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  • American Association for Cancer Research (AACR)  (4)
  • 1
    Online Resource
    Online Resource
    Abstract 2179: Antitumor activity of JNJ-63576253 (TRC253), a small molecule antagonist of F877L mutant and wild-type androgen receptor
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 13_Supplement ( 2019-07-01), p. 2179-2179
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. 2179-2179
    Abstract: Androgen receptor (AR) antagonists have transformed prostate cancer patient care by targeting a key nodal point in tumor cell signaling. However, despite the impressive clinical activity of first- and second-generation antiandrogens, acquired resistance frequently emerges. Point mutations in the ligand-binding domain of AR, such as phenylalanine to leucine at position 877 (ARF877L), account for 10-20% of resistance. Such mutations are characterized by receptor activation, rather than inhibition, by first- and second-generation antiandrogen therapeutics. JNJ-63576253 is a potent, high affinity competitive binder of wild type and mutant AR, including F877L. JNJ-63576253 blocks AR nuclear translocation, AR binding to DNA, and AR-dependent transcription. JNJ-63576253 inhibits the proliferation of androgen receptor driven prostate cancer cell lines, including those bearing ARF877L. In the Hershberger assay in male Sprague Dawley rats, oral administration of JNJ-63576253 inhibited androgen sensitive organ (ASO) development in a dose-dependent manner. In male SHO mice bearing LNCaP xenografts with either wild-type or ARF877L, daily treatment with 30 mg/kg JNJ-63576253 treatment resulted in statistically significant antitumor activity, whereas second-generation antiandrogen enzalutamide had no antitumor efficacy in the LNCaP ARF877L mutant model. Janssen and Tracon Pharma have entered a strategic licensing collaboration, whereby Tracon possesses exclusive rights for clinical development of JNJ-63576253 (now called TRC253). Tracon has entered TRC253 into Ph1/2A clinical evaluation in metastatic castration-resistant prostate cancer patients. Citation Format: Tammy L. Bush, Georges Habineza Ndikuyeze, Gilles Bignan, Jonathan Branch, Janine Ondrus, Yifan Shi, Leopoldo Luistro, James Hastings, Joseph Erhardt, Ian Hickson, Shefali Patel, Peter Connolly, Zhuming Zhang, James Bischoff, Brent Rupnow, Marco Gottardis, Kathryn Packman. Antitumor activity of JNJ-63576253 (TRC253), a small molecule antagonist of F877L mutant and wild-type androgen receptor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2179.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2019-2179
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
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  • 2
    Online Resource
    Online Resource
    Abstract C16: Targeting AR in castration-resistant prostate cancer: Development of ARN-509 and second-generation antiandrogen resistance models
    American Association for Cancer Research (AACR) ; 2012
    In:  Cancer Research Vol. 72, No. 4_Supplement ( 2012-02-06), p. C16-C16
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 72, No. 4_Supplement ( 2012-02-06), p. C16-C16
    Abstract: The androgen receptor (AR) plays a central role in the development and progression of prostate cancer. Recent studies demonstrate that AR remains essential in the majority of castration resistant prostate cancer (CRPC) after classical androgen ablation therapies have failed. The clinical efficacies of MDV3100 and abiraterone acetate, both of which target the AR pathway in the castrate resistant setting, support these findings. ARN-509 is a 2nd generation competitive AR antagonist that, unlike bicalutamide, maintains full antagonist activity in preclinical CRPC models. ARN-509 does not robustly induce AR nuclear localization or DNA binding. However, ARN-509 displays maximal efficacy in the LNCaP/AR xenograft model of CRPC at lower dose and steady state plasma concentrations compared to MDV3100, suggesting potential for higher therapeutic index and ability to deliver the maximally efficacious dose in man. To date, ARN-509 has shown promising antitumor activity in mCRPC patients enrolled in a Phase 1 study. Given that approximately 50% of CRPC patients have suboptimal response to MDV3100 and abiraterone acetate as well as the observation that resistance eventually develops in patients who initially respond to therapy, we sought to determine whether AR remains a viable therapeutic target in the MDV3100 and ARN-509 resistant setting. To this end, we generated several MDV3100 and ARN-509 resistant derivatives of the LNCaP and LNCaP/AR cell lines. While work is underway to determine the molecular mechanisms of resistance, a subset of cell lines does not require androgens for growth in vitro. These androgen independent derivatives express AR at levels comparable to LNCaP/AR (approximately 3X LNCaP) or 2-3 fold LNCaP-AR. When representative lines are injected into castrated mice, they demonstrate a decreased latency of tumor formation compared to the parental cell line both in the presence and absence of ARN-509. Importantly, in all lines tested, small interfering RNA mediated reduction in AR levels dramatically impaired the ability of the androgen independent resistant cell lines to proliferate in the absence of androgens. These data support the hypothesis that AR remains a viable therapeutic target for second generation anti-androgen resistant prostate cancer and is the first step toward establishing a platform to screen for next generation anti-androgens. Citation Format: James D. Joseph, Anna Aparicio, Josh Kaufman, Jackie Julien, Celine Bonnefous, Nicholas D. Smith, Peter Rix, Michael E. Jung, Charles L. Sawyers, Richard A. Heyman, Jeffrey H. Hager, Nicola J. Clegg, John Sensintaffar, Nhin Lu, Kate Grillot, Eric Bischoff, Gang Shao, Jing Qian, Beatrice Darimont. Targeting AR in castration-resistant prostate cancer: Development of ARN-509 and second-generation antiandrogen resistance models [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr C16.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.PRCA2012-C16
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2012
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
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  • 3
    Online Resource
    Online Resource
    ARN-509: A Novel Antiandrogen for Prostate Cancer Treatment
    American Association for Cancer Research (AACR) ; 2012
    In:  Cancer Research Vol. 72, No. 6 ( 2012-03-15), p. 1494-1503
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 72, No. 6 ( 2012-03-15), p. 1494-1503
    Abstract: Continued reliance on the androgen receptor (AR) is now understood as a core mechanism in castration-resistant prostate cancer (CRPC), the most advanced form of this disease. While established and novel AR pathway–targeting agents display clinical efficacy in metastatic CRPC, dose-limiting side effects remain problematic for all current agents. In this study, we report the discovery and development of ARN-509, a competitive AR inhibitor that is fully antagonistic to AR overexpression, a common and important feature of CRPC. ARN-509 was optimized for inhibition of AR transcriptional activity and prostate cancer cell proliferation, pharmacokinetics, and in vivo efficacy. In contrast to bicalutamide, ARN-509 lacked significant agonist activity in preclinical models of CRPC. Moreover, ARN-509 lacked inducing activity for AR nuclear localization or DNA binding. In a clinically valid murine xenograft model of human CRPC, ARN-509 showed greater efficacy than MDV3100. Maximal therapeutic response in this model was achieved at 30 mg/kg/d of ARN-509, whereas the same response required 100 mg/kg/d of MDV3100 and higher steady-state plasma concentrations. Thus, ARN-509 exhibits characteristics predicting a higher therapeutic index with a greater potential to reach maximally efficacious doses in man than current AR antagonists. Our findings offer preclinical proof of principle for ARN-509 as a promising therapeutic in both castration-sensitive and castration-resistant forms of prostate cancer. Cancer Res; 72(6); 1494–503. ©2012 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-11-3948
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2012
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 4
    Online Resource
    Online Resource
    Discovery of JNJ-63576253, a Next-Generation Androgen Receptor Antagonist Active Against Wild-Type and Clinically Relevant Ligand Binding Domain Mutations in Metastatic Castration-Resistant Prostate Cancer
    American Association for Cancer Research (AACR) ; 2021
    In:  Molecular Cancer Therapeutics Vol. 20, No. 5 ( 2021-05-01), p. 763-774
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 20, No. 5 ( 2021-05-01), p. 763-774
    Abstract: Numerous mechanisms of resistance arise in response to treatment with second-generation androgen receptor (AR) pathway inhibitors in metastatic castration-resistant prostate cancer (mCRPC). Among these, point mutations in the ligand binding domain can transform antagonists into agonists, driving the disease through activation of AR signaling. To address this unmet need, we report the discovery of JNJ-63576253, a next-generation AR pathway inhibitor that potently abrogates AR signaling in models of human prostate adenocarcinoma. JNJ-63576253 is advancing as a clinical candidate with potential effectiveness in the subset of patients who do not respond to or are progressing while on second-generation AR-targeted therapeutics.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.MCT-20-0510
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
    detail.hit.zdb_id: 2062135-8
    SSG: 12
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