生物谷报道，HIV药物对癌细胞有抑制作用，抗HIV药物可以阻碍肿瘤的生长速度。被用于治疗其他疾病的药物现在可以用来杀死癌细胞。研究者发现一种通常用于抗HIV病毒的药物可以阻碍癌细胞的生长速度。这个发现增加了现有药物用于治疗另一种疾病的希望。研究成果发表在临床肿瘤研究期刊上。
根据新的研究，抗HIV药物那非那韦第一次试验性地用于多种癌症患者上。肿瘤科学家认为这些抗HIV药物的新药可以拯救生命，并且减少了15年等待新抗癌药物进入到临床和节省了十亿用于研发的开支。 位于马里兰州的Bethesda美国癌症研究所的Phillip Dennis和他的合作者在注意到抗HIV药物对癌细胞和HIV病毒有相似的毒性作用后，开始检测抗HIV药物。对抗癌药物新的搜寻方法导致了先前的止痛药和早孕反应疗法被列为治疗癌症的方法。Dennis的队伍往含有多种癌细胞的培养基中加入了六种已证实的抗HIV药物。其中的三种可以显著阻碍癌细胞的生长速度，加快癌细胞死忙。疗效最好的那非那韦，不仅可以阻碍细胞中的蛋白降解酶的活动，而且可以阻碍被注入癌细胞的小鼠肿瘤的生长。科学家认为像HIV之类的病毒保护它们免于人体免疫系统的攻击的方法是分解寄主细胞的垃圾处理部位－蛋白酶体。这样，在免疫细胞可以抗击病毒之前，防护免疫蛋白就被破坏了。变异的癌症细胞也可以激活蛋白酶体，像那非那韦之类阻断蛋白分解的药物，理论上可以治疗癌症。
那非那韦只是临床试验的第一步，它使我们了解癌症病人的耐药量和药物是如何影响体内坚硬的肿瘤。在药物之间改变其原有用途的想法正在发展，例如已试验的抗HIV药物用来对抗SARS病毒，抗疟药氯喹作为可行的抗癌疗法。
原文出处：
Clinical Cancer Research Sep 1, 2007; 13 (17)
Phillip Dennis et al.
Nelfinavir, a lead HIV protease inhibitor, is a broad spectrum, anti-cancer agent that induces ER stress, autophagy and apoptosis in vitro and in vivo
作者简介：
Phillip A. Dennis, M.D., Ph.D.
Medical Oncology Branch and Affiliates
Head, Signal Transduction Section
Senior Investigator
Dr. Dennis received his B.A. in 1984 as an Echols Scholar from the University of Virginia, and his Ph.D. and M.D. degrees in 1991 and 1992, respectively, from the New York University School of Medicine as part of the Medical Scientist Training Program. He completed his Internal Medicine training on the Osler Medical Service at Johns Hopkins Hospital. Following his residency, he completed a fellowship in Medical Oncology at the Johns Hopkins Oncology Center and then joined the laboratory of Dr. Michael Kastan as a postdoctoral fellow. Dr. Dennis joined the NCI in 1999 as a tenure track investigator. In 2005, he became Clinical Director at NCI/Navy Medical Oncology, and in 2006 became a Senior Investigator in the Medical Oncology Branch. Dr. Dennis is a recipient of the Alton Ochsner Award Relating Tobacco and Health and an NIH Merit Award, and is an elected member of the American Society for Clinical Investigation.
Research
Activation of the PI3K/Akt pathway and the biology of lung cancer
Lung cancer kills more Americans than any other cancer, and ~90,000,000 Americans are at permanent increased risk to develop lung cancer. To address this health problem, our group studies the role of signal transduction pathways that promote the formation, maintenance, and therapeutic resistance of lung cancer. We have focused on one pathway, the Akt/mTOR pathway. Our research can broadly divided into two areas, to understand the mechanisms of activation and consequences of activation of the Akt/mTOR pathway in lung cancer, and to develop approaches to inhibit the pathway. Several studies from our group have validated the Akt/mTOR pathway as a target for prevention of lung cancer. We showed that two tobacco components, nicotine and the tobacco-specific carcinogen, NNK, rapidly activate the pathway in normal human lung epithelial cells. Activation occurred within minutes at concentrations that are achievable in smokers, and could be inhibited with pathway inhibitors or nicotinic antagonists. Because activation of Akt caused a partially transformed phenotype through inhibition of apoptosis and decreased reliance on extracellular growth factors, we have hypothesized that Akt activation serves as a biochemical gatekeeper for tobacco-related carcinogenesis. In support of this hypothesis, we showed that activation of Akt and mTOR increased with phenotypic progression of tobacco-induced lung lesions in a mouse model of lung cancer. Most recently, we showed that rapamycin, an mTOR inhibitor that is FDA-approved for other indications, inhibited the number of tobacco carcinogen-induced lung lesions by 90%, as well as tumor size. Together, these studies have expanded the concept of how tobacco causes lung cancer, and have raised awareness of pathway activation as a biomarker for prevention studies. Importantly, they provide a strong rationale to use mTOR inhibitors in human lung cancer prevention trials.
Other studies from our group have validated inhibition of the Akt pathway as a target for treatment of lung cancer. We first identified constitutive activation of Akt in 16/17 NSCLC cell lines, and showed that pathway activation promoted cellular survival under conditions of serum deprivation or administration of chemotherapy or radiation therapy. Using a set of 252 lung cancer specimens with surrounding normal tissues and clinical outcomes, we have shown that Akt activation is specific for lung cancers and not surrounding lung tissue, and confers a poor prognosis especially for those with early stage disease. This is potentially important because most patients diagnosed with lung cancer through screening will have early stage disease. Determining which subset of patients will benefit most from more intensive observation and/or therapy could be of great clinical benefit. Our studies suggest that Akt activation could be one factor to distinguish patients that are at increased risk to relapse or recur.
Despite the strong rationale to target Akt, no Akt inhibitors are clinically approved. We have led a large collaborative effort in academia, industry and the Developmental Therapeutics Program at NCI, to develop lipid-based inhibitors of Akt called phosphatidylinositol ether lipid analogues (or PIAs). PIAs were synthesized using molecular modeling of Akt, and members of our group and our colleagues at Georgetown University are co-inventors of PIAs. Unlike most pharmaceutical efforts to develop Akt inhibitors that have focused on the ATP binding domain, the PIAs that we are developing target the pleckstrin homology (PH) domain. We identified 5 active PIAs that inhibit Akt within minutes and selectively kill cancer cells with high levels of Akt activation. More recently, we have identified molecular correlates of response to PIAs, as well as other biological effects of PIAs that contribute to their toxicity, and could be used as biomarkers for administration of PIAs. We are continuing to investigate mechanisms of action of PIAs and other lipid-based Akt inhibitors, and we are comparing the biologic activities of lipid-based inhibitors to small molecule inhibitors that target the ATP binding region of Akt. Other efforts to develop pathway inhibitors include the use of bioinformatics to perform virtual screening of large chemical libraries, and the screening of drugs that are FDA-approved for other indications for inhibition of Akt and induction of apoptosis in Akt-dependent cancer cells.
To complement our preclinical efforts to develop Akt inhibitors, we are implementing clinical trials that are testing inhibitors of the Akt/mTOR pathway in lung cancer patients. Examples of proposed trials include first-in-human (so called “Phase 0”) trials with PIAs, trials combining mTOR inhibitors with standard chemotherapies, and trials that will test “off the shelf” drugs for their ability to inhibit Akt in lung cancer patients. Together, these studies could increase therapeutic options for lung cancer patients and could shed insight into the clinical benefit achieved by inhibiting the Akt/mTOR pathway.
Our collaborators in this work are Stephen Hewitt, Curtis C. Harris, NCI; Abdel Elkahloun, NHGRI; and Alan Kozikowski, University of Illinois at Chicago.
背景知识：
#609423
HUMAN IMMUNODEFICIENCY VIRUS TYPE 1, SUSCEPTIBILITY TO
HUMAN IMMUNODEFICIENCY VIRUS TYPE 1, RESISTANCE TO, INCLUDED
Gene map locus 19q13.4, 19p13.3, 17q12, 17q11.2-q12, 17q11.2, 16p12.1-p11.2, 12q14, 10q11.1, 2q35
