Prognostic value of [18F]FDG PET/CT in metastatic hormone-sensitive prostate cancer at initial diagnosis: a retrospective cohort study.

INTRODUCTION: This retrospective study aimed to evaluate the prognostic value of [18F]FDG parameters in patients with visceral and bone metastatic hormone-sensitive prostate cancer (mHSPC). PATIENTS AND METHODS: This analysis included the mHSPC patients who underwent [18F]FDG PET/CT at the initial diagnosis. Baseline characteristics were analyzed, and the uptake of [18F]FDG was quantified using SUVmax. Kaplan-Meier and Cox proportional hazard regression analysis were employed to evaluate the correlation between SUVmax and patient survival. RESULTS: Among the 267 patients enrolled, 90 (33.7%) presented with visceral metastases and 177 (66.3%) had bone metastases. The median follow-up for the visceral metastasis group was 35.5 months (IQR 26-53.8 months). The median overall survival for patients with lung, liver, or both metastases were 30, 21 and 17 months, respectively. Patients exhibiting higher [18F]FDG uptake in metastatic lesions experienced shorter overall survival (OS) in comparison to those with lower [18F]FDG uptake, both in the visceral metastases group (17 vs. 31 months, p = 0.002) and the bone metastases group (27.5 vs. 34.5 months, p < 0.001). Cox regression analysis further revealed that increased [18F]FDG uptake in metastatic lesions emerged as a significant risk factor in both OS and progression-free survival (PFS). In contrast, the variability in [18F]FDG uptake in primary lesions did not provide a reliable indicator for predicting prognosis. CONCLUSIONS: In mHSPC patients, higher [18F]FDG uptake in metastatic lesions indicates shorter survival and increased risk of disease progression. The [18F]FDG SUVmax in primary tumors did not show significant prognostic value. Our study underscores the unique prognostic potential of [18F]FDG PET/CT in mHSPC patients, highlighting its importance in the management of both bone and visceral metastases.

Structural Optimization of Isoquinoline Derivatives from Lycobetaine and Their Inhibitory Activity against Neuroendocrine Prostate Cancer Cells.

Neuroendocrine prostate cancer (NEPC) is a highly aggressive cancer that is resistant to hormone therapy and characterized by poor prognosis, as well as limited therapeutic options. Since the natural product lycobetaine was reported to exhibit good antitumor activities against various types of cancers, we initially simplified the scaffold of lycobetaine to obtain the active compound 1, an isoquinoline derivative with an aryl moiety substitution at the 4-position, which showed apparent antiproliferative activities against NPEC cell line LASCPC-01 in vitro. Subsequently, we carried out structural optimization and systematic structure-activity relationship (SAR) studies on compound 1, leading to the discovery of compound 46, which demonstrated potent inhibitory activities against the LASCPC-01 cell line with an IC50 value of 0.47 µM. Moreover, compound 46 displayed remarkable selectivity over prostate cancer cell line PC-3 with a selectivity index greater than 190-fold. Further cell-based mechanism studies revealed that compound 46 and lycobetaine can effectively induce G1 cell cycle arrest and apoptosis dose dependently. However, lycobetaine inhibited the expression of neuroendocrine markers, while compound 46 slightly upregulated these proteins. This suggested that compound 46 might exert its antitumor activities through a different mechanism than lycobetaine, warranting further study.

ADORA2A-driven proline synthesis triggers epigenetic reprogramming in neuroendocrine prostate and lung cancers.

Cell lineage plasticity is one of the major causes for the failure of targeted therapies in various cancers. However, the driver and actionable drug targets in promoting cancer cell lineage plasticity are scarcely identified. Here, we found that a G protein-coupled receptor, ADORA2A, is specifically upregulated during neuroendocrine differentiation, a common form of lineage plasticity in prostate cancer and lung cancer following targeted therapies. Activation of the ADORA2A signaling rewires the proline metabolism via an ERK/MYC/PYCR cascade. Increased proline synthesis promotes deacetylases SIRT6/7-mediated deacetylation of histone H3 at lysine 27 (H3K27), and thereby biases a global transcriptional output toward a neuroendocrine lineage profile. Ablation of Adora2a in genetically engineered mouse models inhibits the development and progression of neuroendocrine prostate and lung cancers, and, intriguingly, prevents the adenocarcinoma-to-neuroendocrine phenotypic transition. Importantly, pharmacological blockade of ADORA2A profoundly represses neuroendocrine prostate and lung cancer growth in vivo. Therefore, we believe that ADORA2A can be used as a promising therapeutic target to govern the epigenetic reprogramming in neuroendocrine malignancies.

The ELAVL3/MYCN positive feedback loop provides a therapeutic target for neuroendocrine prostate cancer.

Neuroendocrine prostate cancer is a rapidly progressive and lethal disease characterized by early visceral metastasis, poor prognosis, and limited treatment options. Uncovering the oncogenic mechanisms could lead to the discovery of potential therapeutic avenues. Here, we demonstrate that the RNA-binding protein ELAVL3 is specifically upregulated in neuroendocrine prostate cancer and that overexpression of ELAVL3 alone is sufficient to induce the neuroendocrine phenotype in prostate adenocarcinoma. Mechanistically, ELAVL3 is transcriptionally regulated by MYCN and subsequently binds to and stabilizes MYCN and RICTOR mRNA. Moreover, ELAVL3 is shown to be released in extracellular vesicles and induce neuroendocrine differentiation of adenocarcinoma cells via an intercellular mechanism. Pharmacological inhibition of ELAVL3 with pyrvinium pamoate, an FDA-approved drug, effectively suppresses tumor growth, reduces metastatic risk, and improves survival in neuroendocrine prostate cancer mouse models. Our results identify ELAVL3 as a critical regulator of neuroendocrine differentiation in prostate cancer and propose a drug repurposing strategy for targeted therapies.

18 F-FDG PET/CT imaging in neuroendocrine prostate cancer: Relation to histopathology and prognosis.

BACKGROUND: This study aimed to evaluate the effectiveness of 18 F-fluoro-2-deoxy-D-glucose Positron emission tomography/computed tomography (18 F-FDG PET/CT) in predicting prognosis and characterizing the intratumoral glucose uptake of neuroendocrine prostate cancer (NEPC). METHODS: We retrospectively reviewed 189 NEPC patients from two medical centers between January 2009 and April 2021. Of these, 44 patients met the inclusion criteria. The maximum standardized uptake value (SUVmax) was measured to assess the metabolic state of NEPC and comparison were made between different histopathological subtypes. Kaplan-Meier and Cox regression analyses were performed to evaluate the predictive value of SUVmax on overall survival (OS) and progression-free survival (PFS). RESULTS: This study analyzed 44 NEPC patients and found that 13 patients had small cell neuroendocrine carcinoma (SCNC), while 31 were diagnosed with adenocarcinoma with neuroendocrine differentiation (Ad-NED) based on histopathology, and a positive correlation was found between SUVmax and SCNC via Spearman correlation test (rs = 0.60, p < 0.0001). Furthermore, SUVmax demonstrated good diagnostic accuracy in differentiating SCNC from Ad-NED (area under the curve 0.88, 95% confidence interval [CI] 0.76-0.99). Kaplan-Meier survival analyses and univariate analyses revealed that patients with SUVmax > 10.2 had a significantly shorter OS than patients with SUVmax ≤ 10.2 (hazard ratio = 4.83, 95% CI 1.45-16.1, p = 0.01). CONCLUSIONS: The histopathological subtypes in NEPC showed a close correlation with the glucose metabolic activity of primary tumors as assessed by 18 F-FDG PET/CT. High SUVmax values in primary prostate tumors were associated with a worse OS in NEPC patients.

Repurposing ketotifen as a therapeutic strategy for neuroendocrine prostate cancer by targeting the IL-6/STAT3 pathway.

PURPOSE: Neuroendocrine prostate cancer (NEPC), a highly aggressive subtype of prostate cancer displaying resistance to hormone therapy, presents a poor prognosis and limited therapeutic options. Here, we aimed to find novel medication therapies for NEPC and explore the underlying mechanism. METHODS: A high-throughput drug screening utilizing an FDA-approved drug library was performed and ketotifen, an antihistamine agent, was identified as a potential therapeutic candidate for NEPC. The whole-transcriptome sequencing analysis was conducted to explore mechanism of ketotifen inhibitory in NEPC. Multiple cell biology and biochemistry experiments were performed to confirm the inhibitory effect of ketotifen in vitro. A spontaneous NEPC mice model (PBCre4:Ptenf/f;Trp53f/f;Rb1f/f) was used to reveal the inhibitory effect of ketotifen in vivo. RESULTS: Our in vitro experiments demonstrated that ketotifen effectively suppressed neuroendocrine differentiation, reduced cell viability, and reversed the lineage switch via targeting the IL-6/STAT3 pathway. Our in vivo results showed that ketotifen significantly prolonged overall survival and reduced the risk of distant metastases in NEPC mice model. CONCLUSION: Our findings repurpose ketotifen for antitumor applications and endorse its clinical development for NEPC therapy, offering a novel and promising therapeutic strategy for this formidable cancer subtype.

High-throughput drug screening identifies fluoxetine as a potential therapeutic agent for neuroendocrine prostate cancer.

Introduction: Neuroendocrine prostate cancer (NEPC) is an aggressive subtype of prostate cancer with poor prognosis and resistance to hormone therapy, which has limited therapeutic approaches. Therefore, this study aimed to identify a novel treatment for NEPC and provide evidence of its inhibitory effects. Methods: We performed a high-throughput drug screening and identified fluoxetine, originally an FDA-approved antidepressant, as candidate therapeutic agent for NEPC. We carried out both in vitro and in vivo experiments to demonstrate the inhibitory effects of fluoxetine on NEPC models and its mechanism in detail. Results: Our results demonstrated that fluoxetine effectively curbed the neuroendocrine differentiation and inhibited cell viability by targeting the AKT pathway. Preclinical test in NEPC mice model (PBCre4: Ptenf/f; Trp53f/f; Rb1f/f) showed that fluoxetine effectively prolonged the overall survival and reduced the risk of tumor distant metastases. Discussion: This work repurposed fluoxetine for antitumor application, and supported its clinical development for NEPC therapy, which may provide a promising therapeutic strategy.

Comprehensive analysis of androgen receptor status in prostate cancer with neuroendocrine differentiation.

The androgen receptor (AR) signaling is a key contributor to tumorigenesis and the progression of prostate cancer. A subset of patients may develop neuroendocrine (NE) features, resulting in resistance to androgen deprivation therapy and poor prognosis. In this study, we combined immunostaining and bulk and single-cell transcriptome analyses to better characterize the status of AR in prostate cancer with neuroendocrine differentiation. The exploration of online datasets indicated the existence of ARHIGH/NEHIGH prostate cancer and revealed that these double-high cases are majorly present in castration-resistant prostate cancer with a less neuroendocrine-transdifferentiated state. We then reviewed 8,194 prostate cancer cases with available immunohistochemistry reports and found 2.3% cases (n = 189) that showed at least one of the NE markers (chromogranin A, synaptophysin, and neural cell adhesion molecule 1) being positive in at least 5% of epithelial cells. Within these 189 cases, we observed that 81.0% cases (n = 153) showed AR positive and 19.0% (n = 36) showed AR negative. Patients with AR loss tumors demonstrated a correlation with adverse clinical stages, indicating a trade-off between AR and advanced disease in neuroendocrine differentiation. Using multiplex immunofluorescence staining, we observed the co-localization of AR and NE markers in prostate cancer cells. In addition, data mining of single-cell transcriptome further confirmed the existence of ARHIGH/NEHIGH prostate cancer cells in castration-resistant samples and suggested that AR still exerts its androgen response and anti-apoptotic effect in these double-high cells. Thus, our study provides a better understanding of AR signaling in the cellular plasticity of prostate cancer with neuroendocrine differentiation and allows new insights into the therapeutic development.

Docetaxel remodels prostate cancer immune microenvironment and enhances checkpoint inhibitor-based immunotherapy.

Background: Prostate cancer is usually considered as immune "cold" tumor with poor immunogenic response and low density of tumor-infiltrating immune cells, highlighting the need to explore clinically actionable strategies to sensitize prostate cancer to immunotherapy. In this study, we investigated whether docetaxel-based chemohormonal therapy induces immunologic changes and potentiates checkpoint blockade immunotherapy in prostate cancer. Methods: We performed transcriptome and histopathology analysis to characterize the changes of prostate cancer immune microenvironment before and after docetaxel-based chemohormonal therapy. Furthermore, we investigated the therapeutic benefits and underlying mechanisms of chemohormonal therapy combined with anti-PD1 blockade using cellular experiments and xenograft prostate cancer models. Finally, we performed a retrospective cohort analysis to evaluate the antitumor efficacy of anti-PD1 blockade alone or in combination with docetaxel-based chemotherapy. Results: Histopathology assessments on patient samples confirmed the enrichment of tumor-infiltrating T cells after chemohormonal therapy. Moreover, we found that docetaxel activated the cGAS/STING pathway in prostate cancer, subsequently induced IFN signaling, resulting in lymphocytes infiltration. In a xenograft mouse model, docetaxel-based chemohormonal therapy prompted the intratumoral infiltration of T cells and upregulated the abundance of PD1 and PD-L1, thereby sensitizing mouse tumors to the anti-PD1 blockade. To determine the clinical significance of these results, we retrospectively analyzed a cohort of 30 metastatic castration-resistant prostate cancer patients and found that docetaxel combined with anti-PD1 blockade resulted in better prostate-specific antigen progression-free survival when compared with anti-PD1 blockade alone. Conclusions: Our study demonstrates that docetaxel activates the antitumoral immune response and facilitates T cell infiltration in a cGAS/STING-dependent manner, providing a combination immunotherapy strategy that would improve the clinical benefits of immunotherapy.

Downregulation of SHMT2 promotes the prostate cancer proliferation and metastasis by inducing epithelial-mesenchymal transition.

Serine hydroxymethyltransferase 2 (SHMT2) is a key enzyme that regulates serine/glycine transition; however, its specific function and molecular mechanisms in tumors remain controversial. In this study, we aimed to enhance the understanding in this regard. Through in vitro and in vivo experiments, as well as data analyses using public databases, we investigated the effect of SHMT2 in prostate cancer. Our results indicated that SHMT2 acts as a prostate cancer tumor proliferation suppressor and negatively regulates the aggressive behavior of prostate cancer through activation of epithelial-mesenchymal transition. Additionally, downregulated SHMT2 expression was observed in more advanced prostate cancer phenotypes, and further analysis showed that its depletion promoted proliferation and migration in prostate cancer cell lines. Taken together, our results revealed the function of SHMT2 in prostate cancer and may potentially play a role in the exploration of new therapeutic strategies.

The Evolving Role of 18F-FDG PET/CT in Diagnosis and Prognosis Prediction in Progressive Prostate Cancer.

Positron emission tomography/computed tomography (PET/CT) is widely used in prostate cancer to evaluate the localized tumor burden and detect symptomatic metastatic lesions early. 18F-FDG is the most used tracer for oncologic imaging, but it has limitations in detecting early-stage prostate cancer. 68Ga-PSMA is a new tracer that has high specificity and sensibility in detecting local and metastatic tumors. But with the progression of prostate cancer, the enhancement of glucose metabolism in progressive prostate cancer provides a chance for 18F-FDG. This review focuses on PET/CT in the detection and prognosis of prostate cancer, summarizing the literature on 18F-FDG and 68Ga-PSMA in prostate cancer and highlighting that 18F-FDG has advantages in detecting local recurrence, visceral and lymph node metastases compared to 68Ga-PSMA in partial progressive prostate cancer and castration-resistant prostate cancer patients. We emphasize 18F-FDG PET/CT can compensate for the weakness of 68Ga-PSMA PET/CT in progressive prostate cancer.

SUMOylation controls the binding of hexokinase 2 to mitochondria and protects against prostate cancer tumorigenesis.

Human hexokinase 2 is an essential regulator of glycolysis that couples metabolic and proliferative activities in cancer cells. The binding of hexokinase 2 to the outer membrane of mitochondria is critical for its oncogenic activity. However, the regulation of hexokinase 2 binding to mitochondria remains unclear. Here, we report that SUMOylation regulates the binding of hexokinase 2 to mitochondria. We find that hexokinase 2 can be SUMOylated at K315 and K492. SUMO-specific protease SENP1 mediates the de-SUMOylation of hexokinase 2. SUMO-defective hexokinase 2 preferably binds to mitochondria and enhances both glucose consumption and lactate production and decreases mitochondrial respiration in parallel. This metabolic reprogramming supports prostate cancer cell proliferation and protects cells from chemotherapy-induced cell apoptosis. Moreover, we demonstrate an inverse relationship between SENP1-hexokinase 2 axis and chemotherapy response in prostate cancer samples. Our data provide evidence for a previously uncovered posttranslational modification of hexokinase 2 in cancer cells, suggesting a potentially actionable strategy for preventing chemotherapy resistance in prostate cancer.

HOXD13 suppresses prostate cancer metastasis and BMP4-induced epithelial-mesenchymal transition by inhibiting SMAD1.

The HOX genes are a group of highly conserved Homeobox-containing genes that control the body plan organization during development. However, their contributions to tumorigenesis and tumor progression remain uncertain and controversial. Here we provided evidence of tumor-suppressive activity of HOXD13 in prostate cancer. HOXD13 depletion contributes to more aggressiveness of prostate cancer cells in vitro and in vivo. These effects were corroborated in a metastatic mice model, where we observed more bone metastatic lesions formed by prostate cancer cells with HOXD13 ablation. Mechanistically, HOXD13 prevents BMP4-induced epithelial-mesenchymal transition (EMT) by inhibiting mothers against decapentaplegic homolog 1 (SMAD1) transcription. Both bioinformation and our tissue microarray cohort data show that HOXD13 expression inversely correlated in advanced prostate cancer patient specimens. Our findings establish HOXD13 as a negative regulator of prostate cancer progression and metastasis by preventing BMP4/SMAD1 signaling, and potentially suggest new strategies for targeting metastatic prostate cancer.

Controlled Release of Therapeutics from Thermoresponsive Nanogels: A Thermal Magnetic Resonance Feasibility Study.

Thermal magnetic resonance (ThermalMR) accommodates radio frequency (RF)-induced temperature modulation, thermometry, anatomic and functional imaging, and (nano)molecular probing in an integrated RF applicator. This study examines the feasibility of ThermalMR for the controlled release of a model therapeutics from thermoresponsive nanogels using a 7.0-tesla whole-body MR scanner en route to local drug-delivery-based anticancer treatments. The capacity of ThermalMR is demonstrated in a model system involving the release of fluorescein-labeled bovine serum albumin (BSA-FITC, a model therapeutic) from nanometer-scale polymeric networks. These networks contain thermoresponsive polymers that bestow environmental responsiveness to physiologically relevant changes in temperature. The release profile obtained for the reference data derived from a water bath setup used for temperature stimulation is in accordance with the release kinetics deduced from the ThermalMR setup. In conclusion, ThermalMR adds a thermal intervention dimension to an MRI device and provides an ideal testbed for the study of the temperature-induced release of drugs, magnetic resonance (MR) probes, and other agents from thermoresponsive carriers. Integrating diagnostic imaging, temperature intervention, and temperature response control, ThermalMR is conceptually appealing for the study of the role of temperature in biology and disease and for the pursuit of personalized therapeutic drug delivery approaches for better patient care.

Magnetic resonance thermometry: Methodology, pitfalls and practical solutions.

Clinically established thermal therapies such as thermoablative approaches or adjuvant hyperthermia treatment rely on accurate thermal dose information for the evaluation and adaptation of the thermal therapy. Intratumoural temperature measurements have been correlated successfully with clinical end points. Magnetic resonance imaging is the most suitable technique for non-invasive thermometry avoiding complications related to invasive temperature measurements. Since the advent of MR thermometry two decades ago, numerous MR thermometry techniques have been developed, continuously increasing accuracy and robustness for in vivo applications. While this progress was primarily focused on relative temperature mapping, current and future efforts will likely close the gap towards quantitative temperature readings. These efforts are essential to benchmark thermal therapy efficiency, to understand temperature-related biophysical and physiological processes and to use these insights to set new landmarks for diagnostic and therapeutic applications. With that in mind, this review summarises and discusses advances in MR thermometry, providing practical considerations, pitfalls and technical obstacles constraining temperature measurement accuracy, spatial and temporal resolution in vivo. Established approaches and current trends in thermal therapy hardware are surveyed with respect to potential benefits for MR thermometry.

Thermal magnetic resonance: physics considerations and electromagnetic field simulations up to 23.5 Tesla (1GHz).

BACKGROUND: Glioblastoma multiforme is the most common and most aggressive malign brain tumor. The 5-year survival rate after tumor resection and adjuvant chemoradiation is only 10 %, with almost all recurrences occurring in the initially treated site. Attempts to improve local control using a higher radiation dose were not successful so that alternative additive treatments are urgently needed. Given the strong rationale for hyperthermia as part of a multimodal treatment for patients with glioblastoma, non-invasive radio frequency (RF) hyperthermia might significantly improve treatment results. METHODS: A non-invasive applicator was constructed utilizing the magnetic resonance (MR) spin excitation frequency for controlled RF hyperthermia and MR imaging in an integrated system, which we refer to as thermal MR. Applicator designs at RF frequencies 300 MHz, 500 MHz and 1GHz were investigated and examined for absolute applicable thermal dose and temperature hotspot size. Electromagnetic field (EMF) and temperature simulations were performed in human voxel models. RF heating experiments were conducted at 300 MHz and 500 MHz to characterize the applicator performance and validate the simulations. RESULTS: The feasibility of thermal MR was demonstrated at 7.0 T. The temperature could be increased by ~11 °C in 3 min in the center of a head sized phantom. Modification of the RF phases allowed steering of a temperature hotspot to a deliberately selected location. RF heating was monitored using the integrated system for MR thermometry and high spatial resolution MRI. EMF and thermal simulations demonstrated that local RF hyperthermia using the integrated system is feasible to reach a maximum temperature in the center of the human brain of 46.8 °C after 3 min of RF heating while surface temperatures stayed below 41 °C. Using higher RF frequencies reduces the size of the temperature hotspot significantly. CONCLUSION: The opportunities and capabilities of thermal magnetic resonance for RF hyperthermia interventions of intracranial lesions are intriguing. Employing such systems as an alternative additive treatment for glioblastoma multiforme might be able to improve local control by "fighting fire with fire". Interventions are not limited to the human brain and might include temperature driven targeted drug and MR contrast agent delivery and help to understand temperature dependent bio- and physiological processes in-vivo.