Hormone-resistant Prostate Cancer Research Articles

Abstract 2653: Nelfinavir induces apoptosis in hormone-resistant prostate cancer cells through inhibition of regulated intramembrane proteolysis of SREBP-1 and ATF6

Abstract We previously reported that nelfinavir-induced apoptosis in liposarcoma is a direct result of regulated intramembrane proteolysis (RIP) inhibition mediated through inhibition of site-2 protease (S2P) activity. We now report similar effects in hormone-resistant prostate cancer (HR-PC) cells. Nelfinavir-mediated RIP inhibition leads to accumulation of unprocessed sterol regulatory element binding protein-1 (SREBP-1) and activating transcription factor 6 (ATF6). This results in endoplasmic reticulum (ER) stress and inhibition of the unfolded protein response (UPR), which leads to autophagy and caspase activation. Confocal microscopy and proliferation studies demonstrate that nelfinavir inhibits the nuclear translocation of SREBP-1-EGFP and ATF6-EGFP fusion proteins, and reduces PC proliferation, similar to the situation observed in site-1 protease (S1P) and S2P-siRNA knockdown cells. Western blotting in nelfinavir and S1P and/or S2P-siRNA knockdown cells confirms accumulation of precursor SREBP-1 and ATF6. Treatment of PC cells with DCI, an S1P inhibitor did not affect SREBP-1 processing. In contrast, 1,10-phenanthroline, an S2P inhibitor, reproduces the molecular and biological phenotype observed in nelfinavir-treated HR-PC cells. These results are consistent with the hypothesis that S2P is a target of nelfinavir. These findings, together with our previous report, provide new insight into the mechanism of nelfinavir-mediated induction of ER stress and cell death in cancer, and are the first to report targeting S2P therapeutically for cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2653. doi:10.1158/1538-7445.AM2011-2653

Abstract 1675: Identification of KURO3 overexpressed in high-grade prostate cancer

Abstract Prostate cancer is usually androgen-dependent and responds well to androgen ablation therapy. However, at a certain stage some prostate cancers eventually acquire a castration-resistant phenotype. These cancer cells are originally high-grade and show very poor response to any anticancer therapies. To characterize the molecular features of clinical high-grade prostate cancers, we analyzed gene-expression profiles by genome-wide cDNA microarray combined with microdissection and found dozens of trans-activated genes in clinical high-grade prostate cancers. Among them, we report the identification of a new biomarker, KURO3. We confirmed overexpression of KURO3 in high-grade prostate cancer cells by RT-PCR. Knockdown of KURO3 expression by siRNA in a prostate cancer cell line resulted in a drastic decrease of cell numbers. In contrast, KURO3 overexpression in a prostate cancer cell line promoted cell proliferation. These findings suggest that KURO3 could be involved in aggressive phenotype of prostate cancers, including hormone-resistant prostate cancers, and that it should be a potential molecular target for development of new therapeutics and a diagnostic biomarker for aggressive prostate cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1675. doi:10.1158/1538-7445.AM2011-1675

Chemotherapy sensitivity recovery of prostate cancer cells by functional inhibition and knock down of multidrug resistance proteins

In several cancer types, expression of multidrug resistance (MDR) proteins has been associated with lack of chemotherapy response. In advanced prostate cancer (PCa) the use of chemotherapy is mainly palliative due to its high resistance. Previously, we described that MDR phenotype in PCa could be related with high basal and drug-induced expression of MDR proteins P-Glycoprotein (P-Gp), MRP1, and LRP. Using primary cell cultures from PCa patients, we evaluated the effect of function and expression inhibition of P-Gp, MRP1, and LRP, on cell survival after chemotherapy exposure. Cells were treated with specific MDR protein substrates (docetaxel and mitoxantrone for P-Gp, methotrexate for MRP1 and cisplatin for LRP) and pharmacological inhibitors (cyclosporine A, genistein and 3-aminobenzamide), and cell survival was evaluated trough 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and cell cycle analysis. MRP1 activity was evaluated by FACS using the specific inhibitor MK571. Cells were transfected with MDR proteins siRNAs and treated with the corresponding substrates. PCa cell resistance to MDR protein substrates was partially reversed, decreasing cell survival in around 20%, by treating primary cell cultures with specific pharmacological inhibitors. PCa cells transfected with siRNAs against MDR proteins decreased cell survival when treated with the corresponding drugs. Docetaxel was the most effective chemotherapeutic drug to induce cell death and decrease survival. Low chemotherapy response in PCa could be explained, in part, by over-expression of functional MDR proteins. Expression and function of these proteins should be evaluated to enhance efficacy of docetaxel-based therapies of patients with hormone-resistant PCa.

Urological cancer care pathways: development and use in the context of systematic reviews and clinical practice guidelines

BackgroundMaking healthcare treatment decisions is a complex process involving a broad stakeholder base including patients, their families, health professionals, clinical practice guideline developers and funders of healthcare.MethodsThis paper presents a review of a methodology for the development of urological cancer care pathways (UCAN care pathways), which reflects an appreciation of this broad stakeholder base. The methods section includes an overview of the steps in the development of the UCAN care pathways and engagement with clinical content experts and patient groups.ResultsThe development process is outlined, the uses of the urological cancer care pathways discussed and the implications for clinical practice highlighted. The full set of UCAN care pathways is published in this paper. These include care pathways on localised prostate cancer, locally advanced prostate cancer, metastatic prostate cancer, hormone-resistant prostate cancer, localised renal cell cancer, advanced renal cell cancer, testicular cancer, penile cancer, muscle invasive and metastatic bladder cancer and non-muscle invasive bladder cancer.ConclusionThe process provides a useful framework for improving urological cancer care through evidence synthesis, research prioritisation, stakeholder involvement and international collaboration. Although the focus of this work is urological cancers, the methodology can be applied to all aspects of urology and is transferable to other clinical specialties.

Survivin Is Associated With Cell Proliferation and Has a Role in 1a,25-Dihydroxyvitamin D 3 Induced Cell Growth Inhibition in Prostate Cancer

Prostate cancer cell proliferation is inhibited by 1a,25-dihydroxyvitamin D(3). Survivin is a member of the inhibitors of apoptosis protein family. Several studies indicate that survivin down-regulation sensitizes human tumor cells of different histological origins to conventional chemotherapeutic drugs. We assessed the effect of survivin gene expression on the proliferation of prostate cancer cells in vitro and in vivo. We also examined the antitumor sensitization effect of survivin inhibition in 1a,25-dihydroxyvitamin D(3) treatment for prostate cancer cells. We knocked down gene expression levels of survivin using siRNA against survivin in vitro and in vivo. We then assessed survivin expression in 1a,25-dihydroxyvitamin D(3) treatment and examined the antitumor sensitization effect of survivin inhibition using siRNA in 1a,25-dihydroxyvitamin D(3) treatment of hormone resistant prostate cancer cells. In vitro and in vivo siRNA against survivin significantly inhibited cell and tumor growth compared with control siRNA. In LNCaP and PC3 cells 1a,25-dihydroxyvitamin D(3) decreased survivin gene expression and inhibited cell proliferation. However, survivin gene expression and cell proliferation were not inhibited in DU145 cells but after siRNA transfection against survivin DU145 cell proliferation was inhibited by 1a,25-dihydroxyvitamin D(3). Findings suggest that survivin has a significant association with prostate cancer cell proliferation and an essential role in 1a,25-dihydroxyvitamin D(3) induced prostate cancer cell growth inhibition. It seems that the eliminating survivin in 1a,25-dihydroxyvitamin D(3) therapy for hormone refractory prostate cancer is a potential therapeutic option.

Potent Farnesyltransferase Inhibitors with 1,4-Diazepane Scaffolds as Novel Destabilizing Microtubule Agents in Hormone-Resistant Prostate Cancer

A new class of potent farnesyltransferase inhibitors based on a 1,4-diazepane scaffold was synthesized with protein farnesyltransferase inhibition potencies in the low nanomolar range. The compounds block the growth on two hormone-resistant tumor prostatic cell lines (DU145 and PC3). The advanced cellular evaluation of the more potent farnesyltransferase inhibitors was explored and revealed a disorganization of tubulin in PC3 cells.

In vitro and in vivo anticancer action of Saquinavir-NO, a novel nitric oxide-derivative of the protease inhibitor saquinavir, on hormone resistant prostate cancer cells

The NO-derivative of the HIV protease inhibitor saquinavir (Saq-NO) is a nontoxic variant of the parental drug with enhanced anticancer activity on several cell lines. However, it is still unclear whether the p53 status of the target cell might influence the sensitivity to Saq-NO. In this study we evaluated the in vitro and in vivo activity of Saq-NO on the p53-deficient hormone resistant prostate cancer PC-3 cells. We demonstrate that the absence of functional p53 is not essential for the capacity of Saq-NO to reduce prostate cancer cell growth. In contrast to its previously described cytostatic action in B16 and C6 cell lines, Saq-NO exerted cytotoxic effects in PC-3 cells leading to dominant induction of apoptosis and enhanced production of proapoptotic Bim. In addition, differently from saquinavir, Saq-NO restored TRAIL sensitivity that was correlated with increased expression of DR5 independent from ROS/RNS production and YY1 repression. NF-κB activation may be responsible of the Saq-NO induced DR5 expression. Moreover, Saq-NO but not saquinavir, exerted synergistic activity with conventional cytostatic therapy. In agreement with these in vitro studies, Saq-NO inhibited the in vivo growth of PC-3 cells xenotransplants to a greater extent than the parental compound. Taken together, these data indicate that Saq-NO possesses powerful and suitable in vitro and in vivo chemotherapeutic potential to be further studied as a novel drug for the treatment of prostate cancer in the clinical setting.

Experience with sunitinib in hormone-resistant metastatic prostate cancer that is unresponsive to docetaxel

IntroductionSystemic treatment options for patients with hormone-refractory prostate cancer (HRPC) that progress despite the use of Docetaxel are very limited. One of the options of compassionate use currently available is the use of Sunitinib. We present a joint preliminary experience with the use of Sunitinib in this clinical case. Patients and methodsA series of eight cases is presented, which sets forth a prospective multicentre experience with Sunitinib in patients with hormone-refractory metastatic and progressive prostate cancer, previously treated with at least a regimen of Docetaxelbased chemotherapy. Other alternative chemotherapy regimes had already been tried in some patients. The primary objective of our study was the PSA response rate and our secondary objective was the progression-free period. We administered a dosage of 50 mg/day for four-week cycles, followed by a two-week rest per cycle, until we reached a total of eight cycles or up to clinical progression or intolerable toxicity. ResultsIn four cases, the PSA dropped to below 50% of the baseline level at the beginning of the treatment, and five patients presented some decrease in PSA. The progression-free time was 16.4 weeks. Toxicity arising from the treatment was moderate and manageable. ConclusionsDespite the limits of this experience, we can say that Sunitinib appears to be an active and safe option in patients with hormone-refractory prostate cancer that is resistant to chemotherapy with Docetaxel.

Pharmacokinetic and tolerability profile of once-daily zibotentan (ZD4054) in Japanese and Caucasian patients with hormone-resistant prostate cancer

To investigate potential differences in zibotentan pharmacokinetics between Japanese and Caucasian patients with hormone-resistant prostate cancer (HRPC) following single and multiple dosing. In the Japanese study, 18 patients received a single dose of zibotentan 5, 10 or 15 mg followed by 72 h washout before 26 days' once-daily dosing. In the Caucasian study, 21 patients received a single dose of zibotentan 5, 10 or 15 mg followed by 72 h washout before 12 days' once-daily dosing. Pharmacokinetic parameters were similar between populations. Absorption of zibotentan was rapid with maximum plasma concentrations typically achieved within 3 h of dosing. Mean clearance, 17.9 and 18.7 ml/min in Japanese and Caucasian patients, respectively (range 7.0 - 36.3 ml/min in Japanese patients and 7.8 - 29.5 ml/min in Caucasian patients) and volume of distribution, 14.0 and 15.6 l for Japanese and Caucasian patients, respectively (range 7.9 - 29.1 l in Japanese patients and 9.6 - 23.8 l in Caucasian patients) were relatively low, and t1/2 was approximately 12 h (range 5.7 - 18.8 h in Japanese patients and 5.0 - 22.9 h in Caucasian patients) following single dosing. Little accumulation was observed following daily dosing and multiple-dose pharmacokinetics were predictable. Exposure levels achieved in some Japanese patients receiving zibotentan 15 mg were higher than those observed in Caucasian patients, however, this may be due to differences in body weight, as exposure levels were similar when data were normalized for body weight. Zibotentan was well tolerated in both populations. There are no clinically relevant differences in the disposition and pharmacokinetics of zibotentan between Japanese and Caucasian patients with HRPC.

Metronomic administration of Zoledronic Acid and Taxotere combination in castration resistant prostate cancer patients: Phase I ZANTE trial

Background. Docetaxel (DTX) and zoledronic acid (ZOL) are effective in patients with hormone resistant prostate cancer (HRPC) with bone metastases. A phase I clinical trial of metronomic administration of Zoledronic Acid ANd TaxoterE combination (ZANTE trial) in 2 different sequences was conducted in HRPC. Patients and methods. Twenty-two patients enrolled into the study (median age: 73 years; range: 43-80) received one of three escalated doses of DTX (30, 40 and 50mg/m2) in combination with a fixed dose of ZOL (2mg), both administered every 14 days in two different sequences: DTX at the day 1 followed by ZOL at the day 2 (sequence A) or the reverse (sequence B). Patients were evaluated for adverse events and serum IL-8, MMP-2 and MMP-9 were evaluated prior and after therapy with the two sequences of administration of DTX and ZOL. Results. The maximum tolerated dose was not achieved with sequence A. Two patients at third level of sequence B developed dose limiting toxicity. A disease control was obtained in six out of nine patients treated with sequence A, where a decrease of biological markers and PSA were also observed. No evidence of anti-tumor activity was observed in patients treated with sequence B. Conclusions. The bi-weekly combination of DTX (50mg/m2) followed by ZOL was feasible and show promising anti-tumor activity.

Antisense Treatment in Human Prostate Cancer and Melanoma

Antisense reagents and technology have developed as extraordinarily useful tools for analysis of gene function. The capacity of antisense to reduce expression of RNA (including protein-encoding mRNA and non-coding RNA) important in a multitude of diseases (including cancer) has led to the concept of using antisense molecules as drugs to treat those diseases. Both antisense RNA (RNAi) and antisense oligonucleotides (ASOs) are being developed for this purpose, with ASOs currently the most advanced in clinical testing. ASOs inhibit translation or induce degradation of complementary target RNA, and both Phase I and Phase II trials are either completed or in progress for a number of diseases. In this review, we focus on antisense approaches to treatment of two cancers (melanoma and hormone-resistant prostate cancer) where the early application of ASOs has provided important information revealing both potential for success and lessons for future preclinical and clinical investigation of ASOs as anti-cancer drugs. The progress of clinical application of two ASOs showing promise in treatment of human cancers--Oblimersen (G3139), targeting BCL2 for the treatment of metastatic melanoma, and Custirsen (OGX-11), targeting clusterin for the treatment of hormone refractory prostate cancer (HRPC)--is examined.

Effects of bioactive molecules of Beta vulgaris L. ssp. esculenta var. rubra on metastatic prostate cancer

Several reports are known about the effects of nutrition supplements in the improvement of quality of life of patients with tumor, however, the physiological background remains largely unknown. Table beet affects numerous biochemical reactions, enzymes and metabolic-synthesis. Natural table beet product come from commercial service was given twice 10 g daily for 1 month for 24 patients (mean age 68+/-8 years) with hormone-resistant and metastatic prostate cancer treated with taxan chemotherapy, who report themselves first, mean 3,6+/-2,8 years ago with their complains. 18 men's data were amenable after treatment for evaluation. In addition to routine laboratory examination values of HbA1c, 9 cytokines and levels of 3 growth factors, the global parameters of redox-homeostasis, few elements of their metal-ions, Zn- and level of free protoporfirin, trans-metilating processes before and 1 month after treatment were determined. In most of the patients, favorable impact of beet was enforced and significantly high levels of Zn- and free protoporfirin decreased; furthermore, trans-metilating processes fastened. According to results, it seems that moderate and permanent consumption of table beet product affects the life expectancy of patients favorably; however, due to the increasing values of EGF, medical control is necessary for patients with prostate cancer treated by chemotherapy.

An open-label, randomized, single-center, two-period, phase I, crossover study of the effect of zibotentan (ZD4054) on the pharmacokinetics of midazolam in healthy male volunteers

Background: Zibotentan (ZD4054) is an oral, specific endothelin A receptor antagonist presently under investigation for the treatment of hormone-resistant prostate cancer. Preclinical in vitro studies suggest that zibotentan has the potential to act as a time-dependent inhibitor of the cytochrome P450 isozyme 3A4 (CYP3A4) metabolic pathway. In clinical practice, it is likely that zibotentan will be coadministered with drugs metabolized by this pathway; the potential exists, therefore, that zibotentan-induced drug interactions could occur. Objectives: The primary objective of this study was to evaluate the effect of zibotentan on the pharmaco-kinetics of a clinically relevant dose of midazolam in healthy volunteers. Secondary objectives were to evaluate exposure to zibotentan, ensure the safety of the healthy volunteers dosed, and investigate the effect of zibotentan on the pharmacokinetics of the midazolam metabolites 1-hydroxy midazolam and 4-hydroxy midazolam. The potency of zibotentan as a CYP3A4 inhibitor was also assessed. Methods: This was an open-label, randomized, singlecenter, 2-period, Phase I, crossover study. Volunteers were randomized in a 1:1 ratio to 1 of 2 cohorts. In cohort 1, volunteers received a single dose of midazolam 7.5 mg on day 1 (treatment A) of a 2-day study period. After a minimum 7-day washout period, volunteers received zibotentan 10 mg once daily on days 1 through 7, plus a single dose of midazolam 7.5 mg on day 6 (treatment B) of a 7-day study period. In cohort 2, volunteers received treatment B followed by treatment A, with a minimum 7-day washout period between treatments. AUC 0−∞ and C max data were expressed as geometric least squares mean ratios and 90% CIs for midazolam + zibotentan:midazolam. A moderate interaction between midazolam and zibotentan was predefined to have occurred if the upper 90% CI of the ratio was >1.5. Adverse events (AEs) were assessed according to the National Cancer Institute's Common Terminology Criteria for Adverse Events version 3. AE data were assessed based on information provided by the volunteer, through open-ended and nonleading verbal questions to the volunteer at each visit, and through observation by the investigational team, other care providers, or relatives. Results: Six volunteers (all white) were included in each cohort (cohort 1, mean [SD] age, 48 [7] years; mean weight, 74 [6] kg; cohort 2, mean age, 51 [11] years; mean weight, 75 [13] kg). Steady-state levels of zibotentan, achieved over 7 days, increased the midazolam AUC 0−∞ by 1.2-fold compared with midazolam alone. The upper limits of the 90% CIs for the AUC 0−∞ and C max ratios were below the predefined level of 1.5 (1.37 and 1.32, respectively). Zibotentan had no apparent effect on the pharmacokinetics of 1-hydroxy midazolam and 4-hydroxy midazolam. Fatigue was reported in 11 volunteers (92%) receiving midazolam monotherapy and 10 (83%) receiving midazolam combined with zibotentan. Headache was reported in all 12 volunteers after zibotentan monotherapy. Conclusions: In this population of healthy male volunteers, once-daily zibotentan 10 mg increased the AUC 0−∞ of midazolam 1.2-fold; however, the treatment ratio was below the predefined limit for clinical significance. Zibotentan was well tolerated when given alone or in combination with midazolam. The results indicate that once-daily zibotentan 10 mg acted as a weak inhibitor of the CYP3A4 pathway. ClinicalTrials. gov identifier: NCT00709553.

Compensatory Upregulation of Tyrosine Kinase Etk/BMX in Response to Androgen Deprivation Promotes Castration-Resistant Growth of Prostate Cancer Cells

We previously showed that targeted expression of non-receptor tyrosine kinase Etk/BMX in mouse prostate induces prostate intraepithelial neoplasia, implying a possible causal role of Etk in prostate cancer development and progression. Here, we report that Etk is upregulated in both human and mouse prostates in response to androgen ablation. Etk expression seems to be differentially regulated by androgen and interleukin 6 (IL-6), which is possibly mediated by the androgen receptor (AR) in prostate cancer cells. Our immunohistochemical analysis of tissue microarrays containing 112 human prostate tumor samples revealed that Etk expression is elevated in hormone-resistant prostate cancer and positively correlated with tyrosine phosphorylation of AR (Pearson correlation coefficient rho = 0.71, P < 0.0001). AR tyrosine phosphorylation is increased in Etk-overexpressing cells, suggesting that Etk may be another tyrosine kinase, in addition to Src and Ack-1, which can phosphorylate AR. We also showed that Etk can directly interact with AR through its Src homology 2 domain, and such interaction may prevent the association of AR with Mdm2, leading to stabilization of AR under androgen-depleted conditions. Overexpression of Etk in androgen-sensitive LNCaP cells promotes tumor growth while knocking down Etk expression in hormone-insensitive prostate cancer cells by a specific shRNA that inhibits tumor growth under androgen-depleted conditions. Taken together, our data suggest that Etk may be a component of the adaptive compensatory mechanism activated by androgen ablation in prostate and may play a role in hormone resistance, at least in part, through direct modulation of the AR signaling pathway.

Role of DNA methyltransferase 1 in hormone-resistant prostate cancer

Given the poor outcome of patients with hormone-resistant (HR) prostate cancer, new strategies are needed to improve the current therapeutic regimens and/or develop novel treatments. We therefore aimed to provide a better understanding of the molecular mechanisms involved in the aggressive tumor behavior of HR and develop more rational anti-tumor therapies. Three HR prostate cancer cell lines (androgen receptor (AR)-positive LNCaP-HR and 22RV1-HR and AR-negative PC-3) were used. Changes in tumor behavior, treatment response, and related signaling in HR were investigated in vitro and in vivo. The results revealed that constitutional activation of STAT3 and overexpressions of DNMT1 were important in the transition of HR prostate cancer. Furthermore, DNMT1 expression was required for the maintenance of STAT3 activation. When DNMT1 activity in HR was blocked, aggressive tumor behavior and treatment resistance could be overcome, which was seen in both in vitro and in vivo experiments. The underlying changes associated with inhibited DNMT1 included less epithelial-mesenchymal changes, less invasion ability, slower tumor growth, and impaired DNA repair ability, which are independent of AR and p53 status. In conclusion, altered DNMT1 expression associated with activated STAT3 may be crucial in the transition of HR. Targeting DNMT1 could be a promising strategy for the treatment of HR prostate, as evidenced by inhibited tumor growth and enhanced radiosensitivity. These findings provide evidence for therapeutically targeting DNMT1 in HR prostate cancer.

Weekly docetaxel rechallenge in patients with hormone-resistant prostate cancer refractory to conventionally three weekly docetaxel.

e15004 Background: The common standard treatment for hormone resistant prostate cancer is a 3-weekly (q3w) schedule with prednisone 10 mg qd and docetaxel 75 mg/m2 q3w. In case of progression almost 2/3 of patients profit from a docetaxel rechallenge. If the PSA rises again therapy is usually discontinued. Methods: We identified 31 out of 106 patients retrospectively (Jun 2004-Oct 2009) who were reportedly refractory to the q3w schedule and were continued on a weekly (q1w) schedule of prednisone 10 mg qd and docetaxel 30 mg/m2 q1w. 5 patients never responded to q3w, 25 patients responded initially to q3w but then became progressive, 1 patient showed a PSA decline to q3w but was regarded as clinically progressive. Median time to PSA nadir under q3w schedule was 12 weeks. Average age was 71 years and median q3w treatment of docetaxel was 16 weeks. Median baseline PSA was 96 ng/ml. Under the q3w schedule median PSA decline was about 43%. Results: Surprisingly 80% (25/31) of the q3w pretreated patients showed a remarkable median PSA decline of 46% to q1w treatment. Only 6 patients showed PSA progression. Median treatment duration of q1w was 16 weeks. Median time to PSA nadir was 13 weeks and median PSA at the time of rechallenge was 112 ng/ml. PSA response greater than 50% was reached in 45% (14) of patients in the q3w schedule and in 39% (12) of patients in the q1w schedule. Dose intensity of both schedules was comparable (q3w: 28mg/m2, q1w: 27mg/m2). Toxicity profile changed slightly (more nail problems and PNP in q1w) but the q1w schedule was generally well tolerated. Median overall treatment duration was 16 weeks for both schedules. Conclusions: This retrospectively analysed data should be controlled prospectively but until further data is available we suggest a rechallenge with a q1w schedule of docetaxel in all patients refractory to a q3w schedule before discontinuing the drug, notably also for primary nonresponder to the q3w schedule. No significant financial relationships to disclose.

Abstract 2770: An open-label comparative study of the pharmacokinetics and tolerability of zibotentan (ZD4054) in subjects with mild, moderate, or severe hepatic impairment, or normal hepatic function

Abstract Zibotentan (ZD4054) is a small-molecule, specific endothelin A (ETA) receptor antagonist being investigated for the treatment of hormone-resistant prostate cancer. Zibotentan is eliminated by both renal (58%) and metabolic clearance. The current study investigated whether hepatic impairment has a clinically relevant effect on exposure to zibotentan. This open-label, two-centre study investigated the PK and tolerability of zibotentan in subjects with hepatic impairment, compared with subjects with normal hepatic function. Subjects were divided into four categories using the Child-Pugh (CP) classification: mild hepatic impairment (CP A), moderate hepatic impairment (CP B), severe hepatic impairment (CP C) and normal hepatic function. Each subject received a single oral dose of zibotentan 10 mg. AUC and Cmax are expressed as the ratio (R) of geometric means and 90% confidence intervals (CI) for each hepatic impairment group compared with the normal function group. The possibility that hepatic impairment had a clinically relevant effect on exposure of zibotentan was considered if the upper 90% CI for the ratio exceeded two. Thirty-seven subjects were enrolled and 32 subjects (eight per group) received zibotentan and completed the study. Compared with the normal function group, zibotentan Cmax was 7% (R 0.93; 90% CI 0.75-1.15), 11% (R 0.89; 90% CI 0.72-1.1) and 5% (R 0.95; 90% CI 0.77-1.17) lower in subjects with CP A, CP B and CP C hepatic impairment, respectively. Zibotentan AUC was 40% (R 1.40; 90% CI 0.91-2.17), 45% (R 1.45; 90% CI 0.94-2.24) and 190% (R 2.90; 90% CI 1.88-4.49) higher in subjects with CP A, CP B and CP C hepatic impairment, respectively, compared with those with normal function. Mean t½ was 9.28 h, 13.0 h, 14.6 h and 24.8 h for the normal function, CP A, CP B and CP C hepatic impairment groups, respectively. Compared with the normal function group, CL/F was approximately 25%, 29% and 64% lower, respectively, in the CP A, CP B and CP C hepatic impairment groups. Zibotentan was well tolerated by all subjects, with headache (CTC Grade 1-2) being the most common adverse event in each group. Despite increased exposure to zibotentan with increased hepatic impairment, there were no differences in the type or severity of adverse events. In conclusion, following a single oral dose of zibotentan 10 mg, there was no significant difference in Cmax with degree of hepatic impairment, indicating that hepatic impairment did not affect the absorption of zibotentan. AUC was higher and t½ longer in subjects with hepatic impairment than in those with normal function due to the slower clearance of zibotentan, with the extent of the difference being related to the degree of impairment. Trial sponsored by AstraZeneca (NCT00672581; AZ code D4320C00025). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2770.

Abstract 1712: Androgen receptor splicing variants promote therapeutic resistance in prostate cancer

Abstract Androgen receptor (AR) plays a key role in progression to incurable castration-resistant prostate cancer. Recently, we and others have identified multiple alternatively spliced AR isoforms in hormone refractory prostate cancer cells. These AR splice variants contain the intact N-terminal transactivation domain and the DNA binding domain, but lack the ligand binding domain. They function as constitutively active transcription factors and their activity is independent of androgen or anti-androgens. Our tissue microarrays analysis on 429 human prostate tissue samples revealed that AR3, one of the major AR splice variants, is significantly up-regulated during prostate cancer progression and AR3 expression level is correlated with the risk of tumor recurrence after radical prostatectomy. Overexpression of AR3 confers castration-resistant growth of prostate cancer cells, whereas specific knockdown of AR3 expression in hormone-resistant prostate cancer cells attenuates their growth under androgen-depleted conditions, suggesting an indispensable role of AR3 in castration-resistant growth of prostate cancer cells. Furthermore, our gene expression microarray analysis showed that AR3 regulates a unique set of target genes which are not regulated by the prototype AR, suggesting that AR3, as an independent transcription factor, utilizes a distinct transcription programs to achieve its distinct and specific biological functions which are important for castration-resistant growth. In addition to its role in the androgen-ablation resistance, the AR isoforms may also be involved in chemotherapeutic resistance. We found that AR3 is overexpressed in chemotherapeutic resistant prostate cancer cell lines that are more tumorigenic, compared with their parental drug-sensitive lines. Therefore, aberrant expression of AR splicing variants may be a general mechanism underlying the development of multiple therapeutic resistances in prostate cancer. Taken together, our data suggest that AR3 may potentially serve as a prognostic marker to predict patient outcome in response to hormonal and chemo therapy, and targeting these AR splicing variants may offer more effective treatment for advanced prostate cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1712.

Health-related quality of life in pain-free or mildly symptomatic patients with metastatic hormone-resistant prostate cancer following treatment with the specific endothelin A receptor antagonist zibotentan (ZD4054)

Zibotentan (ZD4054) is a specific endothelin A receptor antagonist in clinical development for the treatment of hormone-resistant prostate cancer (HRPC). In a Phase II trial in patients with pain-free or mildly symptomatic metastatic HRPC, zibotentan was well tolerated with a promising signal for prolonged overall survival compared with placebo. As part of this trial, the impact of zibotentan compared with placebo on health-related quality of life (HRQoL) was assessed. Patients were randomized to receive once-daily oral zibotentan 10or 15mg, or matching placebo. Patients were allocated to one of two questionnaires; the Functional Assessment of Cancer Therapy-Prostate (FACT-P) or the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30), supplemented by PR25, specific for prostate cancer. Questionnaires were completed at baseline and every 4weeks until disease progression when study treatment was discontinued. Compliance with questionnaire completion was >90% (286 of 312 patients) of the intention-to-treat population at baseline. Of baseline completers who were available for assessment (i.e., had not clinically progressed), 89% (164 of 184) and 83% (73 of 88) completed questionnaires at 12 and 24weeks, respectively. HRQoL scores from both questionnaires were high at baseline and remained high throughout the study, with scores being similar in the zibotentan and placebo groups. However, some floor and ceiling effects were seen in the EORTC QLQ-C30 questionnaire. High-baseline HRQoL scores were maintained throughout treatment with zibotentan. The FACT-P instrument was selected to further assess the impact of zibotentan on HRQoL in the Phase III clinical trial program.

A Review of the Patterns of Docetaxel Use for Hormone-Resistant Prostate Cancer at the Princess Margaret Hospital

Based on the TAX 327 phase III trial, docetaxel-based chemotherapy is the standard first-line treatment for hormone-resistant prostate cancer (HRPC); however, there is some heterogeneity in the use of this agent in routine clinical practice. The aim of the present study was to examine the patterns of docetaxel use in routine clinical practice at our institution and to compare them with docetaxel use in the TAX 327 clinical trial. We conducted a retrospective chart review of HRPC patients treated with first-line docetaxel between 2005 and 2007 at the Princess Margaret Hospital. In the first-line setting, 88 patients with HRPC received docetaxel. The main reasons for initiating docetaxel were rising prostate-specific antigen (PSA, 98%) and progressive symptoms (77%). The PSA response rate was 67%; median time to response was 1.5 months, and duration of response was 6.8 months. Median survival was 15.9 months (95% confidence interval: 12.4 to 20.5 months). Patients received a median of 7 cycles of treatment, and the main toxicities were fatigue (35%) and neuropathy (24%). Post docetaxel, 36 patients received second-line treatment with a 22% response rate. In routine clinical practice, HRPC patients received docetaxel mainly because of symptomatic disease progression. Overall response rates and toxicities were comparable to those in the TAX 327 trial. However, our patients received a median of only 7 cycles of treatment versus the 9.5 administered on trial, and survival was slightly shorter in our single-institution study. A larger prospective multicentre analysis, including performance status and quality-of-life parameters, may be warranted to determine if docetaxel performs as well in routine clinical practice as it does in the clinical trial setting.