Abstract A056: Is non-mutated GPR89A protein a potential drug target in prostate cancer?
0
Citation
0
Reference
10
Related Paper
Abstract:
Abstract Mutated genes as drug targets to treat cancer are a widely known concept; however, the effect is moderate. Targeting nonmutated genes is an alternative and probably has potential to benefit patients. GPR89A, as a nonmutated protein in prostate cancer, was evaluated as a drug target in this project. Data showed that GPR89A knockdown could induce high cancer cell death rate. Combination use of GPR89A siRNA and docetaxel triggered synergism effect, which implicates a possibility that GPR89A inhibitors could be used together with docetaxel. The high-throughput screening discovered 39 drug candidates that could reduce cancer cell viability and GPR89A expression simultaneously. These findings highlight the importance of nonmutated genes in cancer progression. Targeting nonmutated genes, e.g., GPR89A, should be evaluated further to find significant association between these genes/proteins and cancers. Citation Format: Yuanjun Ma, Yanling Liu, Sten Nilsson, Chunde Li. Is non-mutated GPR89A protein a potential drug target in prostate cancer? [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A056.Previous pharmacokinetic studies with docetaxel have mostly used 3-weekly (75 mg/m2 and 100 mg/m2) or weekly regimens (35–40 mg/m2). The pharmacokinetics and radiosensitizing efficacy of weekly 20 mg/m2 docetaxel, has however not been well characterized. We examined the pharmacokinetics of weekly docetaxel when administered with concurrent radiotherapy and compared the results with a 3-weekly 100 mg/m2 regimen. Thirty-four patients with non small cell lung cancer (NSCLC) were included in this study, 19 receiving 100 mg/m2 docetaxel 3-weekly as single therapy, and 15 receiving 20 mg/m2 docetaxel weekly with concurrent radiotherapy. A newly developed HPLC method was used for measuring docetaxel levels, capable of quantifying docetaxel in plasma down to the nanomolar level. The HPLC method showed detectable concentrations of docetaxel in plasma even after 72 hours. In the present study we have demonstrated that median docetaxel plasma levels of 3 nM can be obtained 72 hours after a dose of 20 mg/m2. The pharmacokinetics of docetaxel is characterized by great inter-individual variability and at some time points plasma concentrations for 20 mg/m2 and 100 mg/m2 docetaxel were overlapping. Extrapolation of these results indicates that radio sensitizing docetaxel concentrations may be present for as long as 1 week, thus supporting the use of 20 mg/m2 weekly docetaxel.
Regimen
Cite
Citations (45)
132 Background: Patients that receive docetaxel are observed closely for HSRs. Severe HSRs have been reported in patients premedicated with corticosteroids. The rate of allergic reactions reported in the TAX 327 trial (n=332) was 8% (any grade) and 1% (grade 3/4). In TAX 327 treatment was stopped after a total of 10 cycles of docetaxel. A recent trial conducted at the NCI has included patients treated with docetaxel-based therapy until radiographic progression with no cap on total dose or cycle number. Most patients have had significantly more than 10 cycles (median greater than 16 with a range of 1 to 48; however, some cycles did not include docetaxel). Given the increased incidence of HSR to docetaxel on our protocols, we developed guidelines for the clinical management of HSRs to docetaxel. Methods: We reviewed the literature on taxane HSRs and developed a 4-step clinical management guideline for the prevention and treatment of HSRs to docetaxel. Our guidelines utilize increasing amounts of H1/H2 antihistamines, corticosteroids, slower infusion rates of docetaxel, and/or decreasing concentrations of docetaxel. Results: From August 2009 to present, 63 mCRPC patients have been treated with docetaxel-based therapy. Twenty-three patients (37%) have experienced a HSR to docetaxel. HSRs initially occurred at cycle 1 (17%), cycle 2 (48%), cycle 3 (17%), cycle 4 (n=2), cycle 14 (n=1), cycle 16 (n=1). All patients were re-challenged with docetaxel using our 4-step clinical management guideline approach. Ten patients continued docetaxel without further HSRs. The remaining 13 patients continued to experience HSRs but were able to safely complete each infusion of docetaxel. No patients required discontinuation of therapy. Of the 23 patients with HSRs, 21 received more than 10 cycles of therapy with a median of 17 and a range of 1 to 38. Conclusions: Patients with mCRPC disease that is taxane sensitive and who experience HSR to docetaxel can continue to receive docetaxel safely. Most of these patients demonstrated a continued PSA, clinical, and radiographic response to therapy.
Taxane
Guideline
Cite
Citations (0)
Taxanes and anthracyclines are active against breast cancer. In this study we investigated the combined antitumor activity of these drugs, with particular regard to sequence-dependency.The combined antitumor activity of docetaxel and tetrahydropyranyladriamycin (THP) against two human breast cancer xenografts was assessed using an in vitro histoculture drug-response assay. The sequence-dependency of the combined cytotoxicity was evaluated by isobologram.A synergistic antitumor activity of combined docetaxel + THP was exhibited against the R-27 xenograft when docetaxel was given first or simultaneously with THP. However, this synergism was diminished when THP was used before docetaxel. While an additive effect of combined docetaxel + THP was observed against MX-1 xenograft when docetaxel was given first or simultaneously with THP, this effect was not marked using the THP/docetaxel sequence.Docetaxel increased the antitumor activity of THP, but only when administered before or simultaneously with THP.
Cite
Citations (1)
Docetaxel is an important anti-microtubule agent used to treat a variety of solid tumors, including breast cancer; notably, docetaxel-containing regimens improve outcomes for patients in metastatic, adjuvant, and neoadjuvant settings. However, the effectiveness of docetaxel in clinical practice can be compromised by suboptimal management of side effects. Here, we report two cases of docetaxel-based chemotherapy regimens in patients who exhibited invasive ductal breast cancer and underwent two different clinical treatment approaches. A 58-year-old postmenopausal female received salvage treatment with 8 cycles of docetaxel (67 mg/m2), and a 74-year-old female received 1 cycle of docetaxel (100 mg/m2). The two patients exhibited considerable hearing loss two days later. Of note, both patients had no hearing loss symptoms prior to docetaxel. Thus, ototoxicity may be a side effect of docetaxel that should be considered during treatment.
Ototoxicity
Cite
Citations (9)
我们的学习的目的是与先进 non-small-cell 肺癌症(NSCLC ) 为老病人作为单个化疗评估 docetaxel 的临床的功效和副作用的目的。化疗天真的有先进 NSCLC 的 42 个老病人在这被注册的方法学习。在 70 mg/m2 的剂量的 Docetaxel 每 21 天作为一个周期静脉内地被管理，每个病人收到了 2 鈥吗？周期。所有病人被跟随在上面直到疾病进行了或病人们死了。在 42 个病人，之中的结果 40 能被评估， 1 完全的回答(CR ) ， 9 部分反应(PR ) ， 13 稳定的疾病(SD ) ， 17 进步疾病(PD ) 。全面反应率(CR + PR ) 是 35% ，疾病控制率(CR +PR + SD ) 是 57.5% 。进行的中部的时间(TTP ) 是 4.2 个月，中部的幸存时间是 6.1 个月， 1 年的幸存率是 35.8% 。主要毒性是 myelosuppression 和减少的血小板。为有先进 NSCLC 的老病人的结论单个代理人 docetaxel 是有低毒性水平的一条有效、容忍得好的化学疗法的途径。关键词 docetaxel - 先进非小的房间肺癌症 - 年长的病人
Cite
Citations (0)
62 歳，男性。4 型胃癌に対し胃全摘術を施行した。T 3， N 1， H 0， P 0， M 0， CYX であり，組織学的にはpoorly differentiated adenocarcinoma， ss， INF γ，ly2， v 2， n 2 であった。術後16 日目からTS-1 100mg/day を4 週投与2 週休薬を1 クールとして内服を開始，2 クールの投与を行った。投与終了ごろより腹部膨満感が出現し，CT を施行したところ著明な腹水の貯留を認めた。CEA は13.5ng/ml と上昇を示し，腹膜再発と診断した。外来にてdocetaxel40mg/body3 週投与1 週休薬を1 クールとして化学療法を開始した。CEA は6 クール目開始時には正常化した。CT でも腹水は消失しており，他の転移も認めなかったためCR と判定した。術後2 年，腹膜再発後1 年8 か月，10 クールのdocetaxel 投与終了後1 年経過した現在，無治療で観察中であるが再燃の徴候を認めていない。docetaxel の休薬や減量は不要であった。docetaxel のweekly 投与は安全に外来で施行可能なレジメンであり，胃癌領域でもその有効性が報告されている。本症例では胃癌に対して奏効率の高いTS-1 を投与中に発症した腹膜再発症例に対してdocetaxel が著効を示した。TS-1 無効例に対する治療についての検討は少ないが，FU 系の薬剤とは作用機序が異なることもあり，docetaxel のweekly 投与は有用な治療法となり得ると思われた。
Cite
Citations (0)
Docetaxel is a new semi-synthetic anticancer agent derived from bacatin III of the needles of the European yew Taxus baccata. Docetaxel has a novel mechanism of action since it binds to tubulin inducing its polymerization and promoting stable microtubule formation. Several differences exist between docetaxel and paclitaxel: (i) broader activity of docetaxel against freshly explanted human tumors than paclitaxel; (ii) a 2-fold higher affinity than paclitaxel; (iii) 2.5-fold more potent than paclitaxel as an inhibitor of cell replication and (iv) docetaxel acts at the S-phase whereas paclitaxel at the G(2)/M phases of the cell cycle. Preclinical and phase II studies revealed that docetaxel is active against NSCLC. In chemotherapy-na ve patients with NSCLC response rates ranged from 19% to 54% with a median duration of survival ranging from 6.3 months to 11 months, and 1-year survival ranging from 21% to 71%. Docetaxel as single agent provided a survival as well as a clinical benefit over BSC in untreated patients with NSCLC. Docetaxel has been efficiently combined with cisplatin (ORR 33%-46%), carboplatin (ORR 30%-48%), vinorelbine (ORR 20%-51%), gemcitabine (ORR 37%-47%), with a median survival ranging from 5-14 months. A preliminary analysis of a multicenter randomized trial comparing docetaxel/CDDP with docetaxel/gemcitabine revealed that the two regimens had comparable activity in terms, of response rates, duration of response, TTP and overall survival; however, the docetaxel/gemcitabine combination has a most favourable toxicity profile compared to docetaxel/CDDP. Docetaxel has also demonstrated radiosensitizing properties and encouraging results have been achieved in combination with irradiation. Finally, docetaxel has shown an important activity in previously-treated patients with NSCLC with ORR ranging from 16% to 25% with a median survival ranging from 7.2 months to 10.5 months. Randomized trials revealed that second-line docetaxel confers a survival benefit over either BSC or ifosfamide/vinorelbine in pretreated patients with NSCLC.
Carboplatin
Vinorelbine
Taxane
Cite
Citations (18)
e20595 Background: Docetaxel is currently approved in non-small cell lung Cancer (NSCLC) after a failure of first line chemotherapy. However, docetaxel has an unfavorable toxicity profile that limits its use. A docetaxel-containing regimen with an improved safety profile would therefore be attractive. Plinabulin, a first-in-class small molecule vascular disruptive agent with potent immuno-oncology effects, is being developed in combination with docetaxel to address this need. Methods: We conducted a Phase 2 study comparing the safety and efficacy of the plinabulin /docetaxel combination (n=90) with docetaxel alone (n=73) in patients with NSCLC entering 2nd or 3rd line therapy. Plinabulin was given intravenously at 20 mg/m2 (n= 40) or 30 mg/m2 (n=50) and docetaxel at 75 mg/m2(n=73). Results: Efficacy results of this study were presented at ASCO 2014. Baseline characteristics for age, gender, ECOG performance score, histology and disease status were comparable between groups. The plinabulin/docetaxel combination improved overall survival, in a subset of patients with large tumors (> 3 cm; HR=0.758, p =0.36), and also had duration of response benefit over docetaxel alone (12.7 vs 1.5 months; P<0.05). We are reporting on the safety profile of plinabulin/ docetaxel combination. Conclusions: In this Phase 2 study, the plinabulin/docetaxel combination mitigated some of the docetaxel toxicities. Most importantly it improved docetaxel dose intensity. The neutropenia benefit was likely due to plinabulin-induced release of cytokines such as IL-1 and IL-6 (data obtained in in-vitro plinabulin studies), which are known to increase neutrophil count. In addition, preliminary results indicated a potential efficacy benefit of the plinabulin/docetaxel combination over docetaxel alone. A global Phase 3 trial with the plinabulin/docetaxel combination vs docetaxel alone is currently underway in the US, China, Australia and New Zealand. Clinical trial information: NCT00630110.Adverse events. Plinabulin/Docetaxel Docetaxel Grade 3/4 Neutropenia * 7 % 25 % Use of G-CSF * 14 % 29 % Sepsis 0 % 3.6 % Severe infections 0 % 3.6 % Asthenia * 13 % 28 % Docetaxel dose reduction due to toxicity * 6 % 20 % *p<0.01; Plinabulin/docetaxel combination vs docetaxel alone.
Regimen
Cite
Citations (3)
Cite
Citations (44)
Taxane
Clinical Practice
Cite
Citations (37)