肺腺治疗过程（骨、脑）——和亲爱的爸爸一起加油！

特罗凯效果真好，羡慕。

1. Α-生育酚类似物具备抗血管生成和抗肿瘤活性

韩国一个研究团队介绍了一种新型 α-生育酚类似物治疗癌症的结果。该化合物称为 BJ-1301，是 α-生育酚的一种氨基吡啶类似物，对其抑制血管形成和肿瘤生长进行了试验。天然及合成抗氧化物（包括维生素 E）通过激活生长因子受体（如血管内皮生长因子受体，VEGFR）而对活性氧（reactive oxygen species，ROS）产生抗氧化活性，随后抑制血管生成，我们对此进行了调查。结果表明合成抗氧化物 BJ-1301 在鸡胚绒毛膜尿囊膜（chorioallantoic membrane，CAM）中抑制了 VEGFR 诱发血管生成及异种移植人肺癌 A549 细胞 CAM 的肿瘤生长。活体内试验中 VEGFR 诱发和肿瘤血管生成及生长抑制效应超过了天然及合成对照剂 α-生育酚 2,2,5,7,8-五甲基-6-羟色烷（PMC）和 SU-4312（一种酪氨酸激酶抑制剂）。该药还抑制了 ROS 的生成，在活体内或活体外的药效都强于α-生育酚 和 PMC。BJ-1301 并未表现出 SU-4312 那样的 VEGFR-2 抑制活性。现已确定这种作用方式是由 NADPH 氧化酶直接活化剂 12-O-十四酰佛波-13-乙酯抑制 ROS 生成所介导的。总之，BJ-1301 抑制了 CAM 模型中的 VEGF 和肿瘤诱发血管生成及肿瘤生长，其部分作用方式也得以确定（Banskota, S. et al Exp Biol (April 26-30, San Diego) 2014, Abst 842.5）。 专利文献中介绍了 BJ-1301 (WO 2013085340)。

2、PHARMAXIS 公司 LOXL2 抑制剂治疗纤维化前景展现

Pharmaxis 公司目前正在开发同工酶赖氨酰氧化酶样蛋白 2（LOXL2）抑制剂，拟用于口服治疗纤维化和癌症，近日在 ATS 大会上报告了这一系列小分子的首批临床前数据。 LOXL2 是纤维化高度上调所致特发性非纤维化的潜在靶标。一种称为 PXS-5120A 的化合物，针对 LOXL2 的 IC50 值为 10 nM，选择性分别是 LOX 和其他胺氧化酶的 200 倍和 500 倍。还发现良好的全身暴露量和 ADME。在 CCl4 诱发纤维化小鼠模型中，PXS-5120A 是有效的抗纤维化化合物，正如天狼星红和 α-平滑肌肌动蛋白染色所见。博莱霉素诱发肺纤维化小鼠中，使用 Ashcroft 评分测量，使用 5 和 15 mg/kg 剂量的 PXS-5120A 前药、LOXL2 抑制剂 PXS-5129A，明显减轻了肺纤维化，其作用呈剂量依赖性。还观察到胶原评分及 α 平滑肌肌动蛋白染色降低。预计将于 2015 年开始 I 期试验（Schilter, H. et al Int Conf Am Thorac Soc (May 16-21, San Diego) 2014, Abst A6669）。

3、TAKELDA 在日本上市

Takeda Pharmaceutical 公司宣布在日本推出低剂量 (100 mg) 阿司匹林和 Takepron(R)（兰索拉唑 15 mg）组成的复方片剂 Takelda(R)。设计新片剂旨在帮助使用低剂量阿司匹林并有胃或十二指肠溃疡史患者预防发生溃疡，将会减轻使用 Takepron 和低剂量阿司匹林患者的药费负担。Takelda 适用于以下情况并有胃溃疡史或十二指肠溃疡史患者减轻血栓和栓塞风险：心绞痛（慢性稳定心绞痛和不稳定心绞痛）、心肌梗死、缺血性脑血管疾病；或者做过冠状动脉搭桥术或经皮腔内冠状动脉成形术（Takeda Pharmaceutical 新闻稿）。

4、INTERMUNE 公司开发出改善了疗效和安全性的新型吡非尼酮类似物

InterMune 公司的研究人员报道发现了新型吡非尼酮类似物，抗纤维化疗效改善，有望减轻对胃的副作用。 吡非尼酮是获批治疗特发性肺纤维化（IPF）的少数几种抗纤维化药物之一。为了在改善疗效的同时减少用药次数、减轻药费负担和副作用，研究人员通过基于细胞的检测，从抑制成纤维细胞增殖、成纤维细胞分化为成肌纤维细胞到促纤维化细胞因子的合成和释放，调查了一大批有此可能的吡非尼酮类似物。然后再对有希望的所有候选药，进行吸收、分布、代谢和排泄（ADME）、药动学及安全性进行优化。确定了前 2 个候选药 ITMN-30162 和 ITMN-14440 在临床前研究物种中的药物血浆暴露量以及在啮齿动物博来霉素诱发肺纤维化模型中的疗效。基于细胞的检测中，该药的效价改善，如与吡非尼酮相比，转化生长因子 β-1（TGF-β-1）-刺激内皮缩血管肽释放改善高达 > 130 倍，血小板源性生长因子（PDGF）刺激成纤维细胞增殖改善 > 40 倍。小鼠 14 天博来霉素诱发肺纤维化模型中，ITMN-30162 和 ITMN-14440 每日用药一次明显降低了 Ashcroft 评分、肺重量、支气管肺泡灌洗（BAL）细胞计数和 BAL 液中的胶原，还有免疫组化证据证明细胞增殖和成肌纤维细胞蓄积减少。大鼠 28 天博来霉素诱发肺纤维化中，两种候选药使 Ashcroft 评分和胶原染色百分比明显降低，并使非组织中的增殖性基因表达明显减少。总之，ITMN-30162 和 ITMN-14440 的人体估计有效 AUC 提示，以吡非尼酮十分之一的剂量便可取得相当的活性水平，而胃肠道副作用微乎其微，光毒性和非临床药动学提示人体可每日一次或每日两次用药。启动 IND 的开发活性正在进行之中 (Ramphal, J. et al Int Conf Am Thorac Soc (May 16-21, San Diego) 2014, Abst A1953)。


5、FDA 提前批准两种特发性肺纤维化治疗药
    FDA 批准了 Boehringer Ingelheim 公司的生长因子受体酪氨酸激酶抑制剂 Ofev(R)（nintedanib，尼达尼布），用于口服治疗特发性肺纤维化（IPF）。FDA 为尼达尼布颁发了快通道、优先评审、罕用药及突破性疗法认定，获批时间早于《处方药用户费用法案 (PDUFA)》的指定日期（2015 年 1 月 2 日）。批准根据的是 II 期试验 TOMORROW 及相同 III 期试验 INPULSIS-1 和 INPULSIS-2 的结果（ClinicalTrials.gov 标识号分别为 NCT00514683、NCT01335464 和 NCT01335477）。这些试验包括对 40 岁以上 IPF 患者每日使用两次 150 mg 尼达尼布和安慰剂治疗进行比较。主要终点是 1 年后用力肺活量（FVC）的变化。TOMORROW 中，尼达尼布和安慰剂组的 FVC 分别降低 60 和 191 mL/年。INPULSIS-1 中，尼达尼布和安慰剂组的 FVC 分别降低 115 和 240 mL/年。INPULSIS-2 中，尼达尼布和安慰剂组的 FVC 分别降低 114 和 207 mL/年。TOMORROW 和 INPULSIS-2 表明，尼达尼布与安慰剂相比，急性 IPF 加重风险明显降低，具有统计学意义。但 III 期试验中，尼达尼布和安慰剂之间的全因死亡率无明显差异。Boehringer Ingelheim 预计在 10 日之内将本药投放市场。妊娠期间或中重度肝功能损害患者，建议不要使用尼达尼布。
    FDA 还批准了 Roche 子公司 InterMune 所产的 IPF 口服治疗药 Esbriet(R) （pirfenidone，吡非尼酮）。FDA 为吡非尼酮颁发了快通道、优先评审、罕用药及突破性疗法认定，获批时间早于PDUFA 指定日期（2014 年 11 月 23 日）。这项批准依据的是 III 期试验 ASCEND、CAPACITY 1 和 CAPACITY 2 的结果（ClinicalTrials.gov 标识号分别为 NCT01366209、NCT00287729 和 NCT00287716）。这些试验包括对 40 - 80 岁 IPF 患者每日使用三次 801 mg 吡非尼酮和安慰剂治疗进行比较。ASCEND 中，吡非尼酮组出现用力肺活量（FVC）下降延迟的患者人数比安慰剂组多（见 2014 年 2 月 26 日《汤森路透药物新闻》）。该药于 2011 年在欧盟获批（Boehringer Ingelheim 新闻稿；Roche 新闻稿；FDA 新闻稿）。

6、中国批准 EPIDAZA 治疗外周 T 细胞淋巴瘤
Chipscreen Biosciences 公司的 Epidaza(R)（chidamide）获中国监管批准，这是世界首个口服给药的亚型选择性组蛋白脱乙酰基酶 (HDAC) 抑制剂，用于治疗复发性或难治性外周 T 细胞淋巴瘤 (PTCL)。Chidamide 可特异性针对 I 类 HDAC 的亚型 1、2 或 3 及 IIb 类 HDAC 的亚型 10。中国和西方国家的 PTCL 亚型分布存在显著差异，侵袭性淋巴结外自然杀伤/T 细胞淋巴瘤鼻腔型 (ENKL) 是中国人口的主要亚型。多项临床试验正在对 Chidamide 单药或联合化疗药治疗各种血液或实体癌症进行研究（Chipscreen Biosciences 新闻稿）。

Cotargeting of Epidermal Growth Factor Receptor and PI3K Overcomes PI3K–Akt Oncogenic Dependence in Pancreatic Ductal Adenocarcinoma

Abstract
Purpose: PI3K–Akt is overexpressed in 50% to 70% of pancreatic ductal adenocarcinoma (PDAC). The hypothesis of this study is that PI3K and EGFR coinhibition may be effective in PDAC with upregulated PI3K–Akt signaling.

Experimental Design: Multiple inhibitors were tested on five PDAC cell lines. EGFR inhibitor (EGFRi)–resistant cell lines were found to have significantly overexpressed AKT2 gene, total Akt, and pAkt. In vitro erlotinib-resistant (ER) cell models (BxPC-ER and PANC-ER) with highly constitutively active PI3K–Akt were developed. These and their respective parent cell lines were tested for sensitivity to erlotinib, IGFIR inhibitor NVP-AEW541 (AEW), and PI3K-alpha inhibitor NVP-BYL719 (BYL), alone or in combination, by RTK-phosphoarray, Western blotting, immunofluorescence, qRT-PCR, cell proliferation, cell cycle, clonogenic, apoptosis, and migration assays. Erlotinib plus BYL was tested in vivo.

Results: Erlotinib acted synergistically with BYL in BxPC-ER (synergy index, SI = 1.71) and PANC-ER (SI = 1.44). Treatment of ER cell lines showing upregulated PI3K–Akt with erlotinib plus BYL caused significant G1 cell-cycle arrest (71%, P < 0.001; 58%, P = 0.003), inhibition of colony formation (69% and 72%, both P < 0.001), and necrosis and apoptosis (75% and 53%, both P < 0.001), more so compared with parent cell lines. In primary patient-derived tumor subrenal capsule (n = 90) and subcutaneous (n = 22) xenografts, erlotinib plus BYL significantly reduced tumor volume (P = 0.005). Strong pEGFR and pAkt immunostaining (2+/3+) was correlated with high and low responses, respectively, to both erlotinib and erlotinib plus BYL.

Conclusion: PDAC with increased expression of the PI3K–Akt pathway was susceptible to PI3K–EGFR coinhibition, suggesting oncogenic dependence. Erlotinib plus BYL should be considered for a clinical study in PDAC; further evaluation of pEGFR and pAkt expression as potential positive and negative predictive biomarkers is warranted. Clin Cancer Res; 20(15); 4047–58. &copy;2014 AACR.

http://clincancerres.aacrjournals.org/content/20/15/4047.abstract

1、Phase I Trial of Hu5F9-G4（CD47）
http://clinicaltrials.gov/ct2/show/study/NCT02216409

2、Bavituximab，一个嵌合IgG1 mAb靶向磷脂酰丝氨酸，在美国对NSCLC给予快速通道指定。联合多西紫杉醇在做三期。anti-PS

http://www.nature.com/ncomms/201 ... ms6073.html#figures

关键字：EGFR、invivo小鼠、糖皮质激素、昼夜抑制

Penbro（PD-L1）临床结果（ESMO2014）

Almost 60% of patients with advanced non–small cell lung cancer (NSCLC) had tumor shrinkage when treated with the PD-L1 inhibitor pembrolizumab, results of a preliminary clinical trial showed. The objective response rate was 21% among 236 evaluable patients, which included a combination of previously treated and untreated patients. Previously untreated patients had an objective response rate of 26%. Analysis of response by PD-L1 expression in a subgroup of patients showed a 37% response rate in patients whose tumors exhibited high PD-L1 expression. High PD-L1 expression was associated with a 48% reduction in the hazard for death or progression and a 41% reduction in the survival hazard, according to a report presented at the 2014 ESMO Congress. “We observed robust antitumor activity in both treatment-na&#239;ve and previously treated advanced non–small cell lung cancer,” said Edward B. Garon, MD, director of thoracic oncology at the Jonsson Comprehensive Cancer Center and the University of California, Los Angeles. “Activity was observed for all doses and schedules evaluated. Responses are durable, and treatment with pembrolizumab was associated with a manageable safety and toxicity profile.” Planning has begun for a follow-up study to validate the PD-L1 cutpoint for strong and weak expression, he added. Pembrolizumab is a humanized monoclonal antibody against PD-1 and is in development for use in a variety of solid tumors. Previous studies demonstrated promising antitumor activity in melanoma, NSCLC, head and neck cancer, gastric cancer, and urothelial cancer, said Garon. The antibody has FDA approval for use in unresectable metastatic melanoma. Garon reported data from a phase 1b trial limited to patients with advanced NSCLC. The PD-L1 status of all patients had been determined, and investigators defined a PD-L1 positive tumor as immunohistochemical (IHC) staining of at least 1% of the tumor. Eligible patients had received no systemic steroid therapy and had no active autoimmune disease and no active brain metastases. EGFR mutation or ALK rearrangement disqualified patients with no previous treatment but not those with a treatment history, including disease progression on the most recent tyrosine kinase inhibitor. The trial involved a total of 307 patients, including expansion cohorts. The primary endpoint was objective response rate as determined by RECIST criteria. A secondary response measure was investigator-assessed immune-mediated response. Treatment with pembrolizumab continued until disease progression, unacceptable toxicity, or death. Response data came from 262 evaluable patients. The cohort had a median age of 65, and men and women accounted for equal proportions of the population. Almost 70% of the patients had ECOG performance status of 1, and the rest had ECOG 0 or status was unknown. Tumor genomic data showed EGFR mutation in 16%, KRAS mutation in 26%, and ALK translocation in 3%. Two thirds of the patients were former smokers, and 28% had never smoked. The most frequent adverse event (all grades) was fatigue (20%). No other adverse event of any grade affected ≥9% of patients, with grade 3-5 adverse events occurring in <1% of patients. Garon reported that 58% of the patients had some degree of tumor shrinkage by RECIST criteria. Subgroup analysis showed consistent response rates in most cases. Smoking status represented a notable exception, as current and former smokers had an objective response rate of 27% versus 9% among never smokers. The response rate was 23% in patients with PD-L1–positive tumors and 9% in those with PD-L1–negative tumors. In general, investigator-assessed antitumor activity was consistent with assessments by RECIST criteria. The response rate for the entire cohort was 23%. Kaplan-Meier survival analyses showed a median progression-free survival (PFS) of 27 weeks and a 24-week PFS of 51% among previously untreated patients. Treatment-experienced patients had a median PFS of 10 weeks and a 24-week PFS of 26%. Pooled data for all patients yielded a median overall survival (OS) of 8.2 months and a 6-month OS of 64%. Assessment of PD-L1 expression by IHC staining and the 22C3 antibody has shown that tumor PD-L1 expression does not correlate with response, said Garon. Investigators in the pembrolizumab trial performed a separate analysis, using a different IHC assay from a different vendor but with the same 22C3 antibody. Investigators defined strong PD-L1 expression as at last 50% membranous staining in tumor cells and weak expression as 1% to 49% staining.
The analysis showed a 37% response rate among 41 patients with strongly positive tumors, 17% for patients with weakly positive tumors, and 10% for PD-L1 negative tumors.

http://www.onclive.com/conferenc ... s-in-Advanced-NSCLC

http://oncologydiscovery.com/201 ... txg17I5pfFq0g%3D%3D

BRD4 JQ1

药物临床试验登记和信息公示平台
http://www.chinadrugtrials.org.cn/

乳铁蛋白区别：

Symbiotics, Lactoferrin, 60 Capsules 含铁：
其他成分
牛初乳，米粉，抗坏血酸棕榈酸酯，二氧化硅，中链甘油三酯，向日葵卵磷脂，明胶（胶囊）。
包含：牛奶

Jarrow：
其他成分
纤维素，硬脂酸镁（植物来源）和二氧化硅，明胶（胶囊）。
包含：牛奶（乳清）。
无麦，无麸质，无大豆，无卵，无鱼/贝类，花生无/树坚果。