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- Volume 13, Issue 2, 2013
Current Cancer Drug Targets - Volume 13, Issue 2, 2013
Volume 13, Issue 2, 2013
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Therapeutic Implications of mTOR Inhibitors in the Treatment of Gastric Cancer
More LessGastric cancer remains one of the most common types of cancer worldwide, and most patients present with advanced disease. Sixty percent of these patients eventually relapse after curative surgical resection, and combination chemotherapy regimens only provide limited survival benefits. Mammalian target of rapamycin (mTOR) is a new target of cancer therapies. Preclinical data suggest that the suppression of the mTOR pathway inhibits the progression of gastric cancer in vitro and in animal models. In clinical trials, the mTOR inhibitor, everolimus, was well tolerated in phase I/II studies on patients with metastatic gastric cancer. The efficacy of everolimus was promising in a phase II clinical trial, but in a recently published phase III clinical trial everolimus monotherapy do not significantly improve the overall survival of patients with advanced gastric cancer who had been previously treated with one or two lines of systemic chemotherapy. Phosphoinositide 3-kinase/mTOR dual inhibitors have not yet entered early-stage clinical trials in patients with advanced gastric cancer. Further studies are needed to establish the role of mTOR inhibitors for the treatment of gastric cancer.
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Dual Inhibition of PI3-Kinase and mTOR in Renal Cell Carcinoma
Authors: Daniel C. Cho and James W. MierAlthough PI3-kinase mutations are uncommon in renal cell carcinoma (RCC), the PI3-kinase/Akt signaling pathway is active in most RCC. The activation of PI3-kinase would be expected to drive protein and lipid synthesis through its effects on mTORC1 and SREBP1, respectively. PI3-kinase also activates numerous transcription factors (e.g. the FOXO family, c-myc, NF-κB) that regulate cell proliferation and viability. The consequences of blocking PI3-kinase in RCC are just now beginning to be elucidated and are expected to include effects on tumor cell proliferation, metabolism, and angiogenesis. Several PI3-kinase inhibitors currently undergoing clinical testing are active site inhibitors of mTOR as well and it is likely that these agents will prove particularly useful in the treatment of RCC.
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Phosphatidylinositol 3-kinase Signaling as a Therapeutic Target for Cervical Cancer
Authors: Jianghong Wu, Chen Chen and Kong-Nan ZhaoCervical cancer is the second most frequent cause of female cancer mortality and remains a major health problem in women worldwide. Surgery, chemotherapy and radiotherapy alone or combined are the three treatments methods commonly used to treat this disease. However, a significant proportion of the cancer patients still experiences recurrence and eventually dies. Recently, the research advances in molecular profiling and genomics have revealed that the phosphatidylinositol 3-kinases (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway plays a crucial role in mediating multiple cellular functions including cell growth, proliferation, metabolism, survival and angiogenesis. Thus, targeting this signal pathway offers a promising perspective for cervical cancer therapy. In this article, we review the published data from both basic and clinical studies showing that the concurrent cervical cancer chemoradiotherapy dramatically improves the local control of this disease and overall survival by triggering tumor cell apoptotic pathways via the PI3K/AKT/mTOR signalings, proving that the PI3K/AKT/mTOR pathway is one of the most important targets for cervical cancer therapy. We also highlight that several phytochemicals strongly inhibit proliferation of the cervical cancer cells and induce apoptosis by targeting one or multiple molecules through the PI3K/AKT/mTOR pathway. While some of these phytochemicals have been used as therapeutic agents or chemoradiotherapy sensitizers, others are currently in clinical development to be the potential therapeutic agents for the advanced cervical cancer therapy.
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The PI3 Kinase Signaling Pathway in Prostate Cancer
Authors: Aymen A. Elfiky and Zhenyang JiangDespite recent advances in our understanding of the biological basis of prostate cancer, the management of the disease, especially in the castration-resistant phase, remains a significant challenge. Deregulation of the phosphatidylinositol 3-kinase (PI3K) pathway is increasingly implicated in a number of malignancies, including prostate carcinogenesis. In this review, we detail the role of this pathway in the pathogenesis of prostate cancer and the therapeutic implications of targeting it.
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Studies of NVP-BEZ235 in Melanoma
Authors: Joshua A. Sznol, Lucia B. Jilaveanu and Harriet M. KlugerThe PI3k pathway represents an attractive target for drug development in melanoma, as numerous studies have shown that this pathway is active in malignant melanocytes. In addition, previous work has shown that multi-level targeting of this pathway might be more effective than targeting the pathway at a single level. In this review, we discuss targeting different members of this pathway, potential escape mechanisms, classes of specific molecular inhibitors, and development of NVP-BEZ235, a novel dual PI3k/mTOR inhibitor.
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Current Status and Future Perspectives of PI3K and mTOR Inhibitor as Anticancer Drugs in Breast Cancer
Authors: Xiaobei Zhang, Xi-ru Li and Jin ZhangThe PI3K/Akt/mTOR signaling pathway is involved in the inhibition of tumor cell apoptosis, the promotion of cell survival, cell cycle regulation, tumor angiogenesis, invasion, and metastasis and therefore plays an important role in tumorigenesis, tumor growth, patient prognosis, and tumor treatment. Recent studies have identified this signaling pathway in breast cancer, and the PI3K/Akt/mTOR pathway is therefore being considered as a new therapeutic target and a hotspot in breast cancer research. Pre-clinical studies have confirmed that PI3K inhibitors and mTOR inhibitors achieve anticancer effects by targeting different levels of the PI3K/Akt/mTOR signaling pathway. Among the PI3K inhibitors, some molecules target only PI3K, whereas others target both PI3K and mTOR. Currently, researchers tend to focus on molecular targets based on the different PI3K subtypes to achieve more targeted and specific inhibition of the PI3K pathway. However, the clinical efficacy and efficiency of these inhibitors need to be further studied. The mTOR inhibitors target mTORC1 and have become relatively well-developed targeted therapies for the PI3K/AKT/mTOR pathway. Rapamycin derivatives have been studied in Phase II / III clinical trials in breast cancer, and these derivatives achieved positive results in the treatment of metastatic breast cancer when combined with endocrine therapy or HER2-targeted therapies. This review summarizes the activation of the PI3K/AKT/mTOR pathway, its role in breast cancer, and the latest clinical trials of a variety of PI3K and mTOR inhibitors to improve the understanding of the role of these drugs in breast cancer treatment.
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Novel Approaches for Molecular Targeted Therapy of Breast Cancer: Interfering with PI3K/AKT/mTOR Signaling
Authors: Thomas W. Grunt and Gabriella L. MarianiBreast cancer is one of the most prevalent and devastating malignant diseases in women worldwide. Fortunately, while breast cancer incidence is still increasing, its death rate is declining. This is mainly due to early diagnosis and potent therapies such as blockade of estrogen receptor- or of ErbB2 (HER2-neu) membrane receptorsignaling. In recent years, the PI3K/AKT/mTOR pathway, which transmits signals from the cell membrane into the nucleus and activates multiple oncogenic programs, has been found to play a crucial role in the regulation of breast cancer cell growth. This pathway is densely interconnected with a multitude of other important regulatory systems for glucose-, lipid- and amino acid-metabolism, for energy balance, and for autophagy. It has been found that PI3K/AKT/mTOR signaling modulates estrogen receptor function. Using transverse and feedback regulatory loops the PI3K/AKT/mTOR cascade can communicate with concurrent and with upstream systems. Thus, PI3K/AKT/mTOR is a crucial element within a complicated signaling network. This pathway is hyperactive in more than 70% of breast tumors. Hence, the protein kinases located along this route represent very attractive and promising drug targets for breast cancer therapy. Currently, numerous small molecular drugs that inhibit PI3K, AKT and/or mTOR are being developed in preclinical and clinical models of breast cancer. Some of these compounds are highly selective blocking only one particular kinase complex, whereas others interfere with two (mTORC1+mTORC2) or even three effectors (PI3K+mTORC1+mTORC2) of the pathway. Due to the many interactions with other regulatory systems, silencing of the pathway can cause unexpected results. Therefore, detailed preclinical and clinical evaluation of these compounds as single drugs and in combination is required to achieve optimal results with maximal clinical benefit and acceptable toxicity. Also, reliable biomarkers for the identification of patient subsets that will maximally benefit from PI3K/AKT/mTOR inhibition need to be developed. Thus, selective silencing of PI3K/AKT/mTOR signaling represents a promising approach for breast cancer and might prove useful when combined with other drugs. Here we review the current preclinical and clinical data and compare the potential benefits of multi- versus single-targeting PI3K/AKT/mTOR drugs.
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Current and Potential Treatments for Cervical Cancer
Authors: Grace P.C. Yee, Paul de Souza and Levon M. KhachigianCervical cancer is the third most common carcinoma in women worldwide. Despite increasing efforts to improve therapy in this disease, a significant proportion of women still die, mostly from recurrent or chemoresistant disease. This review discusses current treatments for early cervical cancer, advanced disease, and recurrent cervical cancer, and covers concurrent chemoradiation, neoadjuvant chemotherapy before surgery and radiation, single agent treatment, combination treatment, platinum-based and non-platinum based therapy. We also discuss promising therapeutic strategies for cervical cancer including targeted therapy, cell-based therapy, combined siRNA and chemotherapy, and immunotherapy.
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The miR-183/96/182 Cluster Regulates Oxidative Apoptosis and Sensitizes Cells to Chemotherapy in Gliomas
Authors: Hailin Tang, Yanhui Bian, Chaofeng Tu, Zeyou Wang, Zhibin Yu, Qing Liu, Gang Xu, Minghua Wu and Guiyuan LiMany microRNAs reside in clusters in the genome, are generally similar in sequence, are transcribed in the same direction, and usually function synergistically. The miR-183/96/182 cluster is composed of 3 miRNA genes, and increased expression of miR-183, 96 and 182 are implicated in glioma carcinogenesis. Knockdown of individual components or of the entire miR-183/96/182 cluster inhibits the survival of glioma cells by regulating the ROS-induced apoptosis pathway. Furthermore, inhibition of the miR-183/96/182 cluster induced ROS-mediated AKT/survival independent of three target genes FGF9, CPEB1, and FOXO1, and inhibition of the miRNA cluster induced p53/apoptosis signaling, which was dependent on these same genes. In addition, knockdown of the miR-183/96/182 cluster enhanced the anticancer effect of Temozolomide on glioma cells by the ROS-mediated apoptosis pathway. Therefore, the miR- 183/96/182 cluster may be a pleiotropic target for glioma therapy.
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Volumes & issues
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Volume 24 (2024)
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Volume 23 (2023)
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Volume 22 (2022)
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Volume 21 (2021)
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Volume 20 (2020)
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Volume 19 (2019)
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Volume 18 (2018)
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Volume 17 (2017)
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Volume 16 (2016)
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Volume 15 (2015)
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Volume 14 (2014)
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Volume 13 (2013)
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Volume 12 (2012)
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Volume 11 (2011)
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Volume 10 (2010)
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Volume 9 (2009)
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Volume 8 (2008)
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Volume 7 (2007)
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Volume 6 (2006)
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Volume 5 (2005)
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Volume 4 (2004)
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Volume 3 (2003)
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Volume 2 (2002)
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Volume 1 (2001)