ABSTRACT
Nuclear transporter importin-β1 is emerging as an attractive target by virtue of its prevalence in many cancers. However, the lack of druggable inhibitors restricts its therapeutic proof of concept. In the present work, we optimized a natural importin-β1 inhibitor DD1 to afford an improved analog DD1-Br with better tolerability (>25 folds) and oral bioavailability. DD1-Br inhibited the survival of castration-resistant prostate cancer (CRPC) cells with sub-nanomolar potency and completely prevented tumor growth in resistant CRPC models both in monotherapy (0.5 mg/kg) and in enzalutamide-combination therapy. Mechanistic study revealed that by targeting importin-β1, DD1-Br markedly inhibited the nuclear accumulation of multiple CRPC drivers, particularly AR-V7, a main contributor to enzalutamide resistance, leading to the integral suppression of downstream oncogenic signaling. This study provides a promising lead for CRPC and demonstrates the potential of overcoming drug resistance in advanced CRPC via targeting importin-β1.
ABSTRACT
Prostate cancer is one of the most common cancers threatening the health of males. The incidence of prostate cancer in China is on the rise. Non-metastatic castration-resistant stage is a special disease stage during the progression of prostate cancer, early identification of nmCRPC and prompt intervention can help delay disease progression and prolong patient survival. In recent years, many studies demonstrated the efficacy of novel androgen receptor inhibitors such as apalutamide, in prolonging metastasis-free survival and time to symptomatic progression in patients with non-metastatic castration-resistant prostate cancer (nmCRPC). This article reviews the recent progress of novel androgen receptor inhibitors for nmCRPC.
ABSTRACT
Traditional endocrine drugs, such as bicalutamide, are the first choice for neoadjuvant therapy of prostate cancer. There are few reports on the use of new endocrine drugs in neoadjuvant therapy in China. The patient, male, 63 years old. He was admitted to the hospital for the finding of prostate space occupying. Blood PSA 53.50 ng / ml. Prostate MRI suggested that the prostate lesion broke through the left capsule, the left seminal vesicle gland was invaded, and the bladder wall was invaded. Bone scan suggested that: the left 8th posterior costal branch radioactivity was limited and increased. Prostate adenocarcinoma was diagnosed by puncture, Gleason score 4 + 4 = 8 points, and stage T 4bN 1M 1. The patient was treated with goserelin combined with enzalutamide for 3 months, and PSMA-PET CT: prostate size was normal, no significant 68Ga PSMA uptake was increased, no abnormally high Ga PSMA uptake in bones. The patient was treated with enzalutamide combined with ADT as neoadjuvant endocrine therapy, winning surgical conditions for the patient to undergo surgical resection.
ABSTRACT
Enzalumide has not been approved for therapy in metastatic hormone sensitive prostate cancer (mHSPC) patients in China. This study retrospectively analyzed the response to treatment of Enzalutamide as first-line neoadjuvant hormonal therapy for mHSPC. A 69-year-old man with prostate cancer characterized with clinical staging T 3bN 1M 1b, tPSA 240.69ng/ml and Gleason score 8, was administrated with Enzalumide as neoadjuvant hormonal therapy for 6 months. Re-examination for prostate MRI indicated the prostate, tumor lesion and the enlarged lymph nodes in the pelvic cavity were significantly smaller than before. Therefore, a robot-assisted laparoscopic radical prostatectomy was performed. Postoperative pathology showed resection margins were negative and no metastasis was observed in lymph nodes of pelvic cavity. After the operation, adjuvant hormonal therapy was performed. Blood tPSA was 0.016ng/ml at 6 weeks, and no tumor recurrence or enlarged lymph nodes were found in pelvic MRI at 6 months. Therefore, in this case, Enzalutamide as first-line neoadjuvant hormonal therapy can reduce the clinical staging of mHSPC, which may allow surgical resection of the tumor.
ABSTRACT
As a second-generation AR antagonist, enzalutamide has shown good effects in the treatment of castration-resistant prostate cancer, and has also been used in the treatment of hormone-sensitive prostate cancer. In 2018, a patient with prostate cancer was admitted to Hangzhou First People's Hospital. After radical prostatectomy, the patients was in PSA persistence. After 29 months of endocrine therapy, the patient developed drug resistance against bicalutamide, and PSA increased month by month. PSA dropped back to undetectable after changing bicalutamide to enzalutamine.
ABSTRACT
In March 2019, a patient with advanced prostate cancer was diagnosed in Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, and the disease progressed to the stage of mCRPC after traditional endocrinotherapy. Serious adverse event occurred after 1 month of treatment with abiraterone, which result in drug withdrawal, and replaced therapy by enzalutamide, the effect was good.
ABSTRACT
As the end-stage of prostate cancer, metastatic castration-resistant prostate cancer(mCRPC) complicates the disease and therefore challenges the doctors. In October 2018, an 87-year-old patient diagnosed with metastatic prostate cancer was admitted to Shanghai General Hospital for evaluation and treatment. Poor basic health condition plus severe side effect resulted in patient’s poor compliance with treatment and irregular follow-up. The patient progressed to mCRPC in September 2020, and was given enzalutamide as first-line therapy, after which the patient’s PSA level was under control with no side effect.
ABSTRACT
Metastatic castration-resistant prostate cancer (mCRPC) is the inevitable form of most prostate cancers after endocrine therapy, and conventional drugs are not effective at this time.In this case, an elderly mCRPC patient with cardiopulmonary diseases admitted to the First Hospital of Shanxi Medical University in August 2020 was selected. After the failure of traditional endocrine therapy, enzalumide+ ADT regimen was adopted, and the patient's blood PSA was significantly reduced without cardiopulmonary adverse events.
ABSTRACT
We reported an advanced prostate cancer patient underwent muti-disciplinary treatment with long time survival. After 18 months of androgen deprive therapy, the disease progressed to metastatic castration-resistant prostate cancer(mCRPC) stage. So enzalutamide was added and combined with radiotherapy for bone metastases, which achieved excellent survival benefits. From the diagnosis to September 2021, the patients survived for 97 months, including 79 months in the mCRPC stage. the tumor related symptoms disappeared, the PSA remained < 0.003ng/ml, and the imaging lesions remained stable.
ABSTRACT
To investigate the efficacy and adverse reactions of enzalutamide in the treatment of metastatic prostate cancer(mPCa). Two male patients were reported, Patient 1 was hospitalized due to elevated PSA for 6 months and fatigue for 2 weeks. Tests on the admission showed that tPSA > 1 000 ng/ml, pathological of prostate biopsy: prostate acinar carcinoma, Gleason score 4+ 4=8, imaging examination revealed multiple metastases of prostate cancer throughout the body. Patient 2 was admitted to hospital due to cough, sputum, chest tightness and difficulty in defecation for more than 20 days, and the patient had radical surgery for prostate cancer five years ago. Tests on admission showed that tPSA > 100 ng/ml, fPSA>50 ng/ml. The patient was diagnosed as postoperative local recurrence of prostate cancer with bilateral pleural effusion, and cancer lymphangitis was considered. Both patients were treated with enzalumide combined with goseraline. Both patients were followed up for 6 months, PSA decreased significantly within half a year, general condition continued to improve, and they were well tolerated, no obvious adverse reactions occurred.
ABSTRACT
In the past two decades, the development and marketing of several novel androgen receptor inhibitors added new options for the treatment of prostate cancer and extended the understanding of the management of prostate cancer. Brief review of the development history and the key aspects of these inhibitors will be conducive to individualised therapy, and further improve patient survival and other clinical benefits.
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A reproducible stability-indicating Reverse Phase-HPLC technique for the quantification of enzalutamide in in pharmaceuticals was developed and validated. Chromatography was achieved on Inertsil-ODS-C18 (250mm×4.6 mm) 5µmanalytical column with acetonitrile: methanol: water in 40:30:30% v/v proportion as mobile phase and flow rate of 1 ml/min. Enzalutamide was detected at 237 nm UV-wavelength maximum. In the present work mobile phase used as a diluent. Developed technique was validated over 20-150 µg/ml linear concentration range for enzalutamide. This method established with linearity coefficient value of 0.99 and the percentage recovery was found to be 99.3%. This method was proven with LOD and LOQ values of 0.53 µg/mL and 1.61µg/ml respectively. The drug was degraded in acid and alkaline conditions and the percentage degradation values were 3.10 % and 4.54 % respectively. There was no degradation of drug when exposed to neutral, UV, thermal, sun-light and oxidative conditions.Drug was undergoing degradation when exposed to acid and alkaline conditions. The developed technique was useful in the routine quantitation of enzalutamide.
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Objective To summarize the characteristics of clinical manifestation of bone flare after the treatment with new endocrine therapy in patients with metastatic castration-resistant prostate cancer (mCRPC) in order to evaluate the curative effect of patients properly and determine the reasonable treatment strategy.Methods We retrospectively analyzed the clinical data of two patients with mCRPC performed "bone flare" defined as PSA decline and bone metastases progression in the initial treatment with new endocrine therapy in Urology Department of Peking University First Hospital,and analyzed the clinical characteristics and treatment methods with the relative literature.Case 1,a 79-year-old man,presented with frequent urination and prostate-specific antigen (PSA) was 115.900 ng/ml,was diagnosed as prostate cancer (cT3N0M1) with bone metastasis.After androgen deprivation therapy of 24 months,PSA elevated and multiple bone metastases progressed.The patient was diagnosed with mCRPC and then began the treatment of enzalutamide.Case 2,a 62-year-old man,complained about emaciation and frequent urination,was diagnosed with prostate cancer(cT4N1M1)with bone and lymph metastases.After androgen deprivation therapy of 22 months,PSA elevated and multiple bone metastases progressed.The patient was diagnosed with mCRPC and then began the treatment of abiraterone.Results Case 1 was treated with enzalutamide and 2 months later PSA decreased from 133.400 ng/ml to 5.530 ng/ml,while bone scan showed multiple bone metastases,part of which was newly metastatic lesions.6 months later,the number of metastatic lesions kept stable,and part of lesions presented metabolism decrease.8 months later,the number of metastatic lesions began to decrease.1 year later,the patient started to receive chemical therapy because of the progression of the disease.After 5 cycles of chemotherapy,PSA progression occurred and chemotherapy was stopped.Liver failure and disseminated intravascular coagulation caused death in June 2016.Case 2 was treated with abiraterone and 2 months later PSA decreased from 54.820 ng/ml to 3.580 ng/ml,while bone scan showed multiple bone metastases,part of which was newly metastatic lesions.6 months later,the number of metastatic lesions began to decline.10 months later,the number of metastatic lesions kept stable.The treatment of abiraterone was continued so far and the patient was in a stable condition.Conclusions Enzalutamide and abiraterone,two new endocrine therapy,are determined as preferred methods for the treatment of mCRPC.The bone scanning is required to evaluate the possibility of "bone flare" which is defined as PSA decline and bone metastases progression in the initial treatment.These patients should be evaluated to make appropriate clinical decision.
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At a time when the population shows increasing longevity, entities such as cancer and chronic kidney disease (CKD) are more frequently connected. In the United States, approximately 6% of the patients on hemodialysis have cancer. The challenge to manage oncologic patients with CKD in a hemodialytic program represents a great shortage of available information on the choice of the best drug, timing, dosage adjustments, dialysis method, and treatment safety. We present the case of a patient with prostate cancer and terminal CKD in hemodialysis, and the treatment sequence after the development of resistance to hormonal blockade therapy, which included docetaxel, enzalutamide, and radium-223.
Subject(s)
Humans , Male , Middle Aged , Adenocarcinoma/complications , Antineoplastic Agents/administration & dosage , Dialysis , Prostatic Neoplasms/complications , Renal Insufficiency, Chronic/drug therapy , Phenylthiohydantoin/administration & dosage , Prostatic Neoplasms, Castration-Resistant/complications , Radium/administration & dosage , Renal Insufficiency, Chronic/complications , Taxoids/administration & dosageABSTRACT
Objective@#To establish enzalutamide-resistant human prostate cancer cell lines and screen out the lncRNA and mRNA expression profiles associated with enzalutamide resistance.@*METHODS@#Human prostate cancer cell lines LNCAP and C4-2B were cultured with 10 μmol/L enzalutamide for 6 months in vitro for the establishment of enzalutamide-resistant subclones LNCAP-ENZA and C4-2B-ENZA. The IC50 value and enzalutamide resistance index of each cell line were examined by MTT assay, the expressions of enzalutamide-related genes FL-AR, AR-V7 and HnRNPA1 were determined by Western blot, and the lncRNA and mRNA differential expressions of C4-2B and C4-2B-ENZA were detected by high-throughout lncRNA microarray.@*RESULTS@#Compared with LNCAP and C4-2B, the IC50 values of enzalutamide-resistant subclones LNCAP-ENZA (60.83 μmol/L) and C4-2B-ENZA (88.32 μmol/L) were increased significantly (P < 0.05) and the enzalutamide-resistance indexes of the LNCAP-ENZA and C4-2B-ENZA cells were 4.94 and 4.67, respectively. The expressions of AR-V7 and HnRNPA1 were markedly up-regulated in the LNCAP-ENZA and C4-2B-ENZA cells as compared with those in the LNCAP and C4-2B cells, but that of FL-AR showed no significant change. A total of 1 440 lncRNAs and 1 236 mRNAs were identified as differentially expressed in the C4-2B-ENZA cells.@*CONCLUSIONS@#Enzalutamide -resistant human prostate cancer cell subclones LNCAP-ENZA and C4-2B-ENZA were successfully established and enzalutamide resistance-associated lncRNA and mRNA were identified, which may provide some molecular evidence for the management of enzalutamide-resistant human prostate cancer.
Subject(s)
Humans , Male , Cell Line, Tumor , Drug Resistance, Neoplasm , Phenylthiohydantoin , Pharmacology , Prostatic Neoplasms , Drug Therapy , Genetics , Pathology , RNA, Long Noncoding , Metabolism , RNA, Messenger , Metabolism , RNA, Neoplasm , Metabolism , Receptors, AndrogenABSTRACT
Objective To summarize the clinical features of prostatic ductal adenocarcinoma and to explore its therapeutic approaches.Methods A case report on an elderly patient with prostatic ductal adenocarcinoma who received endocrine therapy,chemotherapy,radiotherapy,and Enzalutamide therapy after prostate biopsy in November 2013.We summarized and analyzed the patient's clinical manifestations and reviewed relevant literature.Results The patient showed a low sensitivity to Docetaxel;the PSA level of the patient was over 30 times lower than the baseline level after monotherapy with Enzalutamide;bilateral pulmonary nodules and mediastinal lymph nodes reduced in size;a bone scan showed no significant change in bone metastases.At present,there is no report on treatment for prostatic ductal adenocarcinoma with Enzalutamide.Conclusions Enzalutamide therapy is effective and safe for prostate ductal adenocarcinoma and should be encouraged in clinical practice.Studies with larger sample sizes and longer follow-ups are needed in the future.
ABSTRACT
This study was designed to evaluate the efficacy, tolerability, and sequential administration of abiraterone acetate (AA) and enzalutamide (Enz) for metastatic castration-resistant prostate cancer (mCRPC). A literature search was performed with PubMed, Embase, and Web of Science databases to identify relevant studies. Reviewed literature included published phase III trials of AA or Enz in mCRPC and studies regarding their sequential administration. Given the difference in control arms in AA (active comparator) and Enz (true placebo) randomized phase III studies, indirect comparisons between AA and Enz in mCRPC showed no statistically significant difference in overall survival in prechemotherapy and postchemotherapy settings (HR: 0.90, 95% CI, 0.73-1.11; HR: 0.85, 95% CI, 0.68-1.07). Compared with AA, Enz may better outperform control arms in treating mCRPC both before and after chemotherapy regarding secondary endpoints based on indirect comparisons: time to prostate-specific antigen (PSA) progression (HR: 0.34, 95% CI, 0.28-0.42; HR: 0.40, 95% CI, 0.30-0.53), radiographic progression-free survival (HR: 0.37, 95% CI, 0.28-0.48; HR: 0.61, 95% CI, 0.50-0.74), and PSA response rate (OR: 18.29, 95% CI, 11.20-29.88; OR: 10.69, 95% CI, 3.92-29.20). With regard to the effectiveness of Enz following AA or AA following Enz, recent retrospective case series reported overall survival and secondary endpoints for patients with mCRPC progression after chemotherapy. However, confirmatory head-to-head trials are necessary to determine the optimal sequencing of these agents.
ABSTRACT
Objetivo: O objetivo deste estudo foi estimar o número necessário a tratar (NNT) e custo por evento evitado (COPE) de enzalutamida (ENZ) em comparação com abiraterona+prednisona (AA+P) em 12 e 24 meses sob perspectiva do sistema de saúde suplementar em pacientes com câncer de próstata resistente à castração metastático (CPRCM) sem quimioterapia prévia. Métodos: O NNT é calculado pelo inverso da diferença do risco absoluto de uma intervenção versus placebo; adicionalmente, o COPE representa o NNT multiplicado pelo custo de tratamento total de um período determinado. O risco absoluto de ENZ e AA+P e seus respectivos controles foram obtidos das curvas de sobrevida livre de progressão radiográfica (SLPr) e sobrevida global (SG) dos estudos PREVAIL e COU-AA-302, respectivamente. A duração de tratamento média no horizonte de 24 meses foi estimada utilizando a área sob a curva das respectivas curvas de SLPr. Os resultados foram a comparação entre ENZ e AA+P versus seus respectivos placebos em 12 e 24 meses para NNT e COPE. O custo total de tratamento consistiu em custos de medicamento, monitoramento, e manejo de eventos adversos (≥1%, eventos de interesses especiais). Resultados: A análise de 12 meses resultou em NNTSG/ENZ= 12,79; NNTSLPr/ENZ= 2,59; NNTSG/AA+P= 116,28; NNTSLPr/AA+P= 4,72 e COPESG/ENZ= BRL 1.626.583; COPESLPr/ENZ= BRL 329.701; COPESG/AA+P= BRL 15.144.886; COPESLPr/AA+P= BRL 614.368. Para a análise de 24 meses, os resultados foram: NNTSG/ENZ= 11,00; NNTSLPr/ENZ= 3,58; NNTSG/AA+P= 16,56; NNTSLPr/AA+P= 5,00 e COPESG/ENZ= BRL 1.965.454; COPESLPr/ENZ= BRL 639.327; COPESG/AA+P= BRL 2.833.580; COPESLPr/AA+P= BRL 855.741. Conclusão: Para ambos horizontes de tempo, os resultados foram favoráveis para ENZ vs. AA+P em pacientes com CPRCM.
Objective: The aim of this study was to estimate the NNT and COPE of enzalutamide (ENZ) in comparison with abiraterone acetate+prednisone (AA+P) over a 12-month and 24-month period from the Supplementary Health System perspective in metastatic castration-resistant prostate cancer patients who are chemotherapy naïve (MCRPC). Methods: The NNT is calculated by the inverse of the absolute risk reduction of an intervention vs. control; additionally, COPE represents the NNT multiplied by total cost of treatment in a pre-defined period. The absolute risk of ENZ and AA+P, and their respective control treatments, were obtained from the Kaplan Meier curves for the co-primary end points of radiographic progression free survival (rPFS) and overall survival (OS) from the clinical studies PREVAIL and COU-AA-302, respectively. Mean treatment duration was estimated utilizing the area under curve (AUC) technique from the respective intervention rPFS curves. The results analyzed ENZ or AA+P versus its respective placebo at 12 and 24 months for NNT and COPE. Total treatment cost consisted of drug cost, monitoring cost and adverse event (>=1% incidence and special interest adverse events) related cost. Results: The 12 month analysis resulted in NNTOS/ENZ= 12.79; NNTrPFS/ENZ= 2.59; NNTOS/AA+P= 116.28; NNTrPFS/AA+P= 4.72 and COPEOS/ENZ= BRL 1,626,583; COPErPFS/ENZ= BRL 329,701; COPEOS/AA+P= BRL 15,144,886; COPErPFS/AA+P= BRL 614,368. For the 24-month analysis, the results were: NNTOS/ENZ= 11.00; NNTrPFS/ENZ= 3.58; NNTOS/AA+P=16.56; NNTrPFS/AA+P= 5.00 and COPEOS/ENZ= BRL 1,965,454; COPErPFS/ENZ= BRL 639,327; COPEOS/ AA+P= BRL 2,833,580; COPErPFS/AA+P= BRL 855,741. Conclusion: Across the 12- and 24-month time horizons, the NNT and COPE was favorable for ENZ vs. AA+P in patients with MCRPC.
Subject(s)
Humans , Numbers Needed To Treat , Prostatic Neoplasms, Castration-ResistantABSTRACT
Pharmacology , pharmacokinetics , clinical study and safety of enzalutamide in the treatment of castration-resistant pros-tate cancer (CRPC) were reviewed in the paper.Enzalutamide, a pure second-generation androgen receptor antagonist , can inhibit multiple points in the androgen receptor signaling pathway , including the inhibition of androgen binding to the androgens receptor , nu-clear translocation of the androgens receptor complex and binding of the androgens receptor complex to deoxyribonucleix acid ( DNA) . The phase 3 clinical trials have revealed that enzalutamide is effective to delay the progression of metastatic CRPC , reduce the prostate-specific antigen (PSA) levels, decrease the progression time of PSA and prolong the overall survival time and the time of first skeletal -related events .Enzalutamide has become a novel treatment option for CRPC patients .Enzalutamide is well tolerated with low incidence of side effects .
ABSTRACT
Prostate cancer represents the second cancer-related cause of death in North American and Chilean men. The main treatment for incurable stages of disease is surgical or pharmacological castration. However, with time and despite the addition of anti-androgens, the disease progresses to a clinical state that has been commonly referred to as hormone refractory. In recent years, the concept of hormone refractoriness has been challenged and replaced by castration resistance, acknowledging that further and optimal hormonal manipulation can be attained, beyond achieving testosterone levels at castration range. The purpose of this review is to summarize the recent therapeutic breakthroughs in the management of metastatic castrate resistant prostate cancer (mCRPC), with greater emphasis in the newer hormonal therapy agents such as Abiraterone and Enzalutamide. Future combination and sequential treatment strategies are contextualized in the current era of personalized cancer medicine and genomic characterization of prostate cancer.