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Ellen S De Morree - One of the best experts on this subject based on the ideXlab platform.

  • Androgen receptor signalling impairs Docetaxel efficacy in castration-resistant prostate cancer
    British Journal of Cancer, 2020
    Co-Authors: Lisanne Mout, Ellen S De Morree, Corrina M A De Ridder, Ashraf Aghai, Jan M. Moll, Mingqing Chen, Alice Gibson, Debra Stuurman, Sigrun Erkens-schulze, Ron H J Mathijssen
    Abstract:

    Androgen receptor (AR) signalling drives neoplastic growth and therapy resistance in prostate cancer. Recent clinical data show that Docetaxel combined with androgen deprivation therapy improves outcome in hormone-sensitive disease. We studied whether testosterone and AR signalling interferes with Docetaxel treatment efficacy in castration-resistant prostate cancer (CRPC). We found that testosterone supplementation significantly impaired Docetaxel tumour accumulation in a CRPC model, resulting in decreased tubulin stabilisation and antitumour activity. Furthermore, testosterone competed with Docetaxel for uptake by the drug transporter OATP1B3. Irrespective of Docetaxel-induced tubulin stabilisation, AR signalling by testosterone counteracted Docetaxel efficacy. AR-pathway activation could also reverse long-term tumour regression by Docetaxel treatment in vivo. These results indicate that to optimise Docetaxel efficacy, androgen levels and AR signalling need to be suppressed. This study lends evidence for continued maximum suppression of AR signalling by combining targeted therapeutics with Docetaxel in CRPC.

  • Loss of SLCO1B3 drives taxane resistance in prostate cancer
    British Journal of Cancer, 2016
    Co-Authors: Ellen S De Morree, Robert J Van Soest, Ron H J Mathijssen, Ashraf Aghai, Herman Burger, Alice A. Gibson, E.a.c. Wiemer, René Böttcher, Corrina M De Ridder, Alex Sparreboom
    Abstract:

    Background: Both taxanes, Docetaxel and cabazitaxel, are effective treatments for metastatic castration-resistant prostate cancer (mCRPC). However, resistance to taxanes is common. Our objective was to investigate mechanisms of taxane resistance in prostate cancer. Methods: Two Docetaxel-resistant patient-derived xenografts (PDXs) of CRPC were established (PC339-DOC and PC346C-DOC) in male athymic nude mice by frequent intraperitoneal administrations of Docetaxel. Next-generation sequencing was performed on PDX tissue pre- and post-Docetaxel resistance and gene expression profiles were compared. [^14C]-Docetaxel and [^14C]-cabazitaxel uptake assays in vitro and cytotoxicity assays were performed to validate direct involvement of transporter genes in taxane sensitivity. Results: Organic anion-transporting polypeptide (SLCO1B3), an influx transporter of Docetaxel, was significantly downregulated in PC346C-DOC tumours. In accordance with this finding, intratumoural concentrations of Docetaxel and cabazitaxel were significantly decreased in PC346C-DOC as compared with levels in chemotherapy-naive PC346C tumours. In addition, silencing of SLCO1B3 in chemo-naive PC346C resulted in a two-fold decrease in intracellular concentrations of both taxanes. Overexpression of SLCO1B3 showed higher sensitivity to Docetaxel and cabazitaxel. Conclusions: The SLCO1B3 determines intracellular concentrations of Docetaxel and cabazitaxel and consequently influences taxane efficacy. Loss of the drug transporter SLCO1B3 may drive taxane resistance in prostate cancer.

  • Loss of SLCO1B3 drives taxane resistance in prostate cancer
    British journal of cancer, 2016
    Co-Authors: Ellen S De Morree, Corrina M A De Ridder, Ron H J Mathijssen, Robert J. Van Soest, Ashraf Aghai, Herman Burger, Alice A. Gibson, E.a.c. Wiemer, René Böttcher, Alex Sparreboom
    Abstract:

    Both taxanes, Docetaxel and cabazitaxel, are effective treatments for metastatic castration-resistant prostate cancer (mCRPC). However, resistance to taxanes is common. Our objective was to investigate mechanisms of taxane resistance in prostate cancer. Two Docetaxel-resistant patient-derived xenografts (PDXs) of CRPC were established (PC339-DOC and PC346C-DOC) in male athymic nude mice by frequent intraperitoneal administrations of Docetaxel. Next-generation sequencing was performed on PDX tissue pre- and post-Docetaxel resistance and gene expression profiles were compared. [14C]-Docetaxel and [14C]-cabazitaxel uptake assays in vitro and cytotoxicity assays were performed to validate direct involvement of transporter genes in taxane sensitivity. Organic anion-transporting polypeptide (SLCO1B3), an influx transporter of Docetaxel, was significantly downregulated in PC346C-DOC tumours. In accordance with this finding, intratumoural concentrations of Docetaxel and cabazitaxel were significantly decreased in PC346C-DOC as compared with levels in chemotherapy-naive PC346C tumours. In addition, silencing of SLCO1B3 in chemo-naive PC346C resulted in a two-fold decrease in intracellular concentrations of both taxanes. Overexpression of SLCO1B3 showed higher sensitivity to Docetaxel and cabazitaxel. The SLCO1B3 determines intracellular concentrations of Docetaxel and cabazitaxel and consequently influences taxane efficacy. Loss of the drug transporter SLCO1B3 may drive taxane resistance in prostate cancer.

  • Understanding taxanes in prostate cancer; importance of intratumoral drug accumulation.
    The Prostate, 2016
    Co-Authors: Ellen S De Morree, Corrina M A De Ridder, Erik A C Wiemer, Ron H J Mathijssen, Robert J. Van Soest, Ashraf Aghai, Peter De Bruijn, Inge M. Ghobadi Moghaddam-helmantel, Herman Burger, Ronald De Wit
    Abstract:

    BACKGROUND Resistance to Docetaxel is common in metastatic castration-resistant prostate cancer (mCRPC) and may be caused by sub-therapeutic intratumoral drug concentrations. Cabazitaxel demonstrated survival benefit in Docetaxel-pretreated and Docetaxel-refractory patients. In this study, we investigated whether the superior antitumor activity of cabazitaxel in mCRPC is explained by higher intratumoral cabazitaxel levels. Since recent studies suggest a reduced efficacy of Docetaxel following treatment with novel androgen receptor (AR)-targeted agents, we also investigated taxane efficacy in an enzalutamide-resistant tumor model. METHODS Intratumoral concentrations of Docetaxel and cabazitaxel were correlated with antitumor activity in Docetaxel-naive, Docetaxel-resistant, and enzalutamide-resistant patient-derived xenografts (PDXs) of prostate cancer. RESULTS Intratumoral drug levels were negatively related to intrinsic and acquired resistance to Docetaxel. Also, the observed stronger antitumor activity of cabazitaxel was associated with increased cumulative exposure and higher intratumoral of cabazitaxel concentrations in all PDXs. CONCLUSIONS The superior antitumor activity of cabazitaxel in Docetaxel- and enzalutamide-resistant tumors can be partly attributed to higher intratumoral drug concentrations. Especially for patients who are intrinsically resistant to Docetaxel resulting from suboptimal intratumoral Docetaxel concentrations, cabazitaxel may be the preferred chemotherapeutic agent. Prostate 76:927–936, 2016. © 2016 Wiley Periodicals, Inc.

  • targeting the androgen receptor confers in vivo cross resistance between enzalutamide and Docetaxel but not cabazitaxel in castration resistant prostate cancer
    European Urology, 2015
    Co-Authors: Robert J Van Soest, Ellen S De Morree, Charlotte F Kweldam, Corrina M A De Ridder, Erik A C Wiemer, Ron H J Mathijssen, Wytske M Van Weerden
    Abstract:

    Abstract Treatment options for metastatic castration-resistant prostate cancer (CRPC) have evolved with the established benefit of the novel androgen receptor (AR)-targeted agents abiraterone and enzalutamide in the prechemotherapy setting. However, concerns regarding cross-resistance between the taxanes Docetaxel and cabazitaxel and these AR-targeted agents have arisen, and the optimal drug treatment sequence is unknown. We investigated the in vivo efficacy of Docetaxel and cabazitaxel in enzalutamide-resistant CRPC, and mechanisms of cross-resistance between these agents. Castrated mice harboring enzalutamide-resistant tumors and enzalutamide-naive tumors were treated with Docetaxel and cabazitaxel. Tumor growth kinetics, AR nuclear localization, AR-regulated gene expression, Ki67 expression, and serum levels of prostate-specific antigen, Docetaxel, and cabazitaxel were analyzed. Docetaxel inhibited tumor growth, AR nuclear localization, and AR-regulated gene expression in enzalutamide-naive tumors, but did not in enzalutamide-resistant tumors, demonstrating in vivo cross-resistance. By contrast, cabazitaxel remained highly effective in enzalutamide-resistant tumors and demonstrated superior antitumor activity compared to Docetaxel, independent of the AR pathway. These findings demonstrate that the AR pathway is able to confer in vivo cross-resistance between enzalutamide and Docetaxel, but not cabazitaxel, in CRPC. Patient summary We found reduced efficacy of Docetaxel, but not cabazitaxel, in enzalutamide-resistant prostate cancer.

Alex Sparreboom - One of the best experts on this subject based on the ideXlab platform.

  • Loss of SLCO1B3 drives taxane resistance in prostate cancer
    British Journal of Cancer, 2016
    Co-Authors: Ellen S De Morree, Robert J Van Soest, Ron H J Mathijssen, Ashraf Aghai, Herman Burger, Alice A. Gibson, E.a.c. Wiemer, René Böttcher, Corrina M De Ridder, Alex Sparreboom
    Abstract:

    Background: Both taxanes, Docetaxel and cabazitaxel, are effective treatments for metastatic castration-resistant prostate cancer (mCRPC). However, resistance to taxanes is common. Our objective was to investigate mechanisms of taxane resistance in prostate cancer. Methods: Two Docetaxel-resistant patient-derived xenografts (PDXs) of CRPC were established (PC339-DOC and PC346C-DOC) in male athymic nude mice by frequent intraperitoneal administrations of Docetaxel. Next-generation sequencing was performed on PDX tissue pre- and post-Docetaxel resistance and gene expression profiles were compared. [^14C]-Docetaxel and [^14C]-cabazitaxel uptake assays in vitro and cytotoxicity assays were performed to validate direct involvement of transporter genes in taxane sensitivity. Results: Organic anion-transporting polypeptide (SLCO1B3), an influx transporter of Docetaxel, was significantly downregulated in PC346C-DOC tumours. In accordance with this finding, intratumoural concentrations of Docetaxel and cabazitaxel were significantly decreased in PC346C-DOC as compared with levels in chemotherapy-naive PC346C tumours. In addition, silencing of SLCO1B3 in chemo-naive PC346C resulted in a two-fold decrease in intracellular concentrations of both taxanes. Overexpression of SLCO1B3 showed higher sensitivity to Docetaxel and cabazitaxel. Conclusions: The SLCO1B3 determines intracellular concentrations of Docetaxel and cabazitaxel and consequently influences taxane efficacy. Loss of the drug transporter SLCO1B3 may drive taxane resistance in prostate cancer.

  • Loss of SLCO1B3 drives taxane resistance in prostate cancer
    British journal of cancer, 2016
    Co-Authors: Ellen S De Morree, Corrina M A De Ridder, Ron H J Mathijssen, Robert J. Van Soest, Ashraf Aghai, Herman Burger, Alice A. Gibson, E.a.c. Wiemer, René Böttcher, Alex Sparreboom
    Abstract:

    Both taxanes, Docetaxel and cabazitaxel, are effective treatments for metastatic castration-resistant prostate cancer (mCRPC). However, resistance to taxanes is common. Our objective was to investigate mechanisms of taxane resistance in prostate cancer. Two Docetaxel-resistant patient-derived xenografts (PDXs) of CRPC were established (PC339-DOC and PC346C-DOC) in male athymic nude mice by frequent intraperitoneal administrations of Docetaxel. Next-generation sequencing was performed on PDX tissue pre- and post-Docetaxel resistance and gene expression profiles were compared. [14C]-Docetaxel and [14C]-cabazitaxel uptake assays in vitro and cytotoxicity assays were performed to validate direct involvement of transporter genes in taxane sensitivity. Organic anion-transporting polypeptide (SLCO1B3), an influx transporter of Docetaxel, was significantly downregulated in PC346C-DOC tumours. In accordance with this finding, intratumoural concentrations of Docetaxel and cabazitaxel were significantly decreased in PC346C-DOC as compared with levels in chemotherapy-naive PC346C tumours. In addition, silencing of SLCO1B3 in chemo-naive PC346C resulted in a two-fold decrease in intracellular concentrations of both taxanes. Overexpression of SLCO1B3 showed higher sensitivity to Docetaxel and cabazitaxel. The SLCO1B3 determines intracellular concentrations of Docetaxel and cabazitaxel and consequently influences taxane efficacy. Loss of the drug transporter SLCO1B3 may drive taxane resistance in prostate cancer.

  • Limited cerebrospinal fluid penetration of Docetaxel.
    Anti-cancer drugs, 2004
    Co-Authors: Albert J. Ten Tije, Walter J. Loos, Ming Zhao, Sharyn D. Baker, Roelien H. Enting, Hans Van Der Meulen, Jaap Verweij, Alex Sparreboom
    Abstract:

    Our purpose was to investigate the cerebrospinal fluid (CSF) penetration of Docetaxel in cancer patients. Docetaxel was administered as a 1-h infusion at a dose of 75 mg/m2 to two patients with metastatic breast cancer and leptomeningeal carcinomatosis. CSF samples were obtained using a lumbar puncture up to a 72-h time period. Total and unbound Docetaxel concentrations in plasma and CSF were determined by liquid chromatography (lower limit of quantitation: 0.5 nM for plasma and 0.050 nM for CSF) and equilibrium dialysis, respectively. The pharmacokinetics of Docetaxel in plasma are in line with data of previous studies. The concentrations of Docetaxel in CSF did not follow the general pattern in plasma, with relatively stable concentrations over the 72-h time period. The fraction of unbound Docetaxel in plasma ranged from 6 to 13%, while that in CSF ranged from 67 to 103%. For total and unbound Docetaxel, the CSF to plasma concentration ratio progressively increased in 72 h from 0.01 to 0.6% and from 0.1 to 9%, respectively. These data suggest that measurement of unbound Docetaxel is required to accurately assess the extent of drug penetration into CSF and that the drug can produce distribution to CSF at levels associated with significant antitumor activity in experimental models.

Ron H J Mathijssen - One of the best experts on this subject based on the ideXlab platform.

  • Androgen receptor signalling impairs Docetaxel efficacy in castration-resistant prostate cancer
    British Journal of Cancer, 2020
    Co-Authors: Lisanne Mout, Ellen S De Morree, Corrina M A De Ridder, Ashraf Aghai, Jan M. Moll, Mingqing Chen, Alice Gibson, Debra Stuurman, Sigrun Erkens-schulze, Ron H J Mathijssen
    Abstract:

    Androgen receptor (AR) signalling drives neoplastic growth and therapy resistance in prostate cancer. Recent clinical data show that Docetaxel combined with androgen deprivation therapy improves outcome in hormone-sensitive disease. We studied whether testosterone and AR signalling interferes with Docetaxel treatment efficacy in castration-resistant prostate cancer (CRPC). We found that testosterone supplementation significantly impaired Docetaxel tumour accumulation in a CRPC model, resulting in decreased tubulin stabilisation and antitumour activity. Furthermore, testosterone competed with Docetaxel for uptake by the drug transporter OATP1B3. Irrespective of Docetaxel-induced tubulin stabilisation, AR signalling by testosterone counteracted Docetaxel efficacy. AR-pathway activation could also reverse long-term tumour regression by Docetaxel treatment in vivo. These results indicate that to optimise Docetaxel efficacy, androgen levels and AR signalling need to be suppressed. This study lends evidence for continued maximum suppression of AR signalling by combining targeted therapeutics with Docetaxel in CRPC.

  • Loss of SLCO1B3 drives taxane resistance in prostate cancer
    British Journal of Cancer, 2016
    Co-Authors: Ellen S De Morree, Robert J Van Soest, Ron H J Mathijssen, Ashraf Aghai, Herman Burger, Alice A. Gibson, E.a.c. Wiemer, René Böttcher, Corrina M De Ridder, Alex Sparreboom
    Abstract:

    Background: Both taxanes, Docetaxel and cabazitaxel, are effective treatments for metastatic castration-resistant prostate cancer (mCRPC). However, resistance to taxanes is common. Our objective was to investigate mechanisms of taxane resistance in prostate cancer. Methods: Two Docetaxel-resistant patient-derived xenografts (PDXs) of CRPC were established (PC339-DOC and PC346C-DOC) in male athymic nude mice by frequent intraperitoneal administrations of Docetaxel. Next-generation sequencing was performed on PDX tissue pre- and post-Docetaxel resistance and gene expression profiles were compared. [^14C]-Docetaxel and [^14C]-cabazitaxel uptake assays in vitro and cytotoxicity assays were performed to validate direct involvement of transporter genes in taxane sensitivity. Results: Organic anion-transporting polypeptide (SLCO1B3), an influx transporter of Docetaxel, was significantly downregulated in PC346C-DOC tumours. In accordance with this finding, intratumoural concentrations of Docetaxel and cabazitaxel were significantly decreased in PC346C-DOC as compared with levels in chemotherapy-naive PC346C tumours. In addition, silencing of SLCO1B3 in chemo-naive PC346C resulted in a two-fold decrease in intracellular concentrations of both taxanes. Overexpression of SLCO1B3 showed higher sensitivity to Docetaxel and cabazitaxel. Conclusions: The SLCO1B3 determines intracellular concentrations of Docetaxel and cabazitaxel and consequently influences taxane efficacy. Loss of the drug transporter SLCO1B3 may drive taxane resistance in prostate cancer.

  • Loss of SLCO1B3 drives taxane resistance in prostate cancer
    British journal of cancer, 2016
    Co-Authors: Ellen S De Morree, Corrina M A De Ridder, Ron H J Mathijssen, Robert J. Van Soest, Ashraf Aghai, Herman Burger, Alice A. Gibson, E.a.c. Wiemer, René Böttcher, Alex Sparreboom
    Abstract:

    Both taxanes, Docetaxel and cabazitaxel, are effective treatments for metastatic castration-resistant prostate cancer (mCRPC). However, resistance to taxanes is common. Our objective was to investigate mechanisms of taxane resistance in prostate cancer. Two Docetaxel-resistant patient-derived xenografts (PDXs) of CRPC were established (PC339-DOC and PC346C-DOC) in male athymic nude mice by frequent intraperitoneal administrations of Docetaxel. Next-generation sequencing was performed on PDX tissue pre- and post-Docetaxel resistance and gene expression profiles were compared. [14C]-Docetaxel and [14C]-cabazitaxel uptake assays in vitro and cytotoxicity assays were performed to validate direct involvement of transporter genes in taxane sensitivity. Organic anion-transporting polypeptide (SLCO1B3), an influx transporter of Docetaxel, was significantly downregulated in PC346C-DOC tumours. In accordance with this finding, intratumoural concentrations of Docetaxel and cabazitaxel were significantly decreased in PC346C-DOC as compared with levels in chemotherapy-naive PC346C tumours. In addition, silencing of SLCO1B3 in chemo-naive PC346C resulted in a two-fold decrease in intracellular concentrations of both taxanes. Overexpression of SLCO1B3 showed higher sensitivity to Docetaxel and cabazitaxel. The SLCO1B3 determines intracellular concentrations of Docetaxel and cabazitaxel and consequently influences taxane efficacy. Loss of the drug transporter SLCO1B3 may drive taxane resistance in prostate cancer.

  • Understanding taxanes in prostate cancer; importance of intratumoral drug accumulation.
    The Prostate, 2016
    Co-Authors: Ellen S De Morree, Corrina M A De Ridder, Erik A C Wiemer, Ron H J Mathijssen, Robert J. Van Soest, Ashraf Aghai, Peter De Bruijn, Inge M. Ghobadi Moghaddam-helmantel, Herman Burger, Ronald De Wit
    Abstract:

    BACKGROUND Resistance to Docetaxel is common in metastatic castration-resistant prostate cancer (mCRPC) and may be caused by sub-therapeutic intratumoral drug concentrations. Cabazitaxel demonstrated survival benefit in Docetaxel-pretreated and Docetaxel-refractory patients. In this study, we investigated whether the superior antitumor activity of cabazitaxel in mCRPC is explained by higher intratumoral cabazitaxel levels. Since recent studies suggest a reduced efficacy of Docetaxel following treatment with novel androgen receptor (AR)-targeted agents, we also investigated taxane efficacy in an enzalutamide-resistant tumor model. METHODS Intratumoral concentrations of Docetaxel and cabazitaxel were correlated with antitumor activity in Docetaxel-naive, Docetaxel-resistant, and enzalutamide-resistant patient-derived xenografts (PDXs) of prostate cancer. RESULTS Intratumoral drug levels were negatively related to intrinsic and acquired resistance to Docetaxel. Also, the observed stronger antitumor activity of cabazitaxel was associated with increased cumulative exposure and higher intratumoral of cabazitaxel concentrations in all PDXs. CONCLUSIONS The superior antitumor activity of cabazitaxel in Docetaxel- and enzalutamide-resistant tumors can be partly attributed to higher intratumoral drug concentrations. Especially for patients who are intrinsically resistant to Docetaxel resulting from suboptimal intratumoral Docetaxel concentrations, cabazitaxel may be the preferred chemotherapeutic agent. Prostate 76:927–936, 2016. © 2016 Wiley Periodicals, Inc.

  • targeting the androgen receptor confers in vivo cross resistance between enzalutamide and Docetaxel but not cabazitaxel in castration resistant prostate cancer
    European Urology, 2015
    Co-Authors: Robert J Van Soest, Ellen S De Morree, Charlotte F Kweldam, Corrina M A De Ridder, Erik A C Wiemer, Ron H J Mathijssen, Wytske M Van Weerden
    Abstract:

    Abstract Treatment options for metastatic castration-resistant prostate cancer (CRPC) have evolved with the established benefit of the novel androgen receptor (AR)-targeted agents abiraterone and enzalutamide in the prechemotherapy setting. However, concerns regarding cross-resistance between the taxanes Docetaxel and cabazitaxel and these AR-targeted agents have arisen, and the optimal drug treatment sequence is unknown. We investigated the in vivo efficacy of Docetaxel and cabazitaxel in enzalutamide-resistant CRPC, and mechanisms of cross-resistance between these agents. Castrated mice harboring enzalutamide-resistant tumors and enzalutamide-naive tumors were treated with Docetaxel and cabazitaxel. Tumor growth kinetics, AR nuclear localization, AR-regulated gene expression, Ki67 expression, and serum levels of prostate-specific antigen, Docetaxel, and cabazitaxel were analyzed. Docetaxel inhibited tumor growth, AR nuclear localization, and AR-regulated gene expression in enzalutamide-naive tumors, but did not in enzalutamide-resistant tumors, demonstrating in vivo cross-resistance. By contrast, cabazitaxel remained highly effective in enzalutamide-resistant tumors and demonstrated superior antitumor activity compared to Docetaxel, independent of the AR pathway. These findings demonstrate that the AR pathway is able to confer in vivo cross-resistance between enzalutamide and Docetaxel, but not cabazitaxel, in CRPC. Patient summary We found reduced efficacy of Docetaxel, but not cabazitaxel, in enzalutamide-resistant prostate cancer.

Ashraf Aghai - One of the best experts on this subject based on the ideXlab platform.

  • Androgen receptor signalling impairs Docetaxel efficacy in castration-resistant prostate cancer
    British Journal of Cancer, 2020
    Co-Authors: Lisanne Mout, Ellen S De Morree, Corrina M A De Ridder, Ashraf Aghai, Jan M. Moll, Mingqing Chen, Alice Gibson, Debra Stuurman, Sigrun Erkens-schulze, Ron H J Mathijssen
    Abstract:

    Androgen receptor (AR) signalling drives neoplastic growth and therapy resistance in prostate cancer. Recent clinical data show that Docetaxel combined with androgen deprivation therapy improves outcome in hormone-sensitive disease. We studied whether testosterone and AR signalling interferes with Docetaxel treatment efficacy in castration-resistant prostate cancer (CRPC). We found that testosterone supplementation significantly impaired Docetaxel tumour accumulation in a CRPC model, resulting in decreased tubulin stabilisation and antitumour activity. Furthermore, testosterone competed with Docetaxel for uptake by the drug transporter OATP1B3. Irrespective of Docetaxel-induced tubulin stabilisation, AR signalling by testosterone counteracted Docetaxel efficacy. AR-pathway activation could also reverse long-term tumour regression by Docetaxel treatment in vivo. These results indicate that to optimise Docetaxel efficacy, androgen levels and AR signalling need to be suppressed. This study lends evidence for continued maximum suppression of AR signalling by combining targeted therapeutics with Docetaxel in CRPC.

  • Loss of SLCO1B3 drives taxane resistance in prostate cancer
    British Journal of Cancer, 2016
    Co-Authors: Ellen S De Morree, Robert J Van Soest, Ron H J Mathijssen, Ashraf Aghai, Herman Burger, Alice A. Gibson, E.a.c. Wiemer, René Böttcher, Corrina M De Ridder, Alex Sparreboom
    Abstract:

    Background: Both taxanes, Docetaxel and cabazitaxel, are effective treatments for metastatic castration-resistant prostate cancer (mCRPC). However, resistance to taxanes is common. Our objective was to investigate mechanisms of taxane resistance in prostate cancer. Methods: Two Docetaxel-resistant patient-derived xenografts (PDXs) of CRPC were established (PC339-DOC and PC346C-DOC) in male athymic nude mice by frequent intraperitoneal administrations of Docetaxel. Next-generation sequencing was performed on PDX tissue pre- and post-Docetaxel resistance and gene expression profiles were compared. [^14C]-Docetaxel and [^14C]-cabazitaxel uptake assays in vitro and cytotoxicity assays were performed to validate direct involvement of transporter genes in taxane sensitivity. Results: Organic anion-transporting polypeptide (SLCO1B3), an influx transporter of Docetaxel, was significantly downregulated in PC346C-DOC tumours. In accordance with this finding, intratumoural concentrations of Docetaxel and cabazitaxel were significantly decreased in PC346C-DOC as compared with levels in chemotherapy-naive PC346C tumours. In addition, silencing of SLCO1B3 in chemo-naive PC346C resulted in a two-fold decrease in intracellular concentrations of both taxanes. Overexpression of SLCO1B3 showed higher sensitivity to Docetaxel and cabazitaxel. Conclusions: The SLCO1B3 determines intracellular concentrations of Docetaxel and cabazitaxel and consequently influences taxane efficacy. Loss of the drug transporter SLCO1B3 may drive taxane resistance in prostate cancer.

  • Loss of SLCO1B3 drives taxane resistance in prostate cancer
    British journal of cancer, 2016
    Co-Authors: Ellen S De Morree, Corrina M A De Ridder, Ron H J Mathijssen, Robert J. Van Soest, Ashraf Aghai, Herman Burger, Alice A. Gibson, E.a.c. Wiemer, René Böttcher, Alex Sparreboom
    Abstract:

    Both taxanes, Docetaxel and cabazitaxel, are effective treatments for metastatic castration-resistant prostate cancer (mCRPC). However, resistance to taxanes is common. Our objective was to investigate mechanisms of taxane resistance in prostate cancer. Two Docetaxel-resistant patient-derived xenografts (PDXs) of CRPC were established (PC339-DOC and PC346C-DOC) in male athymic nude mice by frequent intraperitoneal administrations of Docetaxel. Next-generation sequencing was performed on PDX tissue pre- and post-Docetaxel resistance and gene expression profiles were compared. [14C]-Docetaxel and [14C]-cabazitaxel uptake assays in vitro and cytotoxicity assays were performed to validate direct involvement of transporter genes in taxane sensitivity. Organic anion-transporting polypeptide (SLCO1B3), an influx transporter of Docetaxel, was significantly downregulated in PC346C-DOC tumours. In accordance with this finding, intratumoural concentrations of Docetaxel and cabazitaxel were significantly decreased in PC346C-DOC as compared with levels in chemotherapy-naive PC346C tumours. In addition, silencing of SLCO1B3 in chemo-naive PC346C resulted in a two-fold decrease in intracellular concentrations of both taxanes. Overexpression of SLCO1B3 showed higher sensitivity to Docetaxel and cabazitaxel. The SLCO1B3 determines intracellular concentrations of Docetaxel and cabazitaxel and consequently influences taxane efficacy. Loss of the drug transporter SLCO1B3 may drive taxane resistance in prostate cancer.

  • Understanding taxanes in prostate cancer; importance of intratumoral drug accumulation.
    The Prostate, 2016
    Co-Authors: Ellen S De Morree, Corrina M A De Ridder, Erik A C Wiemer, Ron H J Mathijssen, Robert J. Van Soest, Ashraf Aghai, Peter De Bruijn, Inge M. Ghobadi Moghaddam-helmantel, Herman Burger, Ronald De Wit
    Abstract:

    BACKGROUND Resistance to Docetaxel is common in metastatic castration-resistant prostate cancer (mCRPC) and may be caused by sub-therapeutic intratumoral drug concentrations. Cabazitaxel demonstrated survival benefit in Docetaxel-pretreated and Docetaxel-refractory patients. In this study, we investigated whether the superior antitumor activity of cabazitaxel in mCRPC is explained by higher intratumoral cabazitaxel levels. Since recent studies suggest a reduced efficacy of Docetaxel following treatment with novel androgen receptor (AR)-targeted agents, we also investigated taxane efficacy in an enzalutamide-resistant tumor model. METHODS Intratumoral concentrations of Docetaxel and cabazitaxel were correlated with antitumor activity in Docetaxel-naive, Docetaxel-resistant, and enzalutamide-resistant patient-derived xenografts (PDXs) of prostate cancer. RESULTS Intratumoral drug levels were negatively related to intrinsic and acquired resistance to Docetaxel. Also, the observed stronger antitumor activity of cabazitaxel was associated with increased cumulative exposure and higher intratumoral of cabazitaxel concentrations in all PDXs. CONCLUSIONS The superior antitumor activity of cabazitaxel in Docetaxel- and enzalutamide-resistant tumors can be partly attributed to higher intratumoral drug concentrations. Especially for patients who are intrinsically resistant to Docetaxel resulting from suboptimal intratumoral Docetaxel concentrations, cabazitaxel may be the preferred chemotherapeutic agent. Prostate 76:927–936, 2016. © 2016 Wiley Periodicals, Inc.

Xiaohong Liu - One of the best experts on this subject based on the ideXlab platform.

  • Preparation and characterization of a submicron lipid emulsion of Docetaxel: submicron lipid emulsion of Docetaxel.
    Drug development and industrial pharmacy, 2008
    Co-Authors: Kun Gao, Jin Sun, Kai Liu, Xiaohong Liu
    Abstract:

    Docetaxel, a widely used anticancer agent, has sparingly low aqueous solubility, thus Tween 80 and ethanol need to be added into its formulation, probably resulting in the toxic effects. In this study, we aimed to utilize submicron lipid emulsions as a carrier of Docetaxel to avoid these potential toxic vehicles. Preformulation study was performed for rational emulsions formulation design, including drug solubility, distribution between oil and water, and degradation kinetics. Supersaturated submicron lipid emulsion of Docetaxel was prepared by temperature elevation method. Soya oil and Miglyol 812 can incorporate Docetaxel up to 1.0% (drug to lipid ratio) and were used as the oil phase of emulsions. The optimal formulation of Docetaxel is composed of 10% oil phase, 1.2% soybean lecithin, 0.3% Pluoronic F68, and 0.4 or 0.8 mg/mL Docetaxel, with particle size in the nanometer range, entrapment efficiency more than 90%, and is physicochemically stable at 4 and 25 degrees C for 6 months. Animal studies showed that Docetaxel emulsion has significantly higher area under the curve (AUC) and C(max) in rats compared to its micellar solution. The results suggested that the submicron lipid emulsion is a promising intravenous carrier for Docetaxel in place of its present commercially available Docetaxel micellar solution with potential toxic effects.