Treatment Of Castration-resistant Prostate Cancer Research Articles

PSA Kinetics Affect Prognosis in Patients With Castration-resistant Prostate Cancer Treated With Enzalutamide.

There is little evidence regarding the predictive value of prostate-specific antigen (PSA) kinetics in patients with castration-resistant prostate cancer treated with an androgen receptor signaling inhibitor. This study investigated the correlation between PSA kinetics and prognosis in patients with castration-resistant prostate cancer treated with enzalutamide. We analyzed data from 103 patients who received enzalutamide as primary treatment for castration-resistant prostate cancer at our hospital, focusing on the associations between overall survival and PSA kinetics variables, such as maximal PSA response, PSA nadir, and time to PSA nadir. The median PSA level at the initiation of enzalutamide was 18.1 ng/ml (interquartile range=7.9-61.2 ng/ml). The median maximal PSA response rate was 88% (interquartile range 55-98), and the median PSA nadir was 1.84 (interquartile range (IQR)=0.38-14.7) ng/ml. The median time to PSA nadir was 19 (IQR=6-28.5) weeks. Maximal PSA response rate <90% [hazard ratio (HR)=2.28, 95% confidence interval (CI)=1.03-5.03, p=0.0413], PSA nadir >2 ng/ml (HR=2.30, 95%CI=1.05-5.07, p=0.0379), time to nadir <19 weeks (HR=2.48, 95%CI=1.15-5.35, p=0.0204) were all independently predictive of shortened overall survival even after adjusting for pre-treatment factors. Maximal PSA response, PSA nadir, and time to PSA nadir correlated with survival in patients with castration-resistant prostate cancer receiving enzalutamide as a first-line therapy.

Investigating High-risk Factors, Precise Diagnosis, and Treatment of Castration- Resistant Prostate Cancer (CRPC).

The treatment of metastatic castration-resistant prostate cancer (mCRPC) in the actual world currently presents difficulties. In light of this, it is crucial to investigate high-risk factors for the progression of advanced prostate cancer and to identify methods for delaying the onset of CRPC. This study aimed to explore the high-risk factors that impact the progression of prostate cancer and emphasize the significance of precise diagnosis and treatment based on etiological classification in the clinical management of castration-resistant prostate cancer. A retrospective analysis was conducted on 277 newly diagnosed cases of PCa treated with endocrine therapy. A follow-up was done on prostate-specific antigen (PSA) levels and testosterone. Additionally, a prospective analysis was performed on the clinical data of 60 patients with CRPC. Following the principle of "4W1H", 30 patients were included in the precision treatment group for a second biopsy and related tests, while another 30 patients were included in the conventional treatment group. The therapeutic effect and prognosis of the two groups were observed. Distant metastasis (HR = 1.879, 95% CI: 1.311 ~ 2.694, P = 0.001), PSA nadir > 0.2 ng/mL (HR = 1.843, 95% CI: 1.338 ~ 2.540, P = 0.001), testosterone nadir > 20 ng/dL (HR = 1.403, 95% CI: 1.035 ~ 1.904, P = 0.029), and time to testosterone nadir > 6 months (HR = 1.919, 95% CI: 1.364 ~ 2.701, P = 0.001) were risk factors for the progression to CRPC. Patients in the CRPC group were treated with precision therapy and conventional therapy based on their molecular subtyping. The precision treatment group showed a significantly prolonged median PSA progression-free survival compared to the conventional treatment group (16.0 months vs. 13.0 months, P=0.025). The median radiographic progression-free survival was also significantly extended in the precision treatment group compared to the conventional treatment group (21.0 months vs. 16.0 months, P=0.042). Patients with prostate cancer diagnosed with distant metastasis at initial presentation require early intervention. Close monitoring of PSA and serum testosterone changes is necessary during the process of endocrine therapy. After entering the CRPC stage, the etiological classification precision treatment can improve the therapeutic effect and improve the prognosis of patients.

Safety and Efficacy of 177Lu-PSMA Therapy Following 223Radium Treatment: A Retrospective Multinational Real-World Analysis

Background177Lu PSMA therapy is increasingly used for metastatic castration-resistant prostate cancer (mCRPC) treatment. However, data on its efficacy and safety in patients previously treated with 223Ra remain limited. MethodsThis retrospective, multicenter study evaluated 233 mCRPC patients treated with 177Lu PSMA at five European centers. The cohort included 27 patients previously treated with 223Ra and 206 Radium-naive patients. Statistical analyses, including Chi-squared, Mann-Whitney U tests, and multivariate logistic regression, were used to assess response and mortality. Predictors of response and mortality were identified using multivariate models. ResultsPatients who experienced a longer interval between castration resistance and the initiation of 177Lu PSMA therapy demonstrated better responses (median 17 months in responders vs. 8.5 months in progressors, p=0.001). Platelet counts were significantly lower in the progressive group compared to the responsive group (p=0.01). Multivariate regression confirmed lower platelet levels as a predictor of poor response (p=0.029). The overall response rate to 177Lu PSMA was 54%, similar between the 223Ra-pretreated and Radium-naive groups. However, mortality was significantly higher in the 223Ra-pretreated group (86%) compared to the Radium-naive group (51%, p=0.003). ECOG performance status (p=0.004) and ALP levels (p=0.030) were significant predictors of mortality, while CRP showed a trend towards significance (p=0.064). Tolerability of 177Lu PSMA was comparable to the safety profile reported in the literature, with 44% of 223Ra-pretreated patients experiencing AEs and 22% experiencing severe AEs (Grade ≥3). Conclusions177Lu PSMA therapy is effective and well-tolerated in mCRPC patients pretreated with 223Ra. However, higher mortality was observed in the 223Ra-pretreated group. ECOG PS, ALP, and platelet counts were significant predictors of response and mortality, and a longer interval between therapies was associated with better outcomes. These findings underscore the importance of treatment sequencing and monitoring prognostic markers. Micro-abstractEven in a real-world setting, 177Lu PSMA remains an effective treatment for mCRPC, achieving response rates up to 54% even in patients previously treated with 223Ra. Our findings indicate that 177Lu PSMA is well-tolerated after 223Ra, with no significant increase in adverse events. However, higher mortality rates were observed in the 223Ra cohort, suggesting a potentially poorer prognosis for patients who received 223Ra as an initial treatment.

Abiraterone and Galeterone, Powerful Tools Against Prostate Cancer: Present and Perspective

Due to the high prostate cancer incidence worldwide, the development of different methods of treatment continues to be a hot research topic. Since its first clinical application at the beginning of the 2010s, abiraterone in the form of prodrug abiraterone acetate continues to be the most used hormone derivative in the treatment of castration-resistant prostate cancer. This is the reason behind the publication of many scientific results regarding its synthesis, biological activity, metabolism, novel designed steroid derivatives based on its structure, etc. A similar steroid compound with a heterocycle in the C17 position, called galeterone, also designed to treat prostate cancer, continues to be in clinical studies, which provides further proof of the importance of these steroid derivatives. Besides prostate cancer treatment, abiraterone showed indications for possible clinical application in the treatment of breast, ovarian, lung, kidney, salivary gland, and adrenocortical cancer, congenital adrenal hyperplasia, Cushing’s syndrome, and COVID-19, while galeterone is investigated for its use against prostate, pancreatic, and breast cancer. Herein, we report a review comprising methods of synthesis, possible clinical applications, and mechanisms of action, as well as structures and bioactivities of derivatives of these two important steroids.

Bone-Targeting Radionuclides in the Treatment of Metastatic Castration-Resistant Prostate Cancer: A Review on Radium-223 Chloride (Alpharadin) in Combination with Other Therapies

Recent advances have broadened the range of therapeutic options for mCRPC, with several new treatments, including novel hormonal therapies (enzalutamide, abiraterone), chemotherapeutic agents (docetaxel, cabazitaxel), immunotherapies (sipuleucel-T), and bone targeting radiopharmaceuticals (radium-223) showing improved clinical outcomes and receiving U.S. Food and Drug Administration approval. These new treatments provide new avenues for improving patient survival and quality of life. Radium-223, a targeted alpha-emitter, specifically targets bone metastases, offering palliative benefits and a potential increase in life expectancy. The integration of radium-223 with other treatments shows promise for managing mCRPC. However, the optimal sequencing and combination of radium-223 with other therapies are still being explored, with various clinical trials investigating new therapeutic approaches. The integration of these therapies, especially to provide more effective, personalized treatment strategies, requires further investigation. A thorough literature review was conducted on current treatments for mCRPC, including chemotherapeutic agents, oral hormonal therapies targeting the androgen receptor axis, immunotherapies, and radium-223. Ongoing clinical trials investigating radium-233 in the context of other therapies for the treatment of mCRPC patients were also reviewed. Further studies should focus on determining the optimal sequencing and dosing and identifying biomarkers that predict treatment response to enhance outcomes of mCRPC patients. This review underlines the rational strategies of combining radium-223 with other therapies, investigating their impact on bone in terms of delaying skeletal-related events, and managing bone disease progression in mCRPC patients.

Seeing the Future of Lung Cancer Vaccination

It has been nearly fifteen years since the Food and Drug Administration (FDA) approved the first therapeutic cancer vaccine for solid tumors, namely Sipuleucel-T (Provenge®), marking a significant milestone in the treatment of metastatic castration-resistant prostate cancer [...]

Prostate Cancer, Pathophysiology and Recent Developments in Management: A Narrative Review.

Prostate cancer is the second most common cancer in men. The different stages of prostate cancer which include localised (low, intermediate, and high risk) disease, locally advanced, non-metastatic castration-resistant prostate cancer (M0 CRPCa), and metastatic disease. The main treatment of locally advanced disease is external beam radiotherapy with hormonal therapy which are associated with good prognosis. Current treatments for M0 CRPCa include androgen deprivation therapy in combination with apalutamide, darolutamide or enzalutamide, all of which are associated with good metastatic-free survival rates in clinical trials. Hormone-naive metastatic prostate cancer comprises the same treatments as M0 CRPCa, whereas further treatment includes docetaxel and abiraterone. Metastatic castration-resistant prostate cancer treatments include sipuleucel-T, radium-223, abiraterone, enzalutamide and cabazitaxel, which aim to slow down the progression of the disease and to prolong life. This article also provides insight into the development of new drugs recently approved for metastatic castration prostate cancer, which include PARP inhibitors and Lutetium-177 which have shown to have significantly good overall survival and to improve radiographic progression-free survival. In addition, new clinical trials are ongoing to test new medications such as cabozantinb and chimeric-antigen receptor T-cell therapy for the treatment of advanced prostate cancer. With the aim to slow down the progression of the disease and to prolong life, new drug developments are underway to hopefully provide a positive impact on overall survival and improve progression-free survival, especially in advanced prostate cancer.

Predicting Response to [177Lu]Lu-PSMA Therapy in mCRPC Using Machine Learning

Background/Objectives: Radioligandtherapy (RLT) with [177Lu]Lu-PSMA has been newly introduced as a routine treatment for metastatic castration-resistant prostate cancer (mCRPC). However, not all patients can tolerate the entire therapeutic sequence, and in some cases, the treatment may prove ineffective. In real-world conditions, the aim is to distinguish between patients who fully benefit from treatment (those who respond effectively and tolerate the entire therapeutic sequence) and those who do not respond or cannot tolerate the entire sequence. This study explores predictive factors to distinguish between fully beneficial RLT treatment patients (FBTP) and not fully beneficial RLT treatment patients (NFBTP). The objective was to enhance the understanding of predictive factors influencing RLT effectiveness and to highlight the significance of machine learning in optimizing patient selection for treatment planning. Methods: Data from 25 mCRPC patients, categorized as FBTP (11) or NFBTP (14) to RLT, were analyzed. The dataset included clinical, imaging, and biological parameters. Data analysis techniques, including exploratory data analysis and feature engineering, were used to develop machine learning models for predicting patient outcomes. Results: Imaging data analysis revealed statistically significant differences in the renal uptake intensity of Choline between the two groups. A discordance of FDG+ and PSMA− was identified as a potential indicator of NFBTP. The integration of biological data enhanced the model’s predictive capability, achieving an accuracy of 0.92, a sensitivity of 0.96, and a precision of 0.96. Adding blood parameters like neutrophils, leukocytes, and alkaline phosphatase greatly increased prediction accuracy. Conclusions: This study emphasizes the significance of an integrated approach that merges imaging and biological data, thereby augmenting the predictive accuracy of patient outcomes in RLT with [177Lu]Lu-PSMA. In particular, including Choline PET among the imaging parameters provides unique insights into the predictive factors affecting RLT efficacy. This approach not only deepens the understanding of predictive factors but also underscores the utility of machine learning in refining the patient selection process for optimized treatment planning.

Comparative efficacy and safety of talazoparib plus enzalutamide and other first-line treatments for metastatic castration-resistant prostate cancer.

Talazoparib plus enzalutamide (TALA + ENZA) has demonstrated antitumor activity in the phase 3 clinical trial (TALAPRO-2; NCT03395197) as first-line (1L) therapy in men with asymptomatic or mildly symptomatic metastatic castration-resistant prostate cancer (mCRPC). Although many active interventions are available, randomized controlled trials (RCTs) involving talazoparib have only been conducted to assess its efficacy and safety compared to enzalutamide. To estimate comparisons between all relevant interventions, indirect comparisons are needed. To estimate the comparative efficacy and safety of TALA + ENZA in 1L patients with mCRPC by conducting a systematic literature review and network meta-analyses (NMAs). Databases were searched using Ovid, along with several gray literature sources to identify RCTs evaluating treatments in 1L mCRPC (PROSPERO registration: CRD42021283512). Feasibility assessment evaluated trial suitability for NMA inclusion and Bayesian or frequentist NMAs were conducted for evaluable efficacy and safety outcomes, respectively. Thirty-three RCTs met the eligibility criteria and were feasible for NMAs. Across multiple efficacy outcomes assessed, except for overall survival (OS), TALA + ENZA was ranked the most efficacious treatment. For OS, TALA + ENZA showed the second-highest probability of being the most effective treatment; second to docetaxel 50mg plus prednisolone 10mg. With respect to safety outcomes, TALA + ENZA, in general, showed increased rates of hematological adverse events. TALA + ENZA showed favorable results across multiple efficacy endpoints, but not across hematological toxicities compared with other 1L treatments in asymptomatic or mildly symptomatic mCRPC in the all-comers patient population.

Novel astatine (211At)-labelled prostate-specific membrane antigen ligand with a neopentyl-glycol structure: evaluation of stability, efficacy, and safety using a prostate cancer xenograft model.

Prostate-specific membrane antigen (PSMA)-targeted alpha therapy is considered a promising alternative treatment for metastatic castration-resistant prostate cancer (mCRPC). Though astatine-211 (211At) is potentially useful alpha-emitter producible by cyclotrons, its clinical application has been limited by instability and a tendency to deastatination in vivo. To overcome these challenges, we developed [211At]At-NpG-PSMA, a novel PSMA ligand with a neopentyl-glycol structure that enhances in vivo stability against deastatination. This study aimed to evaluate the stability, anti-tumour effect, and safety of [211At]At-NpG-PSMA in mice. Xenograft models were prepared by subcutaneous transplantation of PSMA-positive PC-3 PIP cells into BALB/c nu/nu mice. [211At]At-NpG-PSMA was administered to assess biodistribution, and the anti-tumour effect was evaluated at doses of 0.32, 1.00 and 1.93 MBq in comparison with saline. Histopathological examinations were performed to evaluate damage to normal organs. [211At]At-NpG-PSMA demonstrated high tumour uptake (42.0 ± 13.1%ID/g at 3h) with minimal uptake in non-target tissues, including thyroid, stomach and salivary grands (0.28 ± 0.20%ID, 0.71 ± 0.12%ID/g and 0.88 ± 0.10%ID/g at 3h, respectively). A dose-dependent anti-tumour effect was observed, with tumour volumes increasing by 796.0 ± 437.6% in the control versus 161.0 ± 213.4%, -76.4 ± 19.2% and - 59.5 ± 41.6% in the 0.32, 1.00 and 1.93 MBq groups, respectively, by day 15. Mild renal tubule regeneration was noted in the 1.00 MBq group. [211At]At-NpG-PSMA demonstrated significant stability in vivo and anti-tumour effects with minimal side effects, indicating its potential as a new therapeutic drug for PSMA-targeted alpha therapy in mCRPC.

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.

228 (PB216): Discovery of Androgen Metabolism Enhancing Androgen Receptor Antagonists for the Treatment of Castration-Resistant prostate Cancer

228 (PB216): Discovery of Androgen Metabolism Enhancing Androgen Receptor Antagonists for the Treatment of Castration-Resistant prostate Cancer

The role of Cabazitaxel in patients with castration-resistant and osseous metastases prostate cancer. A Hellenic Cooperative Oncology Group Phase II Study.: Cabazitaxel in mCRPC patients with osseous metastases

BackgroundCabazitaxel is an effective treatment in metastatic castration-resistant prostate cancer (mCRPC) patients previously exposed to docetaxel and novel hormonal treatments. Understanding the molecular biology of mCRPC disease and taking into account the several approved treatment options, biomarkers are needed to guide decision making including cabazitaxel treatment. MethodsCababone was a phase II translational study that attempted to identify predictors of cabazitaxel efficacy. mCRPC with documented bone metastases were enrolled prospectively and treated with cabazitaxel 25mg/m2 every three weeks. Prostate cancer biopsies, bone marrow aspirates and blood samples were collected for translational research. ResultsSixty patients were enrolled and 59 received treatment according to protocol. Six-month progression free survival (PFS) rate was 47% (95% CI: 33% - 59%) and 12-month Overall Survival (OS) rate was 70% (95% CI: 56% - 80%). Patients with reactive hematopoiesis had improved PFS and OS with cabazitaxel treatment. Mutations in HRR genes were detected in 7 patients. ConclusionsNo differences in cabazitaxel efficacy were noted according to mutational status of HRR genes analyzed. No new safety issues were detected. In conclusion, CabaBone confirmed efficacy of cabazitaxel in mCRPC patients including the subgroup of patients with HRR mutations. Reactive hematopoiesis in bone marrow biopsies was related to improved survival warranting further investigation of bone biomarkers as predictors of cabazitaxel efficacy. Micro-AbstactCabaBone is a phase II translational study that evaluated the role of bone microenvironment and HRR genes mutations in the efficacy of cabazitaxel in mCRPC patients with bone-only disease. Study confirmed efficacy of cabazitaxel in patients independent of the presence of HRR gene mutations. Reactive hematopoiesis in bone marrow was recognized as a possible predictive and prognostic biomarker of cabazitaxel efficacy.

Home-based Exercise Training Reduces Tnf-α During Treatment For Metastatic Castration-resistant Prostate Cancer

Home-based Exercise Training Reduces Tnf-α During Treatment For Metastatic Castration-resistant Prostate Cancer

Statin use and oncological outcomes in a propensity-matched cohort of nonmetastatic castration resistant prostate cancer patients of the ARAMIS trial

IntroductionWhile observational studies suggest favorable associations between statin use and prostate cancer (CaP) outcomes, data from randomized-controlled trials remain inconclusive. Our study explores the relationship between statin use and survival outcomes in the context of the phase III ARAMIS study, a trial of darolutamide in the treatment of nonmetastatic castration-resistant prostate cancer. MethodsWe reviewed all 1,509 patients in the ARAMIS trial. Statin use was identified at baseline. Statin users were matched 1:2 with nonusers using a propensity score matching model. The primary endpoint was metastasis-free survival (MFS). Kaplan-Meier curves were plotted for MFS comparing statin users and nonusers across ARAMIS trial arms. A multivariate Cox proportional hazards model was fitted using the propensity-matched cohort and incorporating statin use and all covariates. ResultsOf the 1,509 patients in ARAMIS, 334 (22.1%) were statin users. We matched 297 statin users to 550 nonusers. Characteristics appeared well balanced. Among nonusers, 331 (60.3%) and 219 (39.7%) were in the ARAMIS darolutamide and placebo arms, respectively. Among statin users, 179 (60.3%) and 118 (39.7%) were in the ARAMIS darolutamide and placebo arms, respectively. Overall, we found no significant difference in MFS between statin users and nonusers (HR 1.05, 95% CI 0.80–1.38 P = .72). However, we found significant interaction between statin use and ARAMIS trial arm. Specifically, statin use had a stronger association with MFS in the placebo arm (P = 0.024). However, this is likely coincidental and due to the statin-placebo patients having higher nodal positivity than the nonusers-placebo patients (14.3% vs. 5.5%). Statin use was similarly not associated with the secondary outcomes of PSA progression-free survival (P = 0.42), time-to-pain progression (P = 0.85), or overall survival (P = 0.15). ConclusionsIn our secondary analysis of the ARAMIS trial, statin users had similar MFS and secondary outcomes compared to nonusers. These results suggest pursuing further statin synergies with amide-based androgen receptor axis target agents may not be fruitful.

Docetaxel Versus Androgen-Receptor Signaling Inhibitors (ARSI) as Second-Line Therapy After Failure of First-Line Alternative ARSI for the Elderly ≥ 75 Years Old With Metastatic Castration-Resistant Prostate Cancer (mCRPC): A SPARTACUSS—Meet-URO 26 Real-World Study

BackgroundAndrogen receptor signalling inhibitors (ARSIs) abiraterone acetate (AA) enzalutamide (Enza), are currently the standard first-line (L1) treatments for metastatic castration-resistant prostate cancer (mCRPC), and docetaxel (D) is reserved as second-line (L2) after ARSI failure. Nonetheless, D use in men ≥ 75 years old is restricted owing to treatment toxicities and patient comorbidities, and a L2 alternative ARSI is frequently used. We aimed to evaluate real-life survival and toxicity outcomes of these elderly patients after failure of L1 ARSI treatment. Material and MethodsWe retrospectively evaluated efficacy and safety in a real-world international cohort of consecutive patients ≥ 75 years old when starting L1 ARSI for mCRPC according to the choice of L2 treatment (D versus alternative ARSI). ResultsOf the 122 identified patients, 57 (46.7%) had received L2 ARSI and 65 (53.3%) L2 D. No difference was found in the L1 overall survival (OS) for the ARSI and D groups (32.8 vs. 30.0 months, respectively; Hazard ratio [HR] = 1.22; 95% CI, 0.77-1.95; P = .40) or in the L2 OS (18.5 vs. 17.8 months, respectively; HR = 1.09; 95% CI, 0.69-1.74; P = .71). No difference was observed for rPFS from L2 (P = .12), although a trend was observed for a numerically improved rPFS on D. ConclusionWithin the limitations of a retrospective design and small population, our study suggests that D or ARSI after failure of L1 alternative ARSI are clinically comparable L2 options for elderly patients with mCRPC.

Prediction of Lesion-Based Treatment Response after Two Cycles of Lu-177 Prostate Specific Membrane Antigen Treatment in Metastatic Castration-Resistant Prostate Cancer Using Machine Learning

Introduction: Lutetium-177 (Lu-177) prostate-specific membrane antigen (PSMA) therapy is a radionuclide treatment that prolongs overall survival in metastatic castration-resistant prostate cancer (MCRPC). We aimed to predict lesion-based treatment response after Lu-177 PSMA treatment using machine learning with texture analysis data obtained from pretreatment Gallium-68 (Ga-68) PSMA positron emission tomography/computed tomography (PET/CT). Methods: Eighty-three progressed, and 91 nonprogressed malignant foci on pretreatment Ga-68 PSMA PET/CT of 9 patients were used for analysis. Malignant foci with at least a 30% increase in Ga-68 PSMA uptake after two cycles of treatment were considered progressed lesions. All other changes in Ga-68 PSMA uptake of the lesions were considered nonprogressed lesions. The classifiers tried to predict progressed lesions. Results: Logistic regression, Naive Bayes, and k-nearest neighbors’ area under the ROC curve (AUC) values in detecting progressed lesions in the training group were 0.956, 0.942, and 0.950, respectively, and their accuracy was 87%, 85%, and 89%, respectively. The AUC values of the classifiers in the testing group were 0.937, 0.954, and 0.867, respectively, and their accuracy was 85%, 88%, and 79%, respectively. Conclusion: Using machine learning with texture analysis data obtained from pretreatment Ga-68 PSMA PET/CT in MCRPC predicted lesion-based treatment response after two cycles of Lu-177 PSMA treatment.

Identification of blood lipid markers of docetaxel treatment in prostate cancer patients

Docetaxel is commonly used for treatment of castration-resistant prostate cancer. Unfortunately, many prostate cancer patients develop resistance to docetaxel. Clinical markers less invasive than biopsies, such as blood samples, would be ideal for monitoring and predicting patient treatment outcomes to docetaxel. Lipid alterations are often associated with the progression of many cancers, including prostate cancer. This study investigated the use of lipids from whole blood as clinical markers for docetaxel resistance in a small cohort of patients with prostate cancer. Qualitative lipidomics was performed by liquid chromatography-tandem mass spectrometry to assess the lipid composition of prostate cancer cells exposed to docetaxel as well as whole blood from prostate cancer patients before, during and after docetaxel treatment. Three patients had castration resistant prostate cancer, three had castration sensitive prostate cancer, and four had de novo prostate cancer during the extent of the study. Mean decrease accuracy and classical univariate receiving operating characteristic curve analyses were performed to identify potential biomarkers. In total, 245 and 221 altered lipids were identified from a second stage of mass spectrometry analysis of prostate cancer cells and clinical blood samples, respectively. Both models indicated that docetaxel treatment altered ether-linked phosphatidylcholines, lysophosphatidylcholine, diacylglycerols, ceramides, hexosylceramides, and sphingomyelins. The results also indicated several lipid changes were associated with sphingolipid signaling and metabolism, and glycerophospholipid metabolism. Collectively, these data suggest the potential usage of identified lipid species as indicators of docetaxel resistance in prostate cancer.

Design, synthesis and biological evaluation of dual inhibitors targeting AR/AR-Vs and PARP1 in castration resistant prostate cancer therapy

The combination of androgen signaling inhibitors and PARP inhibitors has shown promising results in clinical trials for the treatment of castration-resistant prostate cancer (CRPC). Multi-target inhibitors can inhibit tumors through different pathways, addressing the limitations of traditional single target inhibitors. We designed and synthesized dual inhibitors targeting AR/AR-Vs and PARP1 using a pharmacophore hybridization strategy. The most potent compound, II-3, inhibits AR/AR-Vs signaling and induces DNA damage by inhibiting PARP1. The IC50 values of II-3 in the castration-resistant prostate cancer cell lines 22RV1 and C4–2 are 4.38 ± 0.56 µM, and 3.44 ± 0.63 µM, respectively. II-3 not only suppresses the proliferation and migration of 22RV1 and C4–2 cells, but also promotes their apoptosis. Intraperitoneal injection of II-3 effectively inhibits tumor growth in 22RV1 xenograft nude mice without evident drug-induced toxicity. Overall, a series of novel dual inhibitors targeting AR/AR-Vs and PARP1 were designed and synthesized, and meanwhile the in vivo and in vitro effects were comprehensively explored, which provided a potential new therapeutic strategy for CRPC.

N-terminal domain of androgen receptor is a major therapeutic barrier and potential pharmacological target for treating castration resistant prostate cancer: a comprehensive review.

The incidence rate of prostate cancer (PCa) has risen by 3% per year from 2014 through 2019 in the United States. An estimated 34,700 people will die from PCa in 2023, corresponding to 95 deaths per day. Castration resistant prostate cancer (CRPC) is the leading cause of deaths among men with PCa. Androgen receptor (AR) plays a critical role in the development of CRPC. N-terminal domain (NTD) is the essential functional domain for AR transcriptional activation, in which modular activation function-1 (AF-1) is important for gene regulation and protein interactions. Over last 2decades drug discovery against NTD has attracted interest for CRPC treatment. However, NTD is an intrinsically disordered domain without stable three-dimensional structure, which has so far hampered the development of drugs targeting this highly dynamic structure. Employing high throughput cell-based assays, small-molecule NTD inhibitors exhibit a variety of unexpected properties, ranging from specific binding to NTD, blocking AR transactivation, and suppressing oncogenic proliferation, which prompts its evaluation in clinical trials. Furthermore, molecular dynamics simulations reveal that compounds can induce the formation of collapsed helical states. Nevertheless, our knowledge of NTD structure has been limited to the primary sequence of amino acid chain and a few secondary structure motif, acting as a barrier for computational and pharmaceutical analysis to decipher dynamic conformation and drug-target interaction. In this review, we provide an overview on the sequence-structure-function relationships of NTD, including the polymorphism of mono-amino acid repeats, functional elements for transcription regulation, and modeled tertiary structure of NTD. Moreover, we summarize the activities and therapeutic potential of current NTD-targeting inhibitors and outline different experimental methods contributing to screening novel compounds. Finally, we discuss current directions for structure-based drug design and potential breakthroughs for exploring pharmacological motifs and pockets in NTD, which could contribute to the discovery of new NTD inhibitors.