Antitumor activity of rapamycin in a Phase I trial for patients with recurrent PTEN-deficient glioblastoma.
Antitumor activity of rapamycin in a Phase I trial for patients with recurrent PTEN-deficient glioblastoma.
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雷帕霉素在I期试验中针对复发性PTEN缺陷型胶质母细胞瘤患者的抗肿瘤活性。
DOI：
10.1371/journal.pmed.0050008
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发表时间：
2008-01-22
期刊：
影响因子：
15.8
通讯作者：
Sawyers, Charles L.
中科院分区：
文献类型：
--
作者：
Cloughesy, Tim F.;Yoshimoto, Koji;Nghiemphu, Phioanh;Brown, Kevin;Dang, Julie;Zhu, Shaojun;Hsueh, Teli;Chen, Yinan;Wang, Wei;Youngkin, David;Liau, Linda;Martin, Neil;Becker, Don;Bergsneider, Marvin;Lai, Albert;Green, Richard;Oglesby, Tom;Koleto, Michael;Trent, Jeff;Horvath, Steve;Mischel, Paul S.;Mellinghoff, Ingo K.;Sawyers, Charles L.
癌症开发界有很多讨论，即如何将分子工具纳入早期临床试验中，以评估目标调节，衡量抗肿瘤活性并丰富更可能受益的患者的临床试验人群。分子集中的临床研究提供了对最佳生物剂量和患者群体的早期定义的希望。
基于临床前证据表明，在染色体10（PTEN）损失上缺失磷酸酶和Tensin同源物，使肿瘤抑制了雷帕霉素哺乳动物靶标（MTOR），我们进行了一项概念证明的I阶段I期I阶段I期Rapamycin的NeoAdjuvant试验，对复发性胶质细胞瘤患者进行了NeoAdjuvant试验。 ，其肿瘤缺乏抑制肿瘤的表达。雷帕霉素需要MTOR抑制肿瘤组织，并评估雷帕霉素在PTEN缺陷型胶质母细胞瘤中的抗增殖活性。通过减少的核糖体S6蛋白磷酸化）大大不同（通过KI-67染色测量） 1周雷帕霉素治疗后14例患者中有7例降低，并且与MTOR抑制的大小有关（P = 0.0047，Fisher精确测试），但与肿瘤内雷帕霉素浓度无关。事实表明，对生化MTOR抑制的临床耐药性不是细胞中的，雷帕霉素治疗导致七名患者的Akt激活负面反馈的丧失，这种激活与手术后雷帕霉素治疗期间较短的产生时间有关（P <0.05，Logrank测试）。
雷帕霉素在PTEN缺乏胶质细胞瘤中具有抗癌活性，并保留进一步的临床研究，或与PI3K途径抑制剂结合使用。 。
试用注册：http：//www.clinicaltrials.gov（＃NCT00047073）。
在I期临床试验中，Charles Sawyers及其同事研究了雷帕霉素在缺乏PTEN缺陷型胶质母细胞瘤患者中的作用。
胶质母细胞瘤是大脑的高度恶性肿瘤，与其他分子变化相比，它可以导致多种肿瘤。靶向肿瘤的特定分子变化试验包括各种不同的患者和具有不同遗传变化的肿瘤，可能是测试目标治疗的有效性的不适当方法。
在大约40％的胶质母细胞瘤患者中已经确定的一种特定变化是一种称为PTEN的基因，该基因是抑制肿瘤基因的，当时PTEN被灭活。被称为MTOR抑制剂的药物 - 一种是雷帕霉素（商业名称Sirolimus）。目前，正在针对其他癌症和作为免疫抑制剂的药物进行活跃的药物。
这是一项I期研究，即在人类中进行的药物研究的最早类型 - 旨在研究雷帕霉素在一组选择的患者中的安全性，这些患者在复发胶质母细胞瘤后正在接受手术，肿瘤及其肿瘤的安全性。作者还没有表达PTEN。可以预测患者是否对雷帕霉素有反应。
总共15例患者在手术前用不同剂量治疗雷帕霉素，然后在手术后再次治疗，直到有证据表明肿瘤正在进展。需要治疗的不良反应。与其中两个患者的抑制作用有关。由于该药物无法穿透肿瘤，因此在某些患者中，雷帕霉素的不幸作用是引起另一种细胞内蛋白的激活发生了，患者在手术和疾病的恢复之间的时间较短。
在本阶段试验中的详细分子研究使得对靶向药物的工作方式有更好的了解。但是，要穿透肿瘤并抑制MTOR。第二道路。
请通过此摘要的在线版本访问这些网站，网址为http://dx.doi.org/10.1371/journal.pmed.0050008。
美国国家癌症研究所提供有关癌症各个方面的信息（英文和西班牙语）
英国慈善癌症返回提供有关脑肿瘤的信息
Wikipedia在MTOR上有一个页面（请注意，Wikipedia是一个免费的在线百科全书，任何人都可以编辑；有几种语言可用）
There is much discussion in the cancer drug development community about how to incorporate molecular tools into early-stage clinical trials to assess target modulation, measure anti-tumor activity, and enrich the clinical trial population for patients who are more likely to benefit. Small, molecularly focused clinical studies offer the promise of the early definition of optimal biologic dose and patient population. Based on preclinical evidence that phosphatase and tensin homolog deleted on Chromosome 10 (PTEN) loss sensitizes tumors to the inhibition of mammalian target of rapamycin (mTOR), we conducted a proof-of-concept Phase I neoadjuvant trial of rapamycin in patients with recurrent glioblastoma, whose tumors lacked expression of the tumor suppressor PTEN. We aimed to assess the safety profile of daily rapamycin in patients with glioma, define the dose of rapamycin required for mTOR inhibition in tumor tissue, and evaluate the antiproliferative activity of rapamycin in PTEN-deficient glioblastoma. Although intratumoral rapamycin concentrations that were sufficient to inhibit mTOR in vitro were achieved in all patients, the magnitude of mTOR inhibition in tumor cells (measured by reduced ribosomal S6 protein phosphorylation) varied substantially. Tumor cell proliferation (measured by Ki-67 staining) was dramatically reduced in seven of 14 patients after 1 wk of rapamycin treatment and was associated with the magnitude of mTOR inhibition (p = 0.0047, Fisher exact test) but not the intratumoral rapamycin concentration. Tumor cells harvested from the Ki-67 nonresponders retained sensitivity to rapamycin ex vivo, indicating that clinical resistance to biochemical mTOR inhibition was not cell-intrinsic. Rapamycin treatment led to Akt activation in seven patients, presumably due to loss of negative feedback, and this activation was associated with shorter time-to-progression during post-surgical maintenance rapamycin therapy (p < 0.05, Logrank test). Rapamycin has anticancer activity in PTEN-deficient glioblastoma and warrants further clinical study alone or in combination with PI3K pathway inhibitors. The short-term treatment endpoints used in this neoadjuvant trial design identified the importance of monitoring target inhibition and negative feedback to guide future clinical development. Trial registration: http://www.ClinicalTrials.gov (#NCT00047073). In a Phase I clinical trial Charles Sawyers and colleagues investigated the role of rapamycin in patients with PTEN-deficient glioblastoma. Glioblastoma is a highly malignant tumor of the brain. As with other tumors, it can result from a number of different molecular changes. Traditional chemotherapy does little more than contain these tumors, and cannot cure it. An alternative approach to the treatment of such tumors is to target specific molecular changes in the tumor. Obviously such targeted treatment will work only in patients who have the specific molecular defect being targeted. Hence, traditional clinical trials, which include a large variety of different patients and tumors with different genetic changes, may be an inappropriate way to test how effective targeted treatments are. One specific change that has been identified in around 40% of patients with glioblastoma is inactivation of a gene known as PTEN, which acts as a tumor suppressor gene. When PTEN is inactivated it has previously been shown to make cells more sensitive to a class of drugs known as mTOR inhibitors—one of which is rapamycin (trade name Sirolimus). mTOR is a protein that is involved in the regulation of a number of cellular processes including growth and proliferation. Drugs active against mTOR are currently being tested for effectiveness against other cancers and as immunosuppressive agents. This was a Phase I study—that is, the earliest type of a drug study that is done in humans—which aimed to look at the safety of rapamycin in a selected group of patients who were undergoing surgery after recurrence of glioblastoma, and whose tumors did not express PTEN. In addition, the authors also wanted to assess the feasibility of incorporating detailed molecular studies of the action of this drug into such a Phase I study and whether these molecular studies could predict whether patients were more or less likely to respond to rapamycin. A total of 15 patients were treated with rapamycin at differing doses for one week before surgery and then again after surgery until there was evidence that the tumors were progressing. There was no evidence of very severe toxicity in any of the patients, though there were some adverse effects that required treatment. When samples from the patients were tested after surgery, seven of them showed a reduction in how rapidly the tumor cells divided, and this reduction was associated with how much inhibition there was of mTOR. Two of these patients showed evidence on scans of a reduction in tumor mass. Cells from tumors that appeared resistant to rapamycin in patients were sensitive to rapamycin in tissue culture, suggesting that the lack of response was due to the drug not being able to penetrate the tumor. A second, unfortunate effect of rapamycin was to cause activation of another intracellular protein, Akt, in some patients; when this activation occurred, patients had a shorter time between surgery and a return of their disease. The detailed molecular studies within this Phase I trial allow a better understanding of how this targeted drug works. These findings suggest that the rapamycin can reduce the proliferation rate of glioblastoma cells, and that this reduction appears to be related to how well the drug is able to penetrate the tumor and inhibit mTOR. However, in some patients the activation of a second pathway can speed up the course of the disease, so further trials should incorporate inhibitors of this second pathway. Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050008. The US National Cancer Institute provides information on all aspects of cancer (in English and Spanish) The UK charity Cancerbackup provides information on brain tumors Wikipedia has a page on mTOR (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
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影响因子：
4.8
作者：
Kovacina, KS;Park, GY;Roth, RA
通讯作者：
Roth, RA
DOI：
10.1073/pnas.171060098
发表时间：
2001-08-28
影响因子：
11.1
作者：
Podsypanina, K;Lee, RT;Parsons, R
通讯作者：
Parsons, R
影响因子：
82.9
作者：
Majumder, PK;Febbo, PG;Sellers, WR
通讯作者：
Sellers, WR
影响因子：
50.3
作者：
Fan, Qi-Wen;Knight, Zachary A.;Weiss, William A.
通讯作者：
Weiss, William A.
DOI：
10.1073/pnas.171076798
发表时间：
2001-08-28
影响因子：
11.1
作者：
Neshat, MS;Mellinghoff, IK;Sawyers, CL
通讯作者：
Sawyers, CL