生物谷：美國(guó)德州大學(xué)西南醫(yī)學(xué)院的研究人員發(fā)表于10月版的Cancer Research雜志的研究報(bào)告稱將藥物BEZ235和低劑量輻射(low-dose radiation)結(jié)合能夠阻斷PI3K蛋白的活性,。研究人員將這種新的治療方法應(yīng)用到移植人類非小細(xì)胞肺癌(non-small cell lung cancer, NSCL)的老鼠上,，發(fā)現(xiàn)用BEZ235藥物治療過的小鼠和未用藥治療的老鼠相比,，前者的腫瘤出現(xiàn)明顯縮小,。而將BEZ235與放射性治療相結(jié)合,，發(fā)現(xiàn)這種方法可以使腫瘤完全消失,。
NSCL癌細(xì)胞內(nèi)在K-RAS基因上攜帶多個(gè)突變,，而K-RAS突變體能夠激活調(diào)節(jié)腫瘤生長(zhǎng)的信號(hào)蛋白(signaling proteins),PI3K即為其中一種蛋白,，PI3K蛋白可修復(fù)腫瘤細(xì)胞的DNA損傷,。因此研究人員認(rèn)為PI3K可作為一種潛在的抗癌藥物及靶標(biāo),。目前,，臨床試驗(yàn)中所使用的藥物BEZ235就是以PI3K和另一種信號(hào)蛋白mTOR為腫瘤治療靶標(biāo),。
在開始測(cè)試BEZ235單獨(dú)使用的有效性實(shí)驗(yàn)中,，研究人員發(fā)現(xiàn)該藥物不但能夠抑制活體培養(yǎng)肺癌細(xì)胞的增殖,，還能抑制患肺癌老鼠的腫瘤生長(zhǎng),。
隨后,，研究人員將經(jīng)BEZ235處理過的癌細(xì)胞置于低劑量輻射中，這種低劑量輻射只會(huì)使細(xì)胞內(nèi)DNA出現(xiàn)斷裂但不會(huì)影響細(xì)胞生存,，當(dāng)DNA出現(xiàn)損傷后,，癌細(xì)胞可通過PI3K信號(hào)通路進(jìn)行修復(fù)。研究人員發(fā)現(xiàn),，當(dāng)BEZ235阻斷PI3K信號(hào)蛋白,，MSCL腫瘤細(xì)胞逐漸凋亡。
研究人員稱,，該實(shí)驗(yàn)的下一步將是在臨床上利用BEZ235或類似藥物治療NSCL腫瘤患者,。（生物谷Bioon.com）
更多放射加藥物癌癥治療研究：
Cancer Research：改善腫瘤中血管狀況有助于癌癥放療
JAMA：切除術(shù)后放射療法可增前列腺癌患者存活率
Int.J.Hyp.：熱療加化療治療癌癥效果更好
PLoS ONE：癌癥治療新技術(shù)—放射免疫治療
生物谷推薦原始出處：
Cancer Research 69, 7644, October 1, 2009.doi: 10.1158/0008-5472.CAN-09-0823
Dual Phosphoinositide 3-Kinase/Mammalian Target of Rapamycin Blockade Is an Effective Radiosensitizing Strategy for the Treatment of Non–Small Cell Lung Cancer Harboring K-RAS Mutations
Georgia Konstantinidou1,4, Erik A. Bey2, Andrea Rabellino1, Katja Schuster1, Michael S. Maira5, Adi F. Gazdar3, Augusto Amici4, David A. Boothman2 and Pier Paolo Scaglioni1
1 Division of Hematology and Oncology, 2 Simmons Comprehensive Cancer Center, and 3 Hamon Center for Therapeutic Oncology Research, Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas; 4 Genetic Immunization Laboratory, Department of Molecular, Cellular and Animal Biology, University of Camerino, Camerino, Italy; and 5 Novartis Institutes for Biomedical Research, Oncology Disease Area, Novartis Pharma AG, Basel, Switzerland
Requests for reprints: Pier Paolo Scaglioni, Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, ND3120A, Dallas, TX 75390.
Non–small cell lung cancer (NSCLC) is a leading cause of cancer-related death worldwide. NSCLC often harbors oncogenic K-RAS mutations that lead to the aberrant activation of several intracellular networks including the phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway. Oncogenic K-RAS predicts poor prognosis and resistance to treatment with ionizing radiation (IR). Oncogenic K-Ras expression in the respiratory epithelium is sufficient to initiate NSCLC tumorigenesis, which requires the catalytic subunit of PI3K. Thus, effective inhibition of the PI3K signaling should lead to significant antitumor effects. However, therapy with rapamycin analogues has yielded disappointing results due in part to compensatory up-regulation of AKT. We hypothesized that dual PI3K/mTOR blockade would overcome these limitations. We tested this hypothesis with BEZ235, a novel dual PI3K/mTOR inhibitor that has recently entered clinical development. We found that BEZ235 induces a striking antiproliferative effect both in transgenic mice with oncogenic K-RAS–induced NSCLC and in NSCLC cell lines expressing oncogenic K-RAS. We determined that treatment with BEZ235 was not sufficient to induce apoptosis. However, we found that dual PI3K/mTOR blockade effectively sensitizes NSCLC expressing oncogenic K-RAS to the proapoptotic effects of IR both in vitro and in vivo. We conclude that dual PI3K/mTOR blockade in combination with IR may benefit patients with NSCLC expressing oncogenic K-RAS. These findings may have general applicability in cancer therapy, because aberrant activation of PI3K occurs frequently in human cancer.
