone calculation workflow generalizes worse than the baseline. In peripheral zone segmentation prostate segmentation, transitional zone segmentation and peripheral zone calculation workflow achieves 4.6% lower median Dice score coefficient than the baseline workflow when using the attention U-Net architecture and 3.6% lower median Dice score coefficient when using U-Net architecture. In transitional zone segmentation prostate segmentation, transitional zone segmentation and peripheral zone calculation workflow achieves a similar median Dice score coefficient to the baseline workflow.

6463 A Case of Tumour-Induced Osteomalacia Which Remitted After Treatment of Metastatic Prostate Cancer

Abstract Disclosure: J. Chua: None. M. Chuah: None. A case Tumour-induced osteomalacia (TIO) which remitted after treatment of metastatic prostate cancer. Dr Chua Jia Min, Dr Matthew Chuah Bingfeng Abstract Case report: A 69-year-old gentleman with a known history of bladder cancer presented to the emergency department with fatigue, lower back pain and bilateral lower limb weakness worsening over the past one month. MRI and bone scan revealed extensive osteoblastic bone metastases across the skeletal system. This gentleman was referred to the Endocrinology service for the evaluation of high PTH. His corrected calcium was normal at 2.17mmol/L (2.09-2.46mmol/L) and iPTH was raised at 8.74pmol/L (1.60-6.90pmol/L). He was noted to have severe hypophosphatemia 0.34mmol/L (0.94-1.50mmol/L). Bicarbonate levels were normal, there was no glycosuria or proteinuria. There was no history of IV ferrous carboxymaltose use. Further investigations were consistent with urinary phosphate loss - TRP was 0.398 and TMP-GFR was 0.199. ALP was elevated at 282ug/L (39-99ug/L). 25-hydroxyvitamin D was low at 12 ug/L, which accounted for the high PTH levels (secondary hyperparathyroidism). FGF-23 levels returned high at 1293 RU/ml (<180 RU/ml). BMD showed osteoporosis with T-score of -2.6 at the left femoral neck. He was subsequently diagnosed with metastatic prostate adenocarcinoma, based on histology from a bone biopsy of an affected vertebrae. PSA was markedly raised at 606ug/L. A diagnosis of TIO secondary to metastatic prostate cancer was made. The patient was started on PO sodium-phosphate solution 4ml TDS (approximately 3mmol/kg/day of elemental phosphorus), calcitriol 0.25mcg BD and vitamin D was replaced. After phosphate was replete, the patient's weakness and fatigue improved. He was subsequently started on androgen deprivation therapy with leuprorelin acetate injection once every 3 months and apalutamide daily. SC denosumab 60mg Q6monthly was also commenced in view of extensive bone metastases. Repeat imaging showed response to treatment with decrease in the size of the prostate and bone lesions. His PSA levels are now undetectable and TMP-GFR has normalised. His oral phosphate and calcitriol doses were gradually reduced and subsequently stopped. His calcium and phosphate levels remain within normal limits on no supplementation, suggesting remission of his TIO. PTH levels normalised after vitamin D repletion. Learning points TIO is a rare paraneoplastic syndrome usually associated with mesenchymal tumours, and treatment involves resection of the causative tumour. Cases of TIO secondary to prostate cancer (an epithelial cancer) are exceedingly rare. Despite metastatic disease, this patient responded exceedingly well to his cancer therapy. Suppression of the tumour cells with androgen deprivation therapy resulted in the lack of phosphotonin production and remission of his TIO. Presentation: 6/1/2024

8553 GDF-15 Levels In Patients With Prostate Cancer On Androgen Deprivation Therapy

Abstract Disclosure: S.D. Jaramillo-Quiroz: Other; Self; VAPSHCS: Director Fund Research Fellowship/UW Abrass Family Fellowship Fund. CDMRP (PC170059).. L. Caeiro: None. L.J. Anderson: None. J.M. Garcia: None. Growth Differentiation Factor 15 (GDF-15) is a stress-induced cytokine known to induce anorexia and cachexia and a biomarker of biological aging, mitochondrial dysfunction, and worse hand grip strength and poor survival in different settings. Also, GDF-15 has pleiotropic functions at all stages of tumorigenicity and is suggested as a marker to differentiate BPH from PCa. Androgen Deprivation Therapy (ADT) is the standard treatment for advanced prostate cancer (PCa), but it also decreases muscle mass and function and Quality of life (QOL). The role and effects of GDF-15 in prostate cancer patients undergoing ADT are not well characterized and was explored in this longitudinal, 6-month, observational study that recruited men with (PCa) starting ADT (n=60, mean age 69). Body composition [dual energy X-ray absorptiometry (DEXA), body weight history], physical performance [handgrip strength (HGS), 6-minute walk test (6MWT), energy expenditure (indirect calorimetry and actigraphy)], were assessed before, at 3 and 6 months after starting ADT. QoL was assessed by the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-C30). GDF-15 was measured by ELISA. Mean differences performed with standard error of the mean, repeated measures ANOVA and Tukey’s Post Hoc test. Correlations were assessed by Spearman’s. After 6 months of ADT, fat mass was increased (mean difference: 1.14 ±0.38, p=0.0029), and lean muscle mass (mean difference: -1.214 ± 0.38, p=0.005), appendicular lean mass (ALM, mean difference: -0.879 ± 0.19, p=<0.0001). HGS (mean difference: -2.927 ± 0.59, p=<0.0001), and VO2 max decreased (mean difference -3.31 ± 0.83, p=0.0007). Baseline GDF-15 (mean 1456.59 ± 1022.80) was correlated with the changes in weight (r: -0.38, p=0.01), BMI (r: -0.33, p=0.01), ALM (r: -0.29, p=0.04), and fatigue (r: -0.38, p=0.004). As shown, baseline GDF-15 was inversely correlated with changes in weight, appendicular lean mass, and fatigue in subjects undergoing ADT, highlighting the possibility of its role as a biomarker and therapeutic target of body composition and patient-reported outcomes in this setting. Presentation: 6/1/2024

8127 HOMA-IR Predicts Muscle Wasting During Androgen Deprivation Therapy

Abstract Disclosure: L. Caeiro: None. L.J. Anderson: None. H. Liu: None. J.M. Garcia: None. Androgen deprivation therapy (ADT) is the primary treatment for advanced and metastatic prostate cancer. However, it induces adverse effects like reduced muscle mass and function, increased adiposity, and insulin resistance (IR). While muscle wasting is a known complication of ADT-induced hypogonadism, the extent to which other factors determine the variability in muscle loss remains unknown. In other diseases, IR is associated with muscle wasting, but its role in this setting of ADT has yet to be addressed. We hypothesized that patients with greater IR pre-ADT would display larger decreases of muscle mass and function after six months of ADT. Insulin and glucose (to calculate HOMA-IR), body composition, and physical function were assessed in patients with prostate cancer prior to and after three and six months of ADT. Body composition was assessed by dual x-ray absorptiometry and physical function by VO2 peak and 6-minute walk test (6MWT). Fasting blood samples were obtained to measure insulin and glucose in plasma. Pre-ADT, HOMA-IR was directly correlated with body mass index (BMI) (r=0.65, p<0.001, n=49), fat mass (r=0.55, p<0.001, n=49), and appendicular skeletal muscle index (ASMI) (r=0.33, p=0.021, n=49) and was inversely correlated with VO2 peak (r= -0.39, p=0.007, n=46). After three months, fat mass (p=0.015) and IR (p=0.0014) increased and VO2 peak decreased (p=0.0007), which persisted at the six-month visit. Appendicular lean mass and ASMI decreased after six months (p<0.0001). Pre HOMA-IR was negatively associated with delta BMI (r=-0.49, p<0.001, n=46), delta lean mass (r=-0.58, p<0.001, n=46), delta ASMI (r=-0.52, p<0.001, n=46), and delta 6MWT (r=-0.37, p=0.011, n=45) and positively correlated with delta VO2 peak (r=0.44, p=0.007, n=36). No associations were found with Pre-ADT HOMA-IR and changes in fat mass. In conclusion, those with greater Pre-ADT HOMA-IR lost more muscle mass, body weight, and 6MWT while unexpectedly showing less decrease in VO2 peak. This data suggests that HOMA-IR could potentially serve as a predictor of muscle mass loss in patients undergoing ADT. We propose that the significant decrease in muscle mass seen with ADT can be exacerbated by pre-existing IR. Presentation: 6/3/2024

8127 HOMA-IR Predicts Muscle Wasting during Androgen Deprivation Therapy

Abstract Disclosure: L. Caeiro: None. L.J. Anderson: None. H. Liu: None. J.M. Garcia: None. Androgen deprivation therapy (ADT) is the primary treatment for advanced and metastatic prostate cancer. However, it induces adverse effects like reduced muscle mass and function, increased adiposity, and insulin resistance (IR). While muscle wasting is a known complication of ADT-induced hypogonadism, the extent to which other factors determine the variability in muscle loss remains unknown. In other diseases, IR is associated with muscle wasting, but its role in this setting of ADT has yet to be addressed. We hypothesized that patients with greater IR pre-ADT would display larger decreases of muscle mass and function after six months of ADT. Insulin and glucose (to calculate HOMA-IR), body composition, and physical function were assessed in patients with prostate cancer prior to and after three and six months of ADT. Body composition was assessed by dual x-ray absorptiometry and physical function by VO2 peak and 6-minute walk test (6MWT). Fasting blood samples were obtained to measure insulin and glucose in plasma. Pre-ADT, HOMA-IR was directly correlated with body mass index (BMI) (r=0.65, p<0.001, n=49), fat mass (r=0.55, p<0.001, n=49), and appendicular skeletal muscle index (ASMI) (r=0.33, p=0.021, n=49) and was inversely correlated with VO2 peak (r= -0.39, p=0.007, n=46). After three months, fat mass (p=0.015) and IR (p=0.0014) increased and VO2 peak decreased (p=0.0007), which persisted at the six-month visit. Appendicular lean mass and ASMI decreased after six months (p<0.0001). Pre HOMA-IR was negatively associated with delta BMI (r=-0.49, p<0.001, n=46), delta lean mass (r=-0.58, p<0.001, n=46), delta ASMI (r=-0.52, p<0.001, n=46), and delta 6MWT (r=-0.37, p=0.011, n=45) and positively correlated with delta VO2 peak (r=0.44, p=0.007, n=36). No associations were found with Pre-ADT HOMA-IR and changes in fat mass. In conclusion, those with greater Pre-ADT HOMA-IR lost more muscle mass, body weight, and 6MWT while unexpectedly showing less decrease in VO2 peak. This data suggests that HOMA-IR could potentially serve as a predictor of muscle mass loss in patients undergoing ADT. We propose that the significant decrease in muscle mass seen with ADT can be exacerbated by pre-existing IR. Presentation: 6/3/2024

9389 Defining The Effects Of PARP Inhibition On Androgen Receptor Function In Homologous Recombination-Proficient Prostate Cancer

Abstract Disclosure: E. Wheeler: None. N. Traphagen: None. R. Li: None. A. Tewari: None. X. Qiu: None. M. Brown: None. Recent clinical trials have explored the combination of androgen receptor (AR) pathway inhibitors and poly (ADP-ribose) polymerase (PARP) inhibitors as a potential treatment for advanced prostate cancer. Despite promising preclinical evidence, this combination therapy has shown limited efficacy in patients with homologous recombination (HR)-proficient tumors. As such, combination AR pathway inhibition and PARP inhibition has been approved by the US FDA only in the HR-deficient setting. To elucidate this discrepancy between preclinical and clinical results, we aimed to comprehensively profile the effects of PARP inhibition on AR function in HR-proficient prostate cancer models. In pursuit of this goal, we conducted experiments using HR-proficient prostate cancer cell lines, including LNCaP, 22RV1, VCaP, LN95, and LNCaP-abl, and assessed the effects of the PARP1/2 inhibitors olaparib, rucaparib, talazoparib, and the PARP1-selective inhibitor AZD-5305. Our findings reveal impacts of PARP inhibitor treatment on AR function. RNA-sequencing analysis demonstrates inhibition of AR transcriptional function in PARP inhibitor-treated cells. Treatment with PARP inhibitors inhibited androgen-induced expression of a subset of genes, with analysis revealing enrichment for Hallmark MYC targets in this gene set. Conversely, treatment with PARP inhibitors also inhibited androgen-induced repression of a subset of genes. However, despite these PARP inhibitor-mediated effects on AR function, our testing of the combination of PARP inhibitors and enzalutamide showed no evidence of synergy or enhanced growth-inhibitory effects at physiologically relevant doses of these inhibitors. Additionally, contrary to previously published data, we observed no evidence that androgen deprivation inhibits the expression of DNA damage response gene sets. This is concordant with the lack of synergy between PARP inhibitors and AR inhibition found in these HR-proficient models. Finally, our analysis comparing PARP1/2 with PARP1-selective inhibitors suggests that these drugs exhibit similar biological effects, both in terms of their growth-inhibitory effects and in modulating AR activity. Collectively, our results indicate that while PARP inhibitors influence AR transcriptional function, they do not synergize with androgen deprivation or AR inhibition in HR-proficient prostate cancer cells. Presentation: 6/2/2024

7906 Nanoencapsulated Curcumin-Piperine Complex: A Breakthrough In Targeting CYP17A1 For Castration Resistant Prostate Cancer Therapy

Abstract Disclosure: J. Yakubu: None. Nanoencapsulated Curcumin-Piperine Complex: A Breakthrough in Targeting CYP17A1 for Castration Resistant Prostate Cancer Therapy. Jibira Yakubu a,b,c, Oya Taritd, Evangelos Natsaridisd, Amit V. Pandey a,ba Translational Hormone Research Program, Department of Biomedical Research, Faculty of Medicine, b Paediatric Endocrinology, Diabetology and Metabolism, University Children’s Hospital, Inselspital, Bern, c Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland. d Biointerfaces, Institute of Chemistry and Bioanalytics, University of Life Sciences FHNW, Muttenz, Switzerland. Abstract: Androgens play a pivotal role in prostate cell survival and are implicated in both early-stage and advanced, castration-resistant prostate cancer (CRPC). In CRPC patients on CYP17A1 inhibitors, the development of drug resistance and hypertensive crisis through the inhibition of CYP21A2 and or its substrate are a recognized challenge. Given its crucial role in androgen production, CYP17A1 has become a major target for cancer therapies. In this study, we employed a mini-evaporation technique to nanoencapsulate curcumin, exploring its impact on CYP17A1 activity in human adrenal NCI-H295R cells. We performed steroid profiling with LC-MS, as well as gene and protein expression studies. Initial results demonstrated that curcumin nanoparticles exhibited superior efficacy in reducing CYP17A1 activity compared to known drug Abiraterone acetate. Curcumin and piperine combined in nano-capsules greatly increased the inhibitory effects on CYP17A1 activity. Furthermore, ongoing studies include western blot investigation of the drug's interaction with the CYP17A1 protein and cell cycle effects. We confirmed the efficacy of our nano formulation by testing its impact on the growth of androgen-sensitive prostate cancer cell lines. Notably, nanoencapsulation improved curcumin's inhibitory effects on DHEA production via CYP17A1. Surprisingly, the curcumin-piperine nano-capsules enhanced these effects while having no effect on CYP21A2, offering a promising option for prostate cancer treatment. Our study reveals the promise of nanoencapsulated curcumin-piperine as a game-changing method for targeting CYP17A1 for improved prostate cancer therapy. The synergistic benefits observed in our study open new avenues for addressing the difficulties associated with androgen deprivation therapy. Funding: Cancer Research Switzerland grant number: KFS 5557-02-2022 Presentation: 6/3/2024

8805 Nucleostemin is a novel bifunctional transcriptional coregulator of theandrogenreceptorin prostate cancer cells

Abstract Disclosure: E. Cheung: None. C. Zhang: None. Androgen receptor (AR) is a master transcriptional regulator in prostate cancer, interacting with and recruiting distinct sets of coregulator proteins to mediate the expression of direct target genes. What are the coregulators of AR and how they function in AR transcriptional activity and prostate cancer biology are still unclear. Using chromatin-immunoprecipitation coupled with mass spectrometry, we identified a set of AR interacting proteins that are present in multiple prostate cancer cell lines. We provide biochemical, cell-based, and genomic evidence to show that Nucleostemin, also known as Guanine nucleotide-binding protein-like 3, is a novel AR coregulator. Specifically, we demonstrate Nucleostemin has dual coregulator activities, functioning as both a coactivator and a corepressor of AR-dependent transcription to regulate the expression of genes that are involved for prostate cancer progression and immune response. From cellular and animal studies, we found that inhibiting Nucleostemin sensitizes prostate cancer cells to Enzalutamide. Clinical analyses of Nucleostemin from prostate cancer patient cohorts revealed that it is expressed significantly higher in cancer than normal in tissues. Finally, we found Nucleostemin expression is an excellent predictor of disease-free survival. In conclusion, our work suggests that Nucleostemin is a novel AR coregulator and is a promising diagnostic and therapeutic target for prostate cancer treatment. Presentation: 6/2/2024

Impact of SARS-CoV-2-Pandemic on diagnosis of prostate cancer.

Introduction The aim of this study was to prove if the SARS-CoV-2-pandemic resulted in a delay in diagnosis and treatment of prostate cancer (PC). Methods A monocentric, retrospective analysis was conducted at a university cancer center. Included were all patients with untreated PC diagnosed between January 2019 and December 2021. The observation covered 22 months of the SARS-CoV-2-pandemic and 14 months preceding it. Results 969 men prior (T0) and 1343 during pandemic (T1) where included. Mean age was 68.0 (SD 8.2). Median initial PSA was 8.1 ng/ml (T0) and 7.9 ng/ml (T1, p= 0.288). Time from biopsy to tumor board (T0: 1.3 months vs. T1: 0.9 months, p=0.001), to staging (T0: 1,1 months vs. T1: 0.75 months, p=0.707) and to therapy (T0: 3.0 months vs. T1: 2.0 months, p<0.001) were shortened during pandemic. Classified by d'Amico, a significant shift towards higher risk groups was seen (p=0.024). Local staging showed an insignificant increase in locally advanced PCs. Metastatic diseases decreased from 10.3 % to 8.9% (p=0.433). Pathological staging showed pT3+ in 44.4% vs. 44.7% (p=0.565) and pN+ in 9.9 % vs 9.6% (p=0.899). Conclusion Regarding the diagnosis and treatment of PC, we could not demonstrate any delays due to the SARS-CoV-2-pandemic.

Identification of key genes participating in copper-diethyldithiocarbamate-related cell death process and predicting the development of prostate cancer

Copper (Cu) is used as a cofactor in all organisms, and yet it can be toxic at high intracellular concentrations, causing cell death. Diethyldithiocarbamate (DDC) is a Cu ionophore that can transport Cu effectively into the cell. Copper-diethyldithiocarbamate (Cu-DDC) can treat prostate cancer (PCa) and may correlate with the cell death process. However, the specific Cu-DDC-related cell death genes in PCa are still unknown. Information about the Cu-DDC-related cell death genes was obtained from a previous study. Concurrently, the RNA expression profiles and clinical data were downloaded from public databases such as GEO, TCGA, and CPGEA. Using data from TCGA database, the logistic and lasso regression models were generated using R software. The influence of these genes in affecting PCa progression and prognosis was analyzed. Finally, the expression of these genes was verified in clinical samples. We found five Cu-DDC-related cell death genes associated with the occurrence of PCa from GSE35988, a gene dataset, namely, CDKN2A, PRC1, CDK1, SOX2, and ZNF365. CDKN2A, PRC1, and CDK1 are known to influence PCa patients’ disease-free survival (DFS) status and were overexpressed, whereas SOX2 and ZNF365 were under-expressed in PCa in the different databases. Some of these genes can affect PCa progression. Consistent with the database results, the mRNA and protein expression of CDKN2A, PRC1, and CDK1 was also higher in clinical samples. In conclusion, we identified five hub genes which are important for Cu-DDC-related cell death process that can predict the development of PCa.