Taxane

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David M Gershenson - One of the best experts on this subject based on the ideXlab platform.

  • Metronomic chemotherapy enhances the efficacy of antivascular therapy in ovarian cancer
    Cancer research, 2007
    Co-Authors: Aparna A. Kamat, David M Gershenson, Tae Jin Kim, Charles N. Landen, Liz Y. Han, Yvonne G. Lin, William M. Merritt, Premal H. Thaker, Farideh Z. Bischoff
    Abstract:

    Metronomic chemotherapy is the frequent administration of low doses of chemotherapeutic agents targeting tumor-associated endothelial cells. We examined the efficacy of metronomic Taxanes alone and in combination with AEE788-a dual epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) inhibitor-in an orthotopic mouse model of ovarian cancer. Growth-modulating effects of metronomic and maximum tolerated dose (MTD) regimens on overall survival were tested in vivo using both chemotherapy-sensitive (HeyA8 and SKOV3ip1) and chemotherapy-resistant (HeyA8-MDR) models. Treated tumors were stained for microvessel density (CD31), proliferation index (proliferating cell nuclear antigen), and apoptosis (terminal deoxyribonucleotide transferase-mediated nick-end labeling). The cytotoxic effects of MTD and metronomic dosing were tested with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays. Effects of metronomic regimens on circulating endothelial precursors (CEP) and tumor-specific cell-free DNA levels were assessed. In vivo, metronomic docetaxel resulted in significant reduction of tumor growth in the Taxane-sensitive cell lines, whereas metronomic docetaxel plus AEE788 had an additive effect resulting in significant prolongation in survival. Combination therapy was effective even in the Taxane-resistant model. Metronomic chemotherapy alone and combined with AEE788 resulted in a decrease in the proliferative index and microvessel density of treated tumors, whereas combination therapy increased the apoptotic index (P < 0.001). In vitro, metronomic Taxanes caused endothelial cell toxicity at 10- to 100-fold lower concentrations compared with MTD dosing. Metronomic regimens inhibited mobilization of CEPs (P < 0.05) and led to a decrease in cell-free DNA levels (P < 0.05). Our results suggest that metronomic Taxane chemotherapy with dual EGFR and VEGFR inhibition is highly efficacious and should be considered for future clinical trials.

  • the activity of Taxanes compared with bleomycin etoposide and cisplatin in the treatment of sex cord stromal ovarian tumors
    Gynecologic Oncology, 2005
    Co-Authors: Jubilee Brown, Hyun S Shvartsman, Michael T Deavers, Lois M Ramondetta, Thomas W Burke, Mark F Munsell, David M Gershenson
    Abstract:

    Abstract Objective We compared the efficacy and side effects of Taxanes, with or without platinum, to bleomycin, etoposide, and cisplatin (BEP) in treating sex cord-stromal ovarian tumors. Methods We conducted a retrospective review of all patients with sex cord-stromal ovarian tumors seen at our institution from 1985 to 2002. Eligible patients were those who underwent pathologic confirmation, clinical evaluation, and treatment with a Taxane or BEP for initial or recurrent disease. Results Of 222 patients identified, 21 received BEP for new ( n = 11) or recurrent disease ( n = 10); 44 received a Taxane during 48 treatment episodes (four patients on two occasions each) for new ( n = 11) or recurrent disease ( n = 37). Newly diagnosed patients treated with BEP vs. Taxanes had no significant difference in response rate (Fisher's exact test, P = 1), progression-free survival (PFS) (log-rank test, P = 0.213), or overall survival (log-rank test, P = 0.994). Among patients treated for recurrent measurable disease, the response rate was higher for BEP-treated (71%) than for Taxane-treated patients (37%), but this was not statistically significant. In all patients treated for recurrent disease, there was no significant difference in failure to progress at chemotherapy completion between BEP- (70%) and Taxane-treated patients (62%) or in median PFS (11.2 vs. 7.2 months). The presence of platinum in Taxane-containing regimens correlated with response. Taxane-related side effects included neutropenia ( n = 6), anemia ( n = 1), thrombocytopenia ( n = 1), myelodysplasia ( n = 1), and hypersensitivity ( n = 1). BEP-related side effects included pulmonary fibrosis ( n = 3) and neutropenia ( n = 2). Conclusions Taxanes demonstrated activity against sex cord-stromal tumors of the ovary and may be less toxic than BEP. Taxane and platinum combination chemotherapy warrants further investigation in this disease.

  • the activity of Taxanes in the treatment of sex cord stromal ovarian tumors
    Journal of Clinical Oncology, 2004
    Co-Authors: Jubilee Brown, Hyun S Shvartsman, Michael T Deavers, Thomas W Burke, Mark F Munsell, David M Gershenson
    Abstract:

    Purpose To determine the efficacy and side effects of Taxanes, with or without platinum, for the treatment of sex cord-stromal tumors of the ovary. Patients and Methods We conducted a retrospective review of all patients seen from 1985 to 2002 at The University of Texas M.D. Anderson Cancer Center with ovarian sex cord-stromal tumors. Eligible patients underwent pathology confirmation and clinical evaluation at M.D. Anderson and received a Taxane for initial or recurrent disease. Results Of 222 patients identified, 44 were eligible for analysis. For nine patients treated in the first-line adjuvant setting, median progression-free survival (PFS) was not reached at 51 months. Of two patients treated for measurable disease in the first-line setting, one had a complete response. Median PFS was 34.3 months; median overall survival (OS) was not reached. Median follow-up was 90.3 months (range, 39.4 to 140.5 months). Response rate for 30 patients treated with a Taxane ± platinum for recurrent, measurable disease...

Howard I Scher - One of the best experts on this subject based on the ideXlab platform.

  • assessment of the validity of nuclear localized androgen receptor splice variant 7 in circulating tumor cells as a predictive biomarker for castration resistant prostate cancer
    JAMA Oncology, 2018
    Co-Authors: Howard I Scher, Ryon P Graf, Nicole A Schreiber, Anuradha Jayaram, Eric Winquist, Brigit Mclaughlin, David S K Lu
    Abstract:

    IMPORTANCE A blood test to determine whether to treat patients with metastatic castration-resistant prostate cancer (mCRPC) with an androgen receptor signaling (ARS) inhibitor or Taxane is an unmet medical need. OBJECTIVE To determine whether a validated assay for the nuclear-localized androgen receptor splice variant 7 (AR-V7) protein in circulating tumor cells can determine differential overall survival among patients with mCRPC treated with Taxanes vs ARS inhibitors. DESIGN, SETTING, AND PARTICIPANTS This blinded correlative study conducted from December 31, 2012, to September 1, 2016, included 142 patients with histologically confirmed mCRPC and who were treated at Memorial Sloan Kettering Cancer Center, The Royal Marsden, or the London Health Sciences Centre. Blood samples were obtained prior to administration of ARS inhibitors or Taxanes as a second-line or greater systemic therapy for progressing mCRPC. MAIN OUTCOMES AND MEASURES Overall survival after treatment with an ARS inhibitor or Taxane in relation to pretherapy AR-V7 status. RESULTS Among the 142 patients in the study (mean [SD] age, 69.5 [9.6] years), 70 were designated as high risk by conventional prognostic factors. In this high-risk group, patients positive for AR-V7 who were treated with Taxanes had superior overall survival relative to those treated with ARS inhibitors (median overall survival, 14.3 vs 7.3 months; hazard ratio, 0.62; 95% CI, 0.28-1.39; P = .25). Patients negative for AR-V7 who were treated with ARS inhibitors had superior overall survival relative to those treated with Taxanes (median overall survival, 19.8 vs 12.8 months; hazard ratio, 1.67; 95% CI, 1.00-2.81; P = .05). CONCLUSIONS AND RELEVANCE This study suggests that nuclear-localized AR-V7 protein in circulating tumor cells can identify patients who may live longer with Taxane chemotherapy vs ARS inhibitor treatment.

  • association of ar v7 on circulating tumor cells as a treatment specific biomarker with outcomes and survival in castration resistant prostate cancer
    JAMA Oncology, 2016
    Co-Authors: Howard I Scher, Ryon P Graf, Nicole A Schreiber, Jessica Louw, Hebert Alberto Vargas, Ann Johnson, Adam Jendrisak, Richard Martin Bambury
    Abstract:

    Importance A critical decision in the management of metastatic castration-resistant prostate cancer (mCRPC) is when to administer an androgen receptor signaling (ARS) inhibitor or a Taxane. Objective To determine if pretherapy nuclear androgen-receptor splice variant 7 (AR-V7) protein expression and localization on circulating tumor cells (CTCs) is a treatment-specific marker for response and outcomes between ARS inhibitors and Taxanes. Design, Setting, and Participants For this cross-sectional cohort study at Memorial Sloan Kettering Cancer Center, 265 men with progressive mCRPC undergoing a change in treatment were considered; 86 were excluded because they were not initiating ARS or Taxane therapy; and 18 were excluded for processing time constraints, leaving 161 patients for analysis. Between December 2012 and March 2015, blood was collected and processed from patients with progressive mCRPC immediately prior to new line of systemic therapy. Patients were followed up to 3 years. Main Outcomes and Measures Prostate-specific antigen (PSA) response, time receiving therapy, radiographic progression-free survival (rPFS), and overall survival (OS). Results Overall, of 193 prospectively collected blood samples from 161 men with mCRPC, 191 were evaluable (128 pre-ARS inhibitor and 63 preTaxane). AR-V7–positive CTCs were found in 34 samples (18%), including 3% of first-line, 18% of second-line, and 31% of third- or greater line samples. Patients whose samples had AR-V7–positive CTCs before ARS inhibition had resistant posttherapy PSA changes (PTPC), shorter rPFS, shorter time on therapy, and shorter OS than those without AR-V7–positive CTCs. Overall, resistant PTPC were seen in 65 of 112 samples (58%) without detectable AR-V7–positive CTCs prior to ARS inhibition. There were statistically significant differences in OS but not in PTPC, time on therapy, or rPFS for patients with or without pretherapy AR-V7–positive CTCs treated with a Taxane. A multivariable model adjusting for baseline factors associated with survival showed superior OS with Taxanes relative to ARS inhibitors when AR-V7–positive CTCs were detected pretherapy (hazard ratio, 0.24; 95% CI, 0.10-0.57; P  = .035). Conclusions and Relevance The results validate CTC nuclear expression of AR-V7 protein in men with mCRPC as a treatment-specific biomarker that is associated with superior survival on Taxane therapy over ARS-directed therapy in a clinical practice setting. Continued examination of this biomarker in prospective studies will further aid clinical utility.

Jubilee Brown - One of the best experts on this subject based on the ideXlab platform.

  • the activity of Taxanes compared with bleomycin etoposide and cisplatin in the treatment of sex cord stromal ovarian tumors
    Gynecologic Oncology, 2005
    Co-Authors: Jubilee Brown, Hyun S Shvartsman, Michael T Deavers, Lois M Ramondetta, Thomas W Burke, Mark F Munsell, David M Gershenson
    Abstract:

    Abstract Objective We compared the efficacy and side effects of Taxanes, with or without platinum, to bleomycin, etoposide, and cisplatin (BEP) in treating sex cord-stromal ovarian tumors. Methods We conducted a retrospective review of all patients with sex cord-stromal ovarian tumors seen at our institution from 1985 to 2002. Eligible patients were those who underwent pathologic confirmation, clinical evaluation, and treatment with a Taxane or BEP for initial or recurrent disease. Results Of 222 patients identified, 21 received BEP for new ( n = 11) or recurrent disease ( n = 10); 44 received a Taxane during 48 treatment episodes (four patients on two occasions each) for new ( n = 11) or recurrent disease ( n = 37). Newly diagnosed patients treated with BEP vs. Taxanes had no significant difference in response rate (Fisher's exact test, P = 1), progression-free survival (PFS) (log-rank test, P = 0.213), or overall survival (log-rank test, P = 0.994). Among patients treated for recurrent measurable disease, the response rate was higher for BEP-treated (71%) than for Taxane-treated patients (37%), but this was not statistically significant. In all patients treated for recurrent disease, there was no significant difference in failure to progress at chemotherapy completion between BEP- (70%) and Taxane-treated patients (62%) or in median PFS (11.2 vs. 7.2 months). The presence of platinum in Taxane-containing regimens correlated with response. Taxane-related side effects included neutropenia ( n = 6), anemia ( n = 1), thrombocytopenia ( n = 1), myelodysplasia ( n = 1), and hypersensitivity ( n = 1). BEP-related side effects included pulmonary fibrosis ( n = 3) and neutropenia ( n = 2). Conclusions Taxanes demonstrated activity against sex cord-stromal tumors of the ovary and may be less toxic than BEP. Taxane and platinum combination chemotherapy warrants further investigation in this disease.

  • the activity of Taxanes in the treatment of sex cord stromal ovarian tumors
    Journal of Clinical Oncology, 2004
    Co-Authors: Jubilee Brown, Hyun S Shvartsman, Michael T Deavers, Thomas W Burke, Mark F Munsell, David M Gershenson
    Abstract:

    Purpose To determine the efficacy and side effects of Taxanes, with or without platinum, for the treatment of sex cord-stromal tumors of the ovary. Patients and Methods We conducted a retrospective review of all patients seen from 1985 to 2002 at The University of Texas M.D. Anderson Cancer Center with ovarian sex cord-stromal tumors. Eligible patients underwent pathology confirmation and clinical evaluation at M.D. Anderson and received a Taxane for initial or recurrent disease. Results Of 222 patients identified, 44 were eligible for analysis. For nine patients treated in the first-line adjuvant setting, median progression-free survival (PFS) was not reached at 51 months. Of two patients treated for measurable disease in the first-line setting, one had a complete response. Median PFS was 34.3 months; median overall survival (OS) was not reached. Median follow-up was 90.3 months (range, 39.4 to 140.5 months). Response rate for 30 patients treated with a Taxane ± platinum for recurrent, measurable disease...

Paraskevi Giannakakou - One of the best experts on this subject based on the ideXlab platform.

  • abstract 4311 molecular basis of interaction between erg and microtubule inhibitors in crpc patients
    Cancer Research, 2015
    Co-Authors: Giuseppe Galletti, Cynthia Cheung, David S. Rickman, Paraskevi Giannakakou
    Abstract:

    Microtubules (MTs) are cytoskeletal polymer of α/β tubulin heterodimers that are involved in several cellular functions including mitosis, cell shape and intracellular trafficking. Due to their fundamental role in the maintenance of cell homeostasis, MTs are the target of several chemotherapeutic drugs that act by either stabilizing (Taxanes, epothilones) or destabilizing (vinca alkaloids, Eribulin) the MT network. Taxanes (docetaxel and cabazitaxel) are currently used for first or second line treatment of patients with metastatic castration-resistant prostate caner (CRPC) and are the only class of chemotherapy drugs that improve survival. Despite Taxane clinical success, there is significant heterogeneity in how patients respond to Taxane therapy and most of CRPC patients eventually become refractory and develop resistance to the treatment. The molecular basis underlying this heterogeneity in treatment response is still to be determined. ERG (ETS-related gene) is over-expressed by 30-80 fold in at least 50% of prostate cancers as a result of gene fusion with the 5′ promoter of the AR-induced TMPRSS2 gene. ERG rearrangement is an early event in prostate cancer tumorigenesis and represents the most frequent recurrent genetic alteration in prostate cancer. We recently showed that ERG over-expression is associated with decreased Taxane sensitivity in prostate cancer cell lines, in vivo xenograft models, and in ERG-positive CRPC patients. Mechanistically, we demonstrated that ERG contributes to Taxane resistance by binding tubulin in the cytoplasm, altering MT dynamics towards increased catastrophe rate thereby shifting the dynamic equilibrium between MT polymers (preferred Taxane substrate) and soluble tubulin dimers (preferred substrate for MT-depolymerizing drugs) towards soluble tubulin. Tiling mutant co-immunoprecipitation showed that ERG-tubulin physical interaction is mediated by ERG PNT domain, which has been also implicated with ERG homo-oligomerization and heterodimerization. Moreover, MT-cosedimentation assay elucidated that ERG predominantly interacts with tubulin dimers instead of MT-polymers. Finally, we demonstrated that treatment with the MT-depolymerizing drugs nocodazole or Eribulin is associated with lack of resistance or even enhanced sensitivity in ERG-positive cells. We are currently investigating the molecular basis of the interaction between Eribulin and ERG in CRPC models, in order to elucidate the potential role of Eribulin in the treatment of ERG+ CRPC patients. Overall, our data strongly suggest a new role for ERG as MT-destabilizing MAP, with significant therapeutic implications in CRPC patients. ERG status could emerge as biomarker predictive of response to MT-inhibitors, driving clinical decisions for patient selection to appropriate therapies. Citation Format: Giuseppe Galletti, Cynthia Cheung, David S. Rickman, Paraskevi Giannakakou. Molecular basis of interaction between ERG and microtubule inhibitors in CRPC patients. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4311. doi:10.1158/1538-7445.AM2015-4311

  • androgen receptor splice variants determine Taxane sensitivity in prostate cancer
    Cancer Research, 2014
    Co-Authors: Maria Thadanimulero, Luigi Portella, Shihua Sun, Matthew Sung, Alexandre Matov, Robert L Vessella, Eva Corey, David M Nanus, Stephen R Plymate, Paraskevi Giannakakou
    Abstract:

    Prostate cancer growth depends on androgen receptor (AR) signaling. Androgen ablation therapy induces expression of constitutively active AR splice variants which drive disease progression. Taxanes are a standard of care therapy in castration-resistant prostate cancer (CRPC), however, mechanisms underlying the clinical activity of Taxanes are poorly understood. Recent work suggests that the microtubule network of prostate cells is critical for AR nuclear translocation and activity. In this study, we employed a set of AR deletion mutants to identify the microtubule-binding domain of AR, which encompasses the DNA binding domain plus hinge region. We report that two clinically relevant AR splice variants, ARv567 and ARv7, differentially associate with microtubules and dynein motor protein, thereby resulting in differential Taxane sensitivity in vitro and in vivo. ARv7, which lacks the hinge region, did not co-sediment with microtubules or co-precipitate with dynein motor protein, unlike ARv567. Mechanistic investigations revealed that the nuclear accumulation and transcriptional activity of ARv7 was unaffected by Taxane treatment. In contrast, the microtubule-interacting splice variant ARv567 was sensitive to Taxane-induced microtubule stabilization. In ARv567-expressing LuCap86.2 tumor xenografts, docetaxel treatment was highly efficacious, whereas ARv7-expressing LuCap23.1 tumors xenografts displayed docetaxel resistance. Our results suggest that AR variants which accumulate in CRPC cells utilize distinct pathways of nuclear import that affect the antitumor efficacy of Taxanes, suggesting a mechanistic rationale to customize treatments for CRPC patients which might improve outcomes.

  • a common pharmacophore for epothilone and Taxanes molecular basis for drug resistance conferred by tubulin mutations in human cancer cells
    Proceedings of the National Academy of Sciences of the United States of America, 2000
    Co-Authors: Paraskevi Giannakakou, Rick Gussio, Eva Nogales, Kenneth H Downing, Daniel W Zaharevitz, Birgit Bollbuck, Dan L Sackett, K C Nicolaou, Tito Fojo
    Abstract:

    The epothilones are naturally occurring antimitotic drugs that share with the Taxanes a similar mechanism of action without apparent structural similarity. Although photoaffinity labeling and electron crystallographic studies have identified the Taxane-binding site on β-tubulin, similar data are not available for epothilones. To identify tubulin residues important for epothilone binding, we have isolated two epothilone-resistant human ovarian carcinoma sublines derived in a single-step selection with epothilone A or B. These epothilone-resistant sublines exhibit impaired epothilone- and Taxane-driven tubulin polymerization caused by acquired β-tubulin mutations (β274Thr→Ile and β282Arg→Gln) located in the atomic model of αβ-tubulin near the Taxane-binding site. Using molecular modeling, we investigated the conformational behavior of epothilone, which led to the identification of a common pharmacophore shared by Taxanes and epothilones. Although two binding modes for the epothilones were predicted, one mode was identified as the preferred epothilone conformation as indicated by the activity of a potent pyridine-epothilone analogue. In addition, the structure–activity relationships of multiple Taxanes and epothilones in the tubulin mutant cells can be fully explained by the model presented here, verifying its predictive value. Finally, these pharmacophore and activity data from mutant cells were used to model the tubulin binding of sarcodictyins, a distinct class of microtubule stabilizers, which in contrast to Taxanes and the epothilones interact preferentially with the mutant tubulins. The unification of Taxane, epothilone, and sarcodictyin chemistries in a single pharmacophore provides a framework to study drug–tubulin interactions that should assist in the rational design of agents targeting tubulin.

Maria Thadanimulero - One of the best experts on this subject based on the ideXlab platform.

  • androgen receptor splice variants determine Taxane sensitivity in prostate cancer
    Cancer Research, 2014
    Co-Authors: Maria Thadanimulero, Luigi Portella, Shihua Sun, Matthew Sung, Alexandre Matov, Robert L Vessella, Eva Corey, David M Nanus, Stephen R Plymate, Paraskevi Giannakakou
    Abstract:

    Prostate cancer growth depends on androgen receptor (AR) signaling. Androgen ablation therapy induces expression of constitutively active AR splice variants which drive disease progression. Taxanes are a standard of care therapy in castration-resistant prostate cancer (CRPC), however, mechanisms underlying the clinical activity of Taxanes are poorly understood. Recent work suggests that the microtubule network of prostate cells is critical for AR nuclear translocation and activity. In this study, we employed a set of AR deletion mutants to identify the microtubule-binding domain of AR, which encompasses the DNA binding domain plus hinge region. We report that two clinically relevant AR splice variants, ARv567 and ARv7, differentially associate with microtubules and dynein motor protein, thereby resulting in differential Taxane sensitivity in vitro and in vivo. ARv7, which lacks the hinge region, did not co-sediment with microtubules or co-precipitate with dynein motor protein, unlike ARv567. Mechanistic investigations revealed that the nuclear accumulation and transcriptional activity of ARv7 was unaffected by Taxane treatment. In contrast, the microtubule-interacting splice variant ARv567 was sensitive to Taxane-induced microtubule stabilization. In ARv567-expressing LuCap86.2 tumor xenografts, docetaxel treatment was highly efficacious, whereas ARv7-expressing LuCap23.1 tumors xenografts displayed docetaxel resistance. Our results suggest that AR variants which accumulate in CRPC cells utilize distinct pathways of nuclear import that affect the antitumor efficacy of Taxanes, suggesting a mechanistic rationale to customize treatments for CRPC patients which might improve outcomes.

  • Taxane induced blockade to nuclear accumulation of the androgen receptor predicts clinical responses in metastatic prostate cancer
    Cancer Research, 2011
    Co-Authors: Medha S Darshan, Matthew S Loftus, Maria Thadanimulero, Ben P Levy, Daniel Escuin, Xi Kathy Zhou, Ada Gjyrezi, Chantal Chanelvos, Ruoqian Shen, Scott T Tagawa
    Abstract:

    Prostate cancer progression requires active androgen receptor (AR) signaling which occurs following translocation of AR from the cytoplasm to the nucleus. Chemotherapy with Taxanes improves survival in patients with castrate resistant prostate cancer (CRPC). Taxanes induce microtubule stabilization, mitotic arrest, and apoptotic cell death, but recent data suggest that Taxanes can also affect AR signaling. Here, we report that Taxanes inhibit ligand-induced AR nuclear translocation and downstream transcriptional activation of AR target genes such as prostate-specific antigen. AR nuclear translocation was not inhibited in cells with acquired β-tubulin mutations that prevent Taxane-induced microtubule stabilization, confirming a role for microtubules in AR trafficking. Upon ligand activation, AR associated with the minus-end-microtubule motor dynein, thereby trafficking on microtubules to translocate to the nucleus. Analysis of circulating tumor cells (CTC) isolated from the peripheral blood of CRPC patients receiving Taxane chemotherapy revealed a significant correlation between AR cytoplasmic sequestration and clinical response to therapy. These results indicate that Taxanes act in CRPC patients at least in part by inhibiting AR nuclear transport and signaling. Further, they suggest that monitoring AR subcellular localization in the CTCs of CRPC patients might predict clinical responses to Taxane chemotherapy.

  • Taxane induced blockade to nuclear accumulation of the androgen receptor predicts clinical responses in metastatic prostate cancer
    Cancer Research, 2011
    Co-Authors: Medha S Darshan, Matthew S Loftus, Maria Thadanimulero, Ben P Levy, Daniel Escuin, Xi Kathy Zhou, Ada Gjyrezi, Chantal Chanelvos, Ruoqian Shen, Scott T Tagawa
    Abstract:

    Prostate cancer progression requires active androgen receptor (AR) signaling which occurs following translocation of AR from the cytoplasm to the nucleus. Chemotherapy with Taxanes improves survival in patients with castrate resistant prostate cancer (CRPC). Taxanes induce microtubule stabilization, mitotic arrest, and apoptotic cell death, but recent data suggest that Taxanes can also affect AR signaling. Here, we report that Taxanes inhibit ligand-induced AR nuclear translocation and downstream transcriptional activation of AR target genes such as prostate-specific antigen. AR nuclear translocation was not inhibited in cells with acquired β-tubulin mutations that prevent Taxane-induced microtubule stabilization, confirming a role for microtubules in AR trafficking. Upon ligand activation, AR associated with the minus-end-microtubule motor dynein, thereby trafficking on microtubules to translocate to the nucleus. Analysis of circulating tumor cells (CTC) isolated from the peripheral blood of CRPC patients receiving Taxane chemotherapy revealed a significant correlation between AR cytoplasmic sequestration and clinical response to therapy. These results indicate that Taxanes act in CRPC patients at least in part by inhibiting AR nuclear transport and signaling. Further, they suggest that monitoring AR subcellular localization in the CTCs of CRPC patients might predict clinical responses to Taxane chemotherapy. Cancer Res; 71(18); 6019–29. ©2011 AACR.