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  • American Society of Clinical Oncology (ASCO)  (2)
  • 1
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 33, No. 7_suppl ( 2015-03-01), p. 266-266
    Abstract: 266 Background: The persistent activation of the androgen receptor (AR) signaling axis plays a major role in castration-resistant prostate cancer (CRPC). This knowledge has driven the clinical development of new inhibitors of androgen production (e.g., abiraterone) and AR signaling (e.g., enzalutamide). However, in many patients, the efficacy is short-lived and eventually resistance appears. Reactivation of AR signaling occurs by several mechanisms in CRPC. In this study, we report the biological properties of TAS3681, a new AR antagonist with AR downregulating activity, and propose this concept as a potential new approach for the treatment of CRPC. Methods: For assay of AR transactivation, COS-7 cells were transiently transfected with androgen-responsive reporter gene construct and expression vectors encoding wt or mu ARs. The transfected cells were treated with TAS3681 and androgen in steroid depleted media for 24 h, and luciferase activity was measured. For an in vivo pharmacodynamic assay to confirm AR downregulation in tumor, TAS3681 was orally dosed in CRPC tumor xenograft model. Tumor was isolated and AR level in tumor was determined by Western blot. Results: TAS3681 suppressed the growth of AR positive prostate cancer (PCa) cells but did not affect that of AR-negative DU145 PCa cells, indicating a dependency on AR for efficacy. TAS3681 did not stimulate AR nuclear translocation and suppressed wt and mu ARs (including F876L) transactivation in cells, indicative of its pure AR antagonist profile. In contrast to enzalutamide, TAS3681 effectively suppressed androgen-independent AR transactivation by growth factors and cytokines via AR downregulating activity. Interestingly, in PCa cells which express full-length and splice variant AR, TAS3681 reduced the expression of both ARs. Moreover, TAS3681 treatment effectively decreased AR level in CRPC tumors in vivo. Conclusions: TAS3681 exerts an anti-androgenic effect via two mechanisms of action: pure AR antagonism and AR decreasing activity. It is expected that TAS3681 has a potential to overcome the resistance to current and 2nd-generation therapies targeting AR signaling.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2015
    detail.hit.zdb_id: 2005181-5
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  • 2
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 39, No. 3_suppl ( 2021-01-20), p. 278-278
    Abstract: 278 Background: In clinical practice, the major disadvantage of lenvatinib to treat advanced hepatocellular carcinoma (HCC) is the lack of a posttreatment agent that has shown clear effectiveness. Thus, the establishment of second-line treatment after lenvatinib treatment failure is an urgent clinical issue to be addressed in systemic therapy in patients with advanced HCC. The study used real-world clinical data to explore candidate drugs that might be appropriate as second-line treatment after lenvatinib. Methods: We retrospectively reviewed the medical records of all patients with advanced HCC who received lenvatinib as the first-line agent in seven institutions in Japan between 23 March 2018 and 31 September 2019. Results: During the study period, 178 patients with advanced HCC received lenvatinib as first-line systemic therapy. At the time of lenvatinib administration, most patients were Eastern Cooperative Oncology Group Performance Status grade 0 or 1 (94.9%) and Child–Pugh class A (84.3%). According to the baseline radiological assessments, 25.3% and 36.0% of patients had macrovascular invasion and extrahepatic metastasis, respectively. Overall survival and progression-free survival (PFS) for lenvatinib treatment were 13.3 months (95% CI: 11.5–15.2) and 6.7 months (95% CI: 5.1–8.3), respectively. Of the 151 patients who discontinued lenvatinib, 71 (47.0%) converted to posttreatment. The conversion rates from lenvatinib to a second-line agent and from a second-line agent to a third-line agent were 41.4% and 42.4%, respectively. Based on multivariate analysis, lenvatinib response was defined as complete or partial according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST). Lenvatinib discontinuation due to radiological progression, according to mRECIST, was associated with a significantly higher probability of conversion to posttreatment after lenvatinib. Of the 63 patients who received second-line systemic therapy, 53 (84.1%) were administered sorafenib, with a PFS, response rate (RR), and disease control rate (DCR) of 1.8 months (95% CI: 0.6–3.0), 1.8%, and 20.8%, respectively. According to the Cox proportional hazards regression model, lenvatinib discontinuation due to radiological progression, Child–Pugh class B, and intrahepatic tumor volume 〉 50% at the time of sorafenib administration significantly contributed to a shorter PFS. Of the 22 patients who received regorafenib after lenvatinib discontinuation, five cases were as second-line therapy, and 17 were as third-line therapy. PFS, RR, and DCR for regorafenib treatment were 3.2 months (range, 1.5–4.9 months), 13.6%, and 36.3%, respectively. Conclusions: Sorafenib was not considered a candidate posttreatment agent after lenvatinib, except in a limited number of patients who discontinued lenvatinib without radiological progression. Regorafenib is a potential posttreatment agent after lenvatinib.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2021
    detail.hit.zdb_id: 2005181-5
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
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