Abstracts


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Potential Uses of MicroRNA in Lung Cancer Diagnosis, Prognosis, and Therapy
Qi Zhao Wang, William Xu, Nagy Habib and Ruian Xu

Lung cancer is the leading cause of death from cancer in the world. Although the molecular network of lung carcinogenesis has been partly known at the levels of genes and proteins, and personalized therapy based on the genetic changes has made considerable progress in the last decade, the high mortality rate is not markedly changed. MicroRNAs (miRNAs), a class of short endogenous RNAs, acting as post-transcriptional regulators of gene expression, are similar with siRNAs in both the biosynthesis and the function steps. While, miRNAs mostly silence gene expression by binding imperfectly matched sequences in the 3' UTR of target mRNA, which is different with siRNAs by targeting ORF of mRNA with a perfectly complementary manner. miRNAs have multiple functions in lung development, and abnormal expression of miRNAs could lead to lung tumorigenesis. The different expression profiles of miRNAs in lung cancer, and the stability of miRNAs in serum, all together make them as new potentially clinical biomarkers for diagnosis and prognosis. Moreover, miRNAs may serve as either novel potential targets acting directly as oncogenes (e.g. miR-17-92 cluster) or directly therapeutic molecules working as tumor suppressor genes (e.g. let-7 family). RNAi technology based on miRNAs has many advantages over siRNAs, such as in vivo stability, highly RNA promoter-compatibility and no overt toxicity. Eventually, it might overcome the present disadvantages and become a good candidate for lung cancer therapy.


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Dexamethasone Synergizes with Lenalidomide to Inhibit Multiple Myeloma Tumor Growth, But Reduces Lenalidomide-Induced Immunomodulation of T and NK Cell Function
A.K. Gandhi, J. Kang, L. Capone, A. Parton, L. Wu, L.H. Zhang, D. Mendy, A. Lopez-Girona, T. Tran, L. Sapinoso, W. Fang, S. Xu, G. Hampton, J.B. Bartlett and P. Schafer

To determine the effect of dexamethasone on the antimyeloma effects of lenalidomide, we tested in vitro proliferation, tumor suppressor gene expression, caspase activity, cell cycling, and apoptosis levels in a series of multiple myeloma (MM) and plasma cell leukemia cell lines treated with lenalidomide and dexamethasone, alone or in combination. The effect of dexamethasone on the immunomodulatory activities of lenalidomide such as T cell and natural killer (NK) cell activation was measured via interleukin [IL]-2 production, and interferon-γ and granzyme B production respectively. Lenalidomide inhibited proliferation in most cell lines tested, and this effect was enhanced by dexamethasone. This effect was observed in MM cells containing the high-risk cytogenetic abnormalities t(4;14), t(14;16), del17p, del13, and hypodiploidy. Mechanistically, lenalidomide plus dexamethasone synergistically induced expression of the tumor sup-pressor genes Egr1, Egr2, Egr3, p15, p21, and p27 in MM cell lines and MM patient cells. The combination activated caspases 3, 8, and 9 and induced cell cycle arrest and apoptosis. Lenalidomide alone increased T cell production of IL-2, and NK cell production of interferon-γ and granzyme B. Notably, dexamethasone antagonized these immunostimulatory effects of lenalidomide in a dose-dependent manner. These data further elucidate the mechanism of action of lenalidomide and dexamethasone in MM, and suggest that use of low-dose dexamethasone with lenalidomide may retain the antiprolif-erative effect of lenalidomide while permitting greater immunomodulatory effects of this combination regimen.


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Past, Present and Future of Targeted Therapy in Solid Tumors
A. Palazzo, R. Iacovelli and E. Cortesi

Targeted therapies affecting specific molecular target, expressed preferentially by neoplastic cells, block cancer growth. Current targets are represented by cell-surface trans-membrane proteins, intracellular proteins, and by growth factors. Today atargeted therapy exists formost commonly diagnosed types of human cancer often combined with chemotherapy or sometimes as monotherapy option. The epidermal growth factor receptors (EGFR) and vascular endothelial growth factors (VEGF) are known as the two main control key intracellular pathways, governing fundamental processes in cancer cells. The concept of using anti-EGFR and anti-VEGF strategies, as cancer treatment, has been recently developed and exploited extensively. We review targeted drugs currently available for routine treatment of lung, breast, colorectal and renal cell cancers, summarizing the history of identification and molecular characterization of targets or signaling pathways responsible for abnormal cell growth. We also focus on new targeted strategies, still under investigation, able to affect simultaneously tightly interconnected biological pathways or directed against new molecular targets.


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The mTOR Pathway: A New Target in Cancer Therapy
L. Ciuffreda, C. Di Sanza, U.C. Incani and M. Milella

Mammalian target of rapamycin (mTOR) is a key protein kinase controlling signal transduction from various growth factors and upstream proteins to the level of mRNA translation and ribosome biogenesis, with pivotal regulatory effects on cell cycle progression, cellular proliferation and growth, autophagy and angiogenesis. The mTOR pathway, and its upstream regulators in the PI3K/PTEN/AKT cascade, are altered in a variety of experimental and human malignancies.This has led to the prediction that mTOR inhibitors may be used as anticancer agents. With the recent approval of two mTOR-targeted drugs (temsirolimus and everolimus) for the treatment of renal cell carcinoma and mantle cell lymphoma, this paradigm has been effectively translated into the clinical setting. In this review, we discuss mTOR biology and regulation, the mode of action of mTOR inhibitors as anti-cancer agents, and current clinical evidence supporting the use of rapamycin-like mTOR inhibitors in cancer treatment.


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Editorial [Hot topic: Apoptosis in Carcinogenesis and Cancer Therapy (Guest Editors: George G. Chen and Paul B.S. Lai)]
G.G. Chen and P.B.S. Lai

The form of programmed cell death known as apoptosis has become an intense focus of investigation in various fields including carcinogenesis and cancer therapy. Defects in apoptosis disturb tissue homeostatsis and contribute to the multistep process of carcinogenesis. Since cancer therapy-induced cytotoxicity largely depends on the intact apoptosis signaling cascades, the blockade of apoptotic pathways may enable malignant cells to evade therapy-induced cell death. Treatment failure due to clinical resistance to cancer treatment is common in many types of cancers. With more understanding and accumulation of knowledge in the regulatory and effecter molecules of apoptosis, new strategies and anti-cancer agents have been developed to manipulate the apoptotic balance in cancer cells in favor of apoptosis.

In this special issue of Current Cancer Drug Targets (CCDT), five manuscripts summarize recent development in apoptosisrelated carcinogenesis and cancer therapy from different aspects. Cresce and Koropatnick discussed the application of antisense oligonucleotides (ASOs) to arrest tumor growth via targeting Bcl-2 and clusterin. While Bcl-2 is a well-known anti-apoptotic molecule, clusterin is bi-functional, with a nuclear form of clusterin being pro-apoptotic and a secretory form of clusterin being pro-survival [1]. Several protocols of ASOs are currently under clinical trials for several types of cancers, particularly metastatic melanoma and hormone-refractory prostate cancer, both of which are the focus of the discussion in this review. Bcl-2 ASOs have also been used to treat other tumors, for example, lung cancer and ovarian carcinoma, which have been mentioned in the articles by Han and Roman, and Pennington et al. respectively, in this special issue. Han and Roman have systemically described how lung cancer evades apoptotic death followed by analyzing the implications for treatment with various protocols. Pennington et al. nicely summarized how suicide prevention promotes chemoresistance in ovarian carcinoma. Ovarian cancer is one of malignant epithelial cell types. It appears that cross-talk between the tumor microenvironment and malignant epithelial cells may determine apoptotic response. Traditionally, Bid is a typical pro-apoptotic molecule [2]. Recent development has shown that Bid has double roles with respect to stress-response, which is intricately involved in the carcinogenesis and cancer treatment. Song et al. reviewed the recent development in this area, particularly how Bid is activated and how it contributes to the regulation of the cross-talk of cell cycle arrest and apoptosis. Inflammation is associated with the most of, if not all, cancers [3]. Inflammatory molecules frequently affect the apoptotic pathway, and contribute to carcinogenesis and resistance to multiple drug therapy. Among various inflammatory molecules, nuclear factor kappaB (NF-κB), a transcriptional factor, appears to be an important one. Wang and Cho extensively analyzed the role of NF-κB signaling on the apoptotic effect in inflammation-associated carcinogenesis. Increasing evidence has indicated that targeting NF-κB can improve the sensitization of cancer cells to anti-tumor treatment [4].

We believe that this special issue is an essential compilation of up-to-date research on an emerging topic of central concern in the field of apoptosis in carcinogenesis and cancer therapy, which will be useful for anyone interested in this area.

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Too Much of a Good Thing: Suicide Prevention Promotes Chemoresistance in Ovarian Carcinoma
K. Pennington, H. Pulaski, M. Pennington and J.R. Liu

Ovarian cancer is the most lethal of gynecologic malignancies.  Currently, standard treatment for epithelial ovarian cancer consists of surgical debulking followed by adjuvant chemotherapy with a platinum-based drug coupled with paclitaxel. While initial response to chemotherapy is high, the majority of patients develop recurrent disease which is characterized by chemoresistance.  The primary cytotoxic effect of many chemotherapy drugs is mediated by apoptotic response in tumor cells. Recent data indicates that cross talk between the tumor microenvironment and malignant epithelial cells can influence apoptotic response as well. The identification of molecules involved in the regulation and execution of apoptosis, and their alterations in ovarian carcinoma have provided new insights into the mechanism behind the development of chemoresistance in this disease. Our challenge is now to devise strategies to circumvent cell death defects and ultimately improve response to treatment in ovarian carcinoma patients.


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Bone-Targeted Doxorubicin-Loaded Nanoparticles as a Tool for the Treatment of Skeletal Metastases
M. Salerno, E. Cenni, C. Fotia, S. Avnet, D. Granchi, F. Castelli, D. Micieli, R. Pignatello, M. Capulli, N. Rucci, A. Angelucci, A. Del Fattore, A. Teti, N. Zini, A. Giunti and N. Baldini

Bone metastases contribute to morbidity in patients with common cancers, and conventional therapy provides only palliation and can induce systemic side effects. The development of nanostructured delivery systems that combine carriers with bone-targeting molecules can potentially overcome the drawbacks presented by conventional approaches. We have recently developed biodegradable, biocompatible nanoparticles (NP) made of a conjugate between poly (D,L-lactide-co-glycolic) acid and alendronate, suitable for systemic administration, and directly targeting the site of tumor-induced osteolysis. Here, we loaded NP with doxorubicin (DXR), and analyzed the in vitro and in vivo activity of the drug encapsulated in the carrier system. After confirming the intracellular uptake of DXR-loaded NP, we evaluated the anti-tumor effects in a panel of human cell lines, representative for primary or metastatic bone tumors, and in an orthotopic mouse model of breast cancer bone metastases. In vitro, both free DXR and DXR-loaded NP, (58-580 ng/mL) determined a significant dose-dependent growth inhibition of all cell lines. Similarly, both DXR-loaded NP and free DXR reduced the incidence of metastases in mice. Unloaded NP were ineffective, although both DXR-loaded and unloaded NP significantly reduced the osteoclast number at the tumor site (P = 0.014, P = 0.040, respectively), possibly as a consequence of alendronate activity. In summary, NP may act effectively as a delivery system of anticancer drugs to the bone, and deserve further evaluation for the treatment of bone tumors.


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Wnt/β-Catenin/LEF-1 Signaling in Chronic Lymphocytic Leukemia (CLL): A Target for Current and Potential Therapeutic Options
R.K. Gandhirajan, S.J. Poll-Wolbeck, I. Gehrke and K.-A. Kreuzer

There is a growing body of evidence that Wnt signaling, which is already known to play a critical role in various types of cancer, also has a vital function in B cell neoplasias, particularly in chronic lymphocytic leukemia (CLL). It is known that Wnt proteins are overexpressed in primary CLL cells and several physiological inhibitors are partly inactivated in this disease. Furthermore, β-cateninis upregulated upon Wnt stimulation and cooperates with the transcription factor lymphoid enhancer binding factor-1 (LEF-1). LEF-1 is excessively overexpressed in CLL cells by more than 3,000-fold compared to normal B cells. Moreover, LEF-1 could be identified as an important regulator of pathophysiologically relevant genes in CLL, and several Wnt/β-cateninsignaling components substantially influence CLL cell survival.

In this review we summarize the current state of knowledge about Wnt/β-catenin/LEF-1 signaling in CLL. Following a short overview of current treatment concepts in CLL, we briefly describe Wnt signaling in human cancers. We then discuss recent progress in understanding regulation of the Wnt/β-catenin/LEF-1signaling pathway in this disease. Based on the present scientific evidence we highlight which components of this important signaling pathway could serve as therapeutic targets in CLL. We then present previous results gained from experimental approaches to target different parts of the Wnt/β-catenin/LEF-1 cascade. Together with potentially promising approaches we also critically reflect on the kind of difficulties and problems that may arise using such strategies.


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Cancer Therapy By Targeting Hypoxia-Inducible Factor-1
Y. Li and D. Ye

Tumors are invariably less well-oxygenated than the normal tissues from which they arose. Hypoxia-inducible factor-1 (HIF-1), a key transcriptional regulator, plays a central role in the adaptation of tumor cells to hypoxia by activating the transcription of genes, which regulate several biological processes including angiogenesis, cell proliferation, survival, glucose metabolism and migration. The expression, activity and stability of HIF-1 is not only induced in response to reduced oxygen availability but also modulated through PI-3K, MAPK, autocrine signaling pathways, E3 ubiquitin ligases, and other regulators. The regulators and effects of HIF-1 in cancer have intensively provided us a new clue for the HIF-1 targeting anticancer therapy. This review evaluates the HIF-1 structure, the regulation mechanisms, the functions in cancer and corresponding anticancer strategies.


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Strategies for Overcoming Inherent and Acquired Resistance to EGFR Inhibitors by Targeting Downstream Effectors in the RAS/PI3K Pathway
A.J. Weickhardt, N.C. Tebbutt and J.M. Mariadason

Mutations in K-Ras are observed in approximately 40% of colon tumours. This has significant implications for predicting likelihood of response to the antibody-based EGFR inhibitors, cetuximab and panitumumab, with K-Ras mutant patients now clearly shown to be inherently resistant to these agents. Alternative treatment strategies for K-Ras mutant patients are therefore urgently needed. Farnesyltransferase inhibitors, developed to inhibit K-Ras, have to-date been largely unsuccessful. However, a number of agents which target signaling components in the MAPK and PI3K pathways downstream of mutant K-Ras are currently being evaluated in clinical trials and will be discussed. A further clinical concern is that K-Ras wild type patients who initially respond to EGFR inhibitors eventually develop acquired resistance to these agents and experience tumour progression. Studies from the use of related agents in other disease settings as well as pre-clinical studies provide important insights into mechanisms by which this may occur. While no evidence presently exists for somatic mutations as a basis for acquired resistance to EGFR inhibitors in colon cancer, several studies implicate upregulation and signaling via other Her family members, c-Met, IGFR and Src. Upregulation of the pro-angiogenic factor, VEGF, is also a possible mechanism of acquired resistance. This review discusses drugs currently in clinical trials that may potentially achieve more efficient and prolonged targeting of the EGFR pathway by overcoming these mechanisms of resistance.