Chemotherapy For Castration-resistant Prostate Cancer Research Articles

Prevalence of germline BRCA1/2 pathogenic variants in Japanese patients treated with castration-resistant prostate cancer and efficacy of CRPC treatment in real-world clinical practice.

The companion diagnosis for olaparib, a poly (ADP-ribose) polymerase inhibitor for prostate cancer, aims to detect BRCA1/2 gene variants. In clinical practice, the frequency of germline BRCA1/2 variants in patients receiving castration-resistant prostate cancer treatment is unknown. We aimed to evaluate the prevalence of germline BRCA1/2 variants and their relationship to prognosis and treatment efficacy in castration-resistant prostate cancer. Between June 2021 and 2023, 92 patients receiving castration-resistant prostate cancer treatment were examined for germline BRCA1/2 variants using BRACAnalysis CDx®. Furthermore, the associations between BRCA1/2 pathogenic variants and clinical outcomes were assessed. Of the 92 patients referred for genetic testing, 6 (6.5%) carried germline pathogenic variants in BRCA1/2. The BRCA2 variant was the most frequent (n=5), followed by BRCA1 variant (n=1). Among the five variants in BRCA2, the p.Asp427Thrfs*3 variant was identified for the first time in prostate cancer. Overall survival from castration-resistant prostate cancer for patients with BRCA1/2 variants was significantly shorter than for patients without BRCA1/2 variants (P=0.043). Progression-free survival of androgen receptor signaling inhibitors for patients with BRCA1/2 variants was significantly shorter than for those without (P=0.003). Progression-free survival of taxane chemotherapy was significantly shorter in patients with BRCA1/2 variants than in those without (P=0.0149). In clinical practice, 6.5% of patients treated with castration-resistant prostate cancer carried germline BRCA1/2 pathogenic variants. Japanese castration-resistant prostate cancer patients with germline BRCA1/2 mutants have a poor prognosis and may be less responsive to treatment with androgen receptor signaling inhibitors and taxane-based chemotherapy for castration-resistant prostate cancer.

270P Germline BRCA1/2 pathogenic variants in Japanese patients with prostate cancer are predictive factors for androgen receptor-axis-targeted therapy or chemotherapy for castration-resistant prostate cancer

270P Germline BRCA1/2 pathogenic variants in Japanese patients with prostate cancer are predictive factors for androgen receptor-axis-targeted therapy or chemotherapy for castration-resistant prostate cancer

Lu-PSMA-617 in combination with third-line therapy for castration-resistant prostate cancer: A systemic review and meta-analysis.

e17051 Background: Prostate cancer is the second most common cancer and the sixth leading cause of cancer death among men worldwide. Lu-177 viptriplet, also known as lutetium-177-PSMA-617, is a highly targeted form of radioligand therapy that aims to shrink prostate cancer tumors and slow their progression. It is also recommended as a treatment option by the American Society of Clinical Oncology (ASCO) for patients with prostate-specific membrane antigen (PSMA) positive PET/CT-positive castration resistant prostate cancer (CRPC) who have progressed on at least one prior line of androgen receptor pathway inhibitors (ARPI) and at least one prior line of chemotherapy. However, the evidence on its effectiveness with third-line chemotherapy is scarce. We aim to evaluate the efficacy of Luma-PSMA plus third-line chemotherapy in CRPC. Methods: We conducted a comprehensive literature search in PubMed, PMC, Scopus, and Embase using relevant keywords to identify articles related to Luma-PSMA and third line chemotherapy for prostate cancer from inception to Jan 30, 2023. Three independent reviewers screened the articles for eligibility and extracted data on outcomes such as overall survival (OS), PSA decline > 50%, and partial remission. We used Raveman 5 software to perform a statistical analysis and calculated the odds ratio with a 95% confidence interval for each outcome. Results: A total of 11 studies were included in our analysis with 787 patients. Pooled analysis of studies demonstrated an overall survival after Lu-PSMA-617 therapy plus third line chemotherapy as compared to standalone chemotherapy in castration resistant prostate cancer to be 13.15 months (95% CI = 10.66 – 15.65, P = < 0.001, I2= 69.93%). Pooled prevalence of prostate specific antigen (PSA) decline > 50% was determined to be 49.5% (95% CI = 44.2 – 54.7, P = 0.162 I2= 33.27%) and partial remission was observed in 39.7% patients (95% CI = 28.5 – 50.9, P = 0.952 I2= 0%). Conclusions: Our meta-analysis suggests that Lu-PSMA-617 therapy plus third-line chemotherapy may improve overall survival and PSA response in patients with CRPC compared to chemotherapy alone. However, the quality of evidence is limited by heterogeneity and risk of bias. More high-quality randomized trials are needed to confirm the efficacy and safety of this combination therapy. [Table: see text]

Corrole Nanoparticles for Chemotherapy of Castration-Resistant Prostate Cancer and as Sonodynamic Agents for Pancreatic Cancer Treatment.

A nanoparticle-based system, composed of the gallium(III) complex of a minimally substituted corrole that is coated by transferrin as a targeting vehicle (3-Ga NPs), has been used for pre-clinical evaluation of its efficacy against human metastatic castration-resistant prostate cancer (mCRPC) tumor xenografts. All mice (N = 9) responded to a dose of 10 mg/kg, with a remarkable tumor growth inhibition of 400% following 2 weeks of treatment; Ames and hERG tests excluded potential concerns regarding mutagenicity and cardiotoxicity, respectively. Also demonstrated is the potential application of these 3-Ga NPs as sonodynamic agents for the preclinical treatment of pancreatic cancer. 10 mg/kg 3-Ga NPs combined with exposure to ultrasound waves (2 min of 1 MHz 0.1 w/cm2 twice a week) induced up to 77% tumor shrinkage. Consistently, tumor/tissue distribution and serum levels of 3-Ga NPs in mice revealed high tumor specificity, favorable pharmacokinetics, fast absorption, slower redistribution, and very slow drug clearance.

CD44v8-10 mRNA contained in serum exosomes as a diagnostic marker for docetaxel resistance in prostate cancer patients

BackgroundDocetaxel is first-line chemotherapy for castration-resistant prostate cancer (CRPC), but most patients acquire docetaxel resistance. CD44 has been shown to be involved in drug resistance of cancers including prostate cancer. We hypothesized that CD44 in serum exosomes could be a diagnostic marker for docetaxel resistance in CRPC patients. In this study, we examined CD44 protein and mRNA expression in cell lysates and exosomes isolated from prostate cancer cells, evaluated the effect of CD44v8-10 knockdown on docetaxel sensitivity and measured CD44 mRNA copy numbers contained in serum exosomes in prostate cancer patients. Materials and methodsDocetaxel-sensitive PC-3 prostate cancer cells and docetaxel-resistant PC-3R cells established previously from parental PC-3 cells were used. CD44v8-10 knockdown was performed by siRNA transfection. Blood was collected from 50 docetaxel-naïve and 10 docetaxel-resistant patients and 15 control males. CD44 protein expression was evaluated by Western blotting. CD44 mRNA expression was measured by RT-digital PCR. ResultsThe levels of CD44v8-10 protein and mRNA in cell lysates and exosomes were higher in PC-3R cells than in PC-3 cells. CD44v8-10 knockdown significantly increased docetaxel sensitivity of PC-3R cells. The CD44v8-10 mRNA copy numbers in serum exosomes were higher in docetaxel-resistant patients than in docetaxel-naïve patients and control males (median 46, 12 and 17 copies/mL serum, respectively, P = 0.032). In contrast, the serum exosomal mRNA copy numbers of CD44 standard isoform (CD44s) were not different among 3 groups (median 25, 14 and 13 copies/mL serum, respectively, P = 0.150). ConclusionsCD44v8-10 may be involved in docetaxel resistance in prostate cancer and serum exosomal CD44v8-10 mRNA could be a diagnostic marker for docetaxel-resistant CRPC.

Use of plasma androgen receptor (AR) testing to optimize docetaxel chemotherapy in castration-resistant prostate cancer (CRPC): A multicenter biomarker study.

5546 Background: Plasma AR status has been identified as a potential biomarker of response in CRPC patients receiving docetaxel or the AR-targeted therapies abiraterone or enzalutamide. However, the relevance of plasma AR in the overall management of CRPC patients (pts) receiving docetaxel at different dose due to the toxicity profiles and physician-patient preferences is unknown. Methods: This was a multi-institution study of associations between baseline plasma AR-copy-number status assessed by droplet digital PCR and outcome in 325 CRPC pts. Between September 2011 and July 2019 pts started treatment with docetaxel administered at standard regimen 75mg/m2 every three weeks or adapted regimen (75-80% of standard recommended dose or 30mg/m2 weekly administration) at the discretion of the treating physician. Patients were assigned randomly into 2 sets with a ratio 2:1 to either training (n=217) and internal validation (n=108) cohorts. Results: In our study, adapted regimen of docetaxel was administered in 68 (31.3%) and 35 (32.4%) of training and validation cohorts, respectively. Based on plasma AR status, 67 (30.9%) and 39 (36.1%) validation and training set pts were classified as AR gain, respectively. In men treated with standard docetaxel regimen, no difference in progression-free/overall survival (PFS/OS) was seen between plasma AR normal and gain in both cohorts. In patients treated with adapted docetaxel regimen, we observed a significantly shorter median PFS (3.9 vs. 6.4 months, HR 4.77, 95%CI 1.48-3.80, p=0.0003) and median OS (11.2 vs . 20.4 months, HR 2.87, 95%CI 1.73-2.13, p=0.0008) in the training cohort. This finding was confirmed in the validation cohort (median PFS: 4.8 vs. 7.4 months, HR 2.54, 95%CI 1.40-4.58, p=0.005, and median OS: 11.8 vs. 26.4 months, HR 5.00, 95%CI 2.59-9.65, p<0.0001). In addition, AR-gained patients were less likely than AR normal to have a PSA decline when receiving an adapted regimen in both cohorts (p=0.010 e p=0.003, respectively). Conclusions: This study suggests that plasma AR may improve clinical decision making in choosing not only between AR-directed therapies and taxanes, but also between adapted and standard regimen of docetaxel in first- and subsequent-therapy lines, providing promising clinical implications to select the proper timing and dose of docetaxel. Prospective trials to validate these findings are warranted.

Prognostic significance of lactate dehydrogenase in cabazitaxel chemotherapy for castration-resistant prostate cancer: a multi-institutional study.

This multi-institutional study aimed to identify prognostic factors for cabazitaxel treatment of castration-resistant prostate cancer (CRPC). This study included 74 Japanese patients with CRPC who were treated with cabazitaxel between 2014 and 2017. Associations between clinicopathological factors including serum markers and progression-free survival (PFS) and overall survival (OS) were investigated. On multivariate analysis, high Gleason score [≥9 vs. ≤7; hazard ratio (HR), 95% confidence interval (CI): 2.00 (1.01-4.34); P = 0.047], presence of pain [HR, 95% CI: 2.02 (1.14-3.58); P = 0.016], and lactate dehydrogenase (LDH) level [HR, 95% CI: 47.31 (3.79-577.49); P = 0.0019] were significantly associated with PFS. Similarly, number of docetaxel cycles [HR, 95% CI: 0.050 (0.0037-0.45); P = 0.0057], performance status [≥2 vs. 0; HR, 95% CI: 5.07 (1.57-16.24); P < 0.0001], and LDH level [HR, 95% CI: 2946 (50-420994); P = 0.0001] were significantly associated with OS. This study showed that LDH level is robustly prognostic for both PFS and OS in cabazitaxel chemotherapy for CRPC.

Development of a prognostic model for survival time prediction in castration-resistant prostate cancer patients

BackgroundTo identify predictors of survival in patients treated with docetaxel chemotherapy for castration-resistant prostate cancer (CRPC). MethodsWe retrospectively analyzed clinical data from 186 patients who underwent docetaxel chemotherapy for CRPC from 2005 to 2016 at a single center. Pretreatment baseline variables including demographic and clinicopathological data were reviewed. Disease progression was defined by imaging and/or consecutive prostate-specific antigen (PSA) elevation. The systemic immune-inflammation index (SII), the modified Glasgow Prognostic Score (mGPS), and the neutrophil-lymphocyte ratio (NLR) were calculated. Univariable and multivariable Cox proportional hazards regression analyses reporting hazard ratios assessed the risk for disease progression and overall survival (OS). A survival nomogram was constructed. ResultsMost patients (n = 139, 74.7%) completed at least 6 cycles of docetaxel chemotherapy. 156 patients (82.9%) experienced disease progression during the studied period. Only mGPS was independently associated with disease progression in a multivariable model (P < 0.01). During the studied period, 98 patients (52.1%) died. The built survival nomogram included statistically significant variables for OS in univariable analysis: hemoglobin, PSA, alkaline phosphatase (AP), lactate dehydrogenase, SII, neutrophil-lymphocyte ratio, mGPS, and site of metastases; and had a concordance index of 0.703. At decision curve analysis, the nomogram led to superior outcomes for any decision associated with a threshold probability of above 40%. In multivariable analysis, only AP (P = 0.02), hemoglobin and PSA (P < 0.01, respectively) remained associated with OS. ConclusionsPSA, AP, and hemoglobin are independent prognosticators for OS. Although mGPS is a promising marker for tumor progression and SII is a plausible prognostic marker for OS, valid integration of inflammatory indices into a prognostic model requires validation studies. Predictive and prognostic biomarkers are desperately needed to guide physicians in treatment counseling given the heterogeneous nature of CRPC and the plethora of effective therapies.

Efficacy of Novel Bromodomain and Extraterminal Inhibitors in Combination with Chemotherapy for Castration-Resistant Prostate Cancer

BackgroundChemotherapy is the treatment of choice for metastatic castration-resistant prostate cancer (mCRPC) nonresponsive to androgen receptor–targeted therapies. Nevertheless, the impact of chemotherapy on patient survival is limited and clinical outcome remain dismal. Bromodomain and extraterminal inhibitors (BETis) are attractive therapeutic agents and currently in clinical trials to be tested for their efficacy in prostate cancer patients. ObjectiveIn this study, we evaluated the activity of two clinical stage BETis, INCB054329 and INCB057643, alone and in combination with chemotherapeutics used for the treatment of mCRPC. Design, setting, and participantsDrug activity was evaluated in vitro by MTT, clonogenic, prostato-sphere, and flow cytometry assays. The activity in vivo was evaluated in mice bearing prostate tumor (22Rv1) xenografts. Outcome measurements and statistical analysisCell growth data were analyzed to determine the maximum effect and the concentration that reduces by 50%. For concomitant treatments, the combination index was determined according to the Chou-Talalay method. For in vivo activity, changes in tumor size (T/Ci%), weight (T/Cd%), doubling time, and mouse body weight were monitored. Statistical significance was determined by one-way analysis of variance followed by a Student-Newman-Keuls or Turkey a posteriori test. Results and limitationsINCB054329 and INCB057643 had significant activity as single agents in human prostate cancer cell lines and 22Rv1 tumor xenografts. Combined treatment with INCB057643 and any of docetaxel, olaparib, or carboplatin was synergistic/additive in vitro. Notably, INCB057643, given with a low-intensity dosing schedule, greatly enhanced the anti-tumor activity of docetaxel, carboplatin, and olaparib in 22Rv1 tumor xenografts. ConclusionsCollectively, these results provide the first evidence of the therapeutic benefit obtainable by combining BETis with non–androgen receptor–targeted therapies for the treatment of mCRPC. Patient summaryChemotherapy has limited efficacy in patients with metastatic castration-resistant prostate cancer. This study provides evidence of enhanced efficacy of clinically used chemotherapeutics when given in combination with the bromodomain and extraterminal inhibitor INCB057643, expanding the horizon of the current options for the treatment of prostate cancer.

Abstract 4282: Crosstalk between apoptosis and autophagy induced by docetaxel-magnetic nanoparticles with different surface in prostate cancer cells

Abstract Although docetaxel-based chemotherapy prolongs life and relieves symptoms in patients with castration resistant prostate cancer (CRPC), this needs to be improved because of limitations such as systemic toxicity, and progression of docetaxel-resistance. Nanotechnology including nanoparticles has served a new role in medical sciences, leading to theranostics. Fe3O4 magnetic nanoparticles (MgNPs) have potential applications in drug delivery, cancer diagnosis and hyperthermia. We have already reported that MgNPs would modify the effect of docetaxel (DTX) in prostate cancer cells by oxidative DNA damage in prostate cancer cell lines. Combined treatment of docetaxel and MgNPs has also shown to induce apoptosis and autophagic cell death in DU145 cells. In this study, we analyzed the combined effect of DTX-carboxyl-modified MgNPs (MgNPs-COOH) on DU145 cells in a view of crosstalk between apoptosis and autophagy. The combination treatment of DTX and MgNPs-COOH more effectively inhibited cancer cell growth and induced apoptosis and autophagic cell death although MgNPs-COOH did exert no ROS production. This combination preferred autophagic cell death than apoptosis. These results suggest that MgNPs-COOH may induce different responses compared with MgNPs, and result in favorable development of current chemotherapy for CRPC. Citation Format: Masatoshi Watanabe, Sanai Takahashi, Eri Usugi, Kenichiro Ishii, Yoshifumi Hirokawa. Crosstalk between apoptosis and autophagy induced by docetaxel-magnetic nanoparticles with different surface in prostate cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4282.

Effects of Black Raspberries and Their Ellagic Acid and Anthocyanin Constituents on Taxane Chemotherapy of Castration-Resistant Prostate Cancer Cells

Cancer patients often use dietary supplements while on therapy, but little is known about interactions of supplements with cancer chemotherapy. Black raspberries (BRB) have anti-cancer effects, but have not been evaluated for interference with chemotherapy for castrate-resistant prostate cancer (CRPC). Here we studied whether BRB and some of their constituents interact with docetaxel and cabazitaxel on CRPC cells in culture and implanted into nude mice. Ellagic acid increased, but BRB extract inhibited, microtubule assembly. Ellagic acid decreased tubulin polymerization by cabazitaxel and bound to tubulin. Ellagic acid, its metabolite urolithin A, BRB extract, and the anthocyanin metabolite protocatechuic acid (PCA) did not alter cytotoxicity of taxanes. Ellagic acid inhibited drug efflux in CRPC cells, but BRB extract and PCA did not. None of these compounds altered CYP3A4 activity. Although dietary ellagic acid did not alter the tumor growth inhibition by docetaxel of xenografted 22Rv1 cells, ellagic acid has the potential to interfere with taxane chemotherapy by reducing tubulin polymerization while inhibiting P-glycoprotein drug efflux. These data are cause for concern of consuming ellagic acid during treatment for CRPC and indicate need for further research, but BRB consumption appears safe.

Combination of the natural product capsaicin and docetaxel synergistically kills human prostate cancer cells through the metabolic regulator AMP-activated kinase

BackgroundCurrent chemotherapy for castration-resistant prostate cancer is established on taxane-based compounds like docetaxel. However, eventually, the development of toxic side effects and resistance limits the therapeutic benefit being the major concern in the treatment of prostate cancer. Combination therapies in many cases, enhance drug efficacy and delay the appearance of undesired effects, representing an important option for the treatment of castration-resistant prostate cancer. In this study, we tested the efficacy of the combination of docetaxel and capsaicin, the pungent ingredient of hot chili peppers, on prostate cancer cells proliferation.MethodsProstate cancer LNCaP and PC3 cell lines were used in this study. Levels of total and phosphorylated forms of Akt, mTOR, S6, LKB1, AMPK and ACC were determined by Western blot. AMPK, LKB1 and Akt knock down was performed by siRNA. PTEN was overexpressed by transient transfection with plasmids. Xenograft prostate tumors were induced in nude mice and treatments (docetaxel and capsaicin) were administered intraperitoneally. Statistical analyses were performed with GraphPad software. Combination index was calculated with Compusyn software.ResultsDocetaxel and capsaicin synergistically inhibited the growth of LNCaP and PC3 cells, with a combination index lower than 1 for most of the combinations tested. Co-treatment with docetaxel and capsaicin notably decreased Akt and its downstream targets mTOR and S6 phosphorylation. Overexpression of PTEN phosphatase abrogated the synergistic antiproliferative effect of docetaxel and capsaicin. The combined treatment also increased the phosphorylation of AMP-activated kinase (AMPK) and the phosphorylation of its substrate ACC. In addition, pharmacological inhibition of AMPK with dorsomorphin (compound C) as well as knock down by siRNA of AMPK or its upstream kinase LKB1, abolished the synergy of docetaxel and capsaicin. Mechanistically, we showed that the synergistic anti-proliferative effect may be attributed to two independent effects: Inhibition of the PI3K/Akt/mTOR signaling pathway by one side, and AMPK activation by the other. In vivo experiments confirmed the synergistic effects of docetaxel and capsaicin in reducing the tumor growth of PC3 cells.ConclusionCombination of docetaxel and capsaicin represents a therapeutically relevant approach for the treatment of Prostate Cancer.

Lack of combination effects of soy isoflavones and taxane chemotherapy of castration-resistant prostate cancer.

Patients with cancer, including prostate cancer, often use dietary supplements, such as soy or isoflavones, before, during, or after therapy. There is little information about possible interactions between supplements and cancer chemotherapy. There are some reports suggesting enhancement by genistein of taxane chemotherapy for castrate-resistant prostate cancer (CRPC). We investigated whether physiologically attainable concentrations of soy isoflavones (≤10 μM) interact with taxanes on growth inhibition of CRPC cells in vitro and in vivo in nude mice exposed via the diet, on microtubule disassembly in vitro, and on P-glycoprotein-mediated drug efflux in 22Rv1 cells and CYP3A4 activity in microsomes. Genistein, daidzein, and equol did not affect growth of VCaP, 22Rv1, C4-2, and PC-3 CRPC cells or growth inhibition of these cells by docetaxel and cabazitaxel. These isoflavones did not inhibit microtubule disassembly in vitro or inhibit the microtubule effects of taxanes and genistein did not bind substantially to microtubules. Genistein considerably inhibited P-glycoprotein-mediated drug efflux in 22Rv1 cells and CYP3A4 activity in microsomes. However, dietary supplementation with genistein at 250 and 500 ppm did not affect the tumor growth inhibiting effect of docetaxel on 22Rv1 cells xenografted in nude mice. Our results with relevant cell models and clinically achievable concentrations of soy isoflavones do not support the notion that genistein or other soy isoflavones can enhance the effects of taxane chemotherapy in CRPC cell and xenograft models. Yet, the inhibitory effects of genistein on drug efflux in 22Rv1 cells and on microsomal CYP3A4 activity raise the possibility that genistein can affect taxane effects on CRPC cells in other circumstances than those we studied, which merits further research.

Real world evidence: Abiraterone use post-docetaxel in metastatic castrate-resistant prostate cancer.

The COU-AA-301 trial demonstrated that in men with metastatic castrate-resistant prostate cancer using abiraterone post-docetaxel increased overall survival. This study aims to assess this conclusion in a real world context. Retrospective chart review of a provincial Pharmacy BDM Database (a pharmacy dispensing software) and a provincial Electronic Chart (ARIA). Dispensing data, information on the state of the disease before and after abiraterone use, and information regarding effects of abiraterone were gathered. Cancer centers in Alberta, Canada. Metastatic castrate-resistant prostate cancer (CRPC) patients on abiraterone outside of a clinical trial who have previously had docetaxel chemotherapy for CRPC between February 2012 and May 2014. Overall survival from the time of abiraterone initiation. Overall survival increase of 17 months was consistent with the survival increase of 14.8 months observed in the pivotal trial. Abiraterone is a valuable therapy post-docetaxel for metastatic CRPC, as in a real world context it demonstrated an increase in overall survival that was consistent with the findings of the clinical trial despite including a patient population of older age and lower performance status.

Burden of illness of chemotherapy in castration-resistant prostate cancer patients in Japan: a retrospective database analysis

Objective: The objective was to assess the burden of chemotherapy for castration-resistant prostate cancer (CRPC) in Japan.Methods: Utilizing a large administrative hospital database we compared a set of outcome measures 12 months before and after initiation of chemotherapy, namely total medical costs, number of outpatient visits, number of hospital admissions and number of days spent in hospital.Results: A total of 598 CRPC patients were identified in the database. Total healthcare costs increased from 143,578 Japanese Yen (JPY) per patient per month (PPPM), before chemotherapy, to 333,628 JPY after start of chemotherapy. The number of hospital admissions increased by 280%, and the number of days spent in hospital by 380%.Conclusions: The overall costs of chemotherapy for patients diagnosed with castration-resistant prostate cancer in Japan are high. Our findings can serve as a basis for health economic evaluations.

New NO- and H2S-releasing doxorubicins as targeted therapy against chemoresistance in castration-resistant prostate cancer: in vitro and in vivo evaluations.

Chemotherapy for castration-resistant prostate cancer (CRPC) is only temporarily effective due to the onset of chemoresistance. We investigated the efficacy of NO- and H2S-releasing doxorubicins (NitDox and H2SDox) in overcoming drug resistance and evaluated their safety. New and innovative NO- and H2S-releasing doxorubicins (NitDox and H2SDox) showed a good intracellular accumulation and high cytotoxic activity in vitro in an androgen-independent and doxorubicin-resistant DU-145 prostate cancer cell line. Nude mice were subcutaneously injected with 4*106 DU-145 cells and treated once a week for 3 weeks with 5mg/kg doxorubicin, NitDox, H2SDox or vehicle, i.p. Animal weight, tumor volume, intra-tumoral drug accumulation, apoptosis and the presence of nitrotyrosine and sulfhydryl (SH) groups within the tumor, were evaluated. Cardiotoxicity was assessed by measuring troponin plasma levels and the left ventricular wall thickness. In vivo, NitDox and H2SDox accumulated inside the tumors, significantly reduced tumor volumes by 60%, increased the percentage of apoptotic cells in both the inner and the outer parts of the tumors and the presence of nitrotyrosine and SH groups. Doxorubicin treatment was associated with reduced body weight and cardiotoxicity. On the contrary, NitDox and H2SDox were well tolerated and had a better safety profile. Combining efficacy with reduced cardiovascular side effects, NitDox and H2SDox are promising novel therapeutic agents for reversing chemoresistance in CRCP.

A randomized, double-blind, placebo-controlled phase II study of maintenance therapy with tasquinimod in patients with metastatic castration-resistant prostate cancer responsive to or stabilized during first-line docetaxel chemotherapy

BackgroundThis phase II study was conducted to assess clinical efficacy of tasquinimod maintenance therapy in patients with metastatic castrate-resistant prostate cancer not progressing during first-line docetaxel-based therapy. Patients and methodsPatients were randomly assigned (1:1) to receive tasquinimod (0.25–1.0mg/day orally) or placebo. The primary end point was radiologic progression-free survival (rPFS); secondary efficacy end points included: overall survival (OS); PFS on next-line therapy (PFS 2) and symptomatic PFS, assessed using the Brief Pain Inventory (BPI) questionnaire and analgesic use. Quality of life was measured by the Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire and by the EuroQol-5 Dimension Quality of Life Instrument (EQ-5D). Adverse events were recorded. ResultsA total of 219 patients were screened and 144 patients randomized. The median duration of treatment was 18.7weeks (range 0.6–102.7weeks) for the tasquinimod arm and 19.2weeks (range 0.4–80.0weeks) for the placebo arm. Median (90% CI) rPFS was 31.7 (24.3–53.7) and 22.7 (16.1–25.9)weeks in the tasquinimod and placebo arms, respectively [HR (90% CI) 0.6 (0.4–0.9), P=0.0162]. The median OS was not reached because only 14 deaths occurred by the cut-off date. No statistically significant differences between treatment arms were noted for symptomatic PFS, PFS 2, BPI score, FACT-P score, or EQ-5D. The incidence of any treatment emergent adverse event (TEAE) was similar in the tasquinimod and placebo arms (97.2% versus 94.3%, respectively), whereas severe TEAEs (NCI-CTC Grade 3–5) incidence was higher in the tasquinimod group (50.7% versus 27.1%). ConclusionsRandomized trials testing new drugs as maintenance can be successfully conducted after chemotherapy in castrate-resistant prostate cancer. Maintenance tasquinimod therapy significantly reduced the risk of rPFS by 40%. ClinicalTrialsgov identifier NCT01732549.

Dual action of NSC606985 on cell growth and apoptosis mediated through PKCδ in prostatic cancer cells.

Chemotherapy is a vital therapeutic strategy for castration-resistant prostate cancer (CRPC). We have previously shown that NSC606985 (NSC), a camptothecin (CPT) analog, induced cell apoptosis via interacting with topoisomerase I (Topo I) in prostate cancer cells. In the present study, the effect and mechanism of CPT analogs in LAPC4 cells were investigated. LAPC-4 cells were treated with NSC, CPT, and topotecan. Cell proliferation, apoptosis, and protein kinase Cδ (PKCδ) subcellular activation were measured at different doses and time-points, with or without PKCδ inhibition or knockdown of PKCδ expression. NSC at doses ranging from 10 to 100 nM induced a dose-dependent increase in viable cell number and DNA biosynthesis with mild cell apoptosis, whereas, at doses ranging from 500 nM to 5 mM, NSC produced a dose-dependent decrease in cell proliferation and DNA biosynthesis with a significant induction of cell apoptosis. Both NSC-induced cell proliferation and apoptosis were blocked by knockdown of PKCδ with a specific RNAi, or by the co-administration of rottlerin, a PKCδ inhibitor. Moreover, NSC produced a dose-dependent subcellular activation of PKCδ. The dose-dependent dual action of NSC is mediated at least in part through the differential subcellular activation of PKCδ in LAPC4 cells. The demonstration of a differential cell response to camptothecin analogs would facilitate the identification of biomarker(s) to CPT sensitivity and promote the personalization of CPT chemotherapy in CRPC.

A prospective multicenter study of intermittent chemotherapy with docetaxel and prednisolone for castration-resistant prostate cancer.

The optimal schedule of docetaxel chemotherapy for castration-resistant prostate cancer is unknown, although continuous administration is accepted as the standard. We conducted a Phase II trial to evaluate the outcome of intermittent docetaxel and prednisolone therapy in castration-resistant prostate cancer. The patients were treated using a 28-day cycle of docetaxel (70 mg/m2 on Day 1) and oral prednisolone (10 mg/day). After three consecutive administrations of docetaxel, a holiday was taken until prostate specific antigen levels returned to the baseline. The therapy was continued intermittently until the disease progressed, drug toxicity occurred, or the patients refused further treatment. The primary endpoint was overall survival. Time to treatment failure, adverse events, the duration of chemotherapy holiday and quality of life were also evaluated. A total of 120 patients were enrolled. The median age and pretreatment prostate specific antigen level were 72 years and 37.5 ng/ml, respectively. Sixty (50.0%) patients resumed chemotherapy after the first holiday, and a maximum of six courses were administered to four patients. The median period of the first, second and third-to-fifth holiday was 18.6, 11.0 and 4.9 weeks, respectively. Toxicity was moderate, except for two fatal adverse events. The median time to treatment failure and overall survival from the initiation of docetaxel and prednisolone therapy in all patients were 17.5 and 35.0 months, respectively. All quality-of-life scores were unchanged statistically from the start of docetaxel and prednisolone therapy to the beginning of the second course. Intermittent docetaxel and prednisolone therapy might be a feasible treatment option for castration-resistant prostate cancer with comparable outcome and successful chemotherapy holidays.

A randomized, phase II study of repeated rhenium-188-HEDP (rhenium) combined with docetaxel versus docetaxel alone in castration resistant prostate cancer (CRPC) metastatic to bone: The Taxium II trial.

5081Background: Docetaxel is first line chemotherapy in CRPC. Re-188 is a beta-emitting radiopharmaceutical that targets bone metastases. We investigated whether treatment with docetaxel plus Re-18...