Current Cancer Drug Targets - Volume 10, Issue 8, 2010

The new millennium brought the transition from classical therapy to targeted cancer therapy. Although multiple pathways are involved in cancer initiation and progression, the RAS pathway seems to emerge as particularly important. In their review article entitled “RAS oncogenes: the first 30 years”, Marcos Malumbres and Mariano Barbacid emphasized that RAS genes have always been at the leading edge of research in various disciplines such as tumor virology, molecular oncology and signal transduction biology [1]. The general interest in RAS research is spurred by the fact that RAS genes are the most common targets for oncogenic mutations in human cancer and by the identification of germ-line mutations causing several developmental disorders [2]. The most recent interest in RAS mutations is fuelled by the finding that therapies targeting the epidermal growth factor receptor (EGFR) are only efficient in cancer patients carrying wild-type KRAS genes, while tumors with KRAS mutation are therapy-refractory [3]. While this finding was not too surprising for experts working in the field of signal transduction and RAS tumor biology, the current clinical impact is enormous and RAS mutation diagnostics has entered clinical routine. The various aspects of RAS function in cancers of viral and non-viral origin, the role of RAS proteins as molecular switches in signal transduction, in growth control and development have been covered in many excellent review articles, of which the most recent one is a publication by Karnoub and Weinberg [4]. In bibliometrical terms, the publication intensity on RAS-related topics slowed down somewhat after 1999, but did not reach a plateau or diminish in the years thereafter (Fig. 1). While the publications devoted to the retrovirological aspects of RAS research stayed constantly between 1985 and 2004 and showed a tendency to decrease from 2005 onwards (not shown), there is a growing number of gene expression profiling studies, mostly based on microarray analysis, aiming at assessing RAS pathway-related transcriptional alterations (Fig. 1). In this hot-topic issue, we cover three different aspects of RAS-related targeted therapy. First, predictive markers to EGFR/RAS targeted therapies are evaluated in two different papers. Barton et al. sum up all available biomarkers of resistance found at different levels of the RAS signaling cascade. Timar et al. critically elaborate on the most critically investigated biomarker, on the role of KRAS mutation testing in colorectal cancer. In the second part, three different cancer types are portrayed in detail. Weickhardt et al. focus on colorectal cancer, and evaluate the agents acting through MAPK and PI3K pathways downstream of mutated K-RAS. The signaling via other HER family members, CMET, IGFR and SRC are also rigorously assessed. Whitaker and Neal assess the role of RAS isoforms in prostate cancer progression, as current evidence already supports the role of RAS in activation of androgen receptor in hormone sensitive cells. Lo summarizes the role of the RAS pathway in malignant gliomas and evaluates the efficacy of RAS-targeted therapies. Finally, in the third part we get an exciting in-depth look on some selected topics: RAS signaling is involved in the switch from tumorsuppressive to tumor-promoting functions of the TGF-beta family, a topic discussed by Grusch et al. The first genome-wide search for RAS pathway targets was published in 2000. Since then, a number of studies were performed in human, mouse and rat model systems. Gyorffy and Schafer critically evaluate commonly deregulated target genes and discuss some of the key genes identified. Although oncogenes like RAS usually promote neoplastic transformation, over-expression of mutant RAS results in cellular senescence. Details of the RAS-induced senescence as well as its effects on cancer therapy are discussed by DiMauro and David. In summary, this hot-topic issue covers recent advances in RAS-related carcinogenesis and therapy response as well as the potential role of other members of the RAS signalling cascade.

Constitutive activation of the EGFR/RAS/PI3K cell-signaling pathway that may occur through molecular aberrations in core pathway components occurs in many solid tumours, including colorectal cancer(CRC), non-small-cell lung cancer(NSCLC) and breast cancer. Predictive biomarkers of response to therapeutics targeting this pathway are necessary to select patients more likely to respond, and importantly, to avoid treating patients likely to suffer a worse outcome with therapy compared to standard of care. Determination of EGFR by immunohistochemistry(IHC) is not strongly predictive of response to EGFR-targeted therapy in CRC and NSCLC. EGFR gene mutations in the tyrosine kinase(TK) domain are predictive of response to EGFR tyrosine kinase inhibitors(TKIs) in NSCLC, and the acquisition of a point mutation in an amino acid in an adjacent area, T790M, is predictive of resistance. However, novel irreversible EGFR inhibitors such as BIBW-2992 and HKI-272 may retain activity in tumours with T790M mutations. It is well established in CRC that mutations in KRAS are predictive of resistance to EGFR pathway inhibition, and may predict for a poorer outcome with therapy. Other potentially useful biomarkers of resistance to EGFR-targeted therapy in the process of clinical validation include mutations in BRAF, PTEN loss and PIK3CA mutations, nuclear factor-kappa beta(NF-KB) pathway activity, and expression of alternative EGFR ligands. Functional genomics elucidation of drug resistance pathways using RNA interference(RNAi) techniques may provide novel therapeutic approaches in disease resistant to EGFR pathway targeting and accelerate predictive biomarker development.

KRAS mutation testing opened up a new era in routine pathological diagnostics of colorectal cancer similar to the introduction of HER-2 testing in breast cancer with the significant difference that mutational analysis exclusively relies on molecular methodologies. In order to critically analyze the current rational of KRAS mutation testing in colorectal carcinoma we have performed evaluation of related articles available in PubMed/Medline, Society recommendations, anti-EGFR antibody registration documents and NCCN guidelines. KRAS mutation is frequent in colorectal cancer and data suggest a negative prognostic, but neutral predictive significance, with the exception of its strong negative predictive value in case of anti-EGFR antibody therapies. However, there is only scattered information on the significance of rare mutations and copy number changes of KRAS. Furthermore, other mutations in EGFR signaling pathway may also have predictive value such as BRAF, PIK3CA or PTEN. It also seems to be a critical issue whether the K-RAS testing must be done on primary, regional or distant metastatic tissues: data already suggest a small but significant chance of alteration during tumor progression. Technically KRAS mutation testing can be performed by various methods characterized by different sensitivities and specificities, although the clinical significance of these parameters are unknown at the present. The consensus strongly suggests the need for an effective quality control program for these methods. KRAS mutation testing in colorectal cancer raised fundamental biological, clinical and molecular pathological questions as it has become a standard application for predicting sensitivity for anti-EGFR antibody therapies. However, these questions can only be answered by rigorous, dogma-free preclinical and clinical studies.

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.

Although not frequently mutated in prostate cancer Ras isoforms play a pivotal role in multiple pathways that have been implicated in prostate cancer progression to androgen independence. These have included growth factor and cytokine induced activation of the androgen receptor and its coregulators by post translational modification. Current evidence suggests that Ras is also required for androgen receptor activation in hormone sensitive cells. More recently Ras has been shown to work synergistically with other pathways to promote prostate tumorigenesis. We review the multiple lines of evidence implicating Ras as therapeutic target in androgen dependent and independent prostate cancer.

Malignant gliomas are the most common and the deadliest brain malignancies in adults. Despite the lack of a complete understanding of the biology of these tumors, significant advances have been made in the past decades. One of the key discoveries made in the area of malignant gliomas is that these tumors can be induced and maintained by aberrant signaling networks. In this context, the Ras pathway has been extensively exploited, from both basic and translational perspectives. Although somatic oncogenic mutations of Ras genes are frequent in several cancer types, early investigations on gliomas revealed disappointing facts that the Ras mutations are nearly absent in malignant gliomas and that the BRAF mutations are present in a very small percentage of gliomas. Therefore, the observed deregulation of the Ras-RAF-ERK signaling pathway in gliomas is attributed to its upstream positive regulators, including, EGFR and PDGFR known to be highly active in the majority of malignant gliomas. In contrast to the initial negative results on the somatic mutations of H-Ras, K-Ras and BRAF, recent breakthrough studies on pediatric low-grade astrocytomas uncovered genetic alterations of the BRAF gene involving copy number gains and rearrangements. The 7q34 rearrangements result in a novel in-frame KIAA1549:BRAF fusion gene that possesses constitutive BRAF kinase activity resembling oncogenic BRAF (V600E). In light of the earlier findings and recent breakthroughs, this review summarizes our current understanding of the Ras-RAF-ERK signaling pathway in gliomas and the outcome of preclinical and clinical studies that evaluated the efficacy of Ras-targeted therapy in malignant gliomas.

Both RAS and transforming growth factor (TGF)-β signaling cascades are central in tumorigenesis and show synergisms depending on tumor stage and tissue context. In this review we focus on the interaction of RAS subeffector proteins with signaling components of the TGF-β family including those of TGF-βs, activins and bone morphogenic proteins. Compelling evidence indicates that RAS signaling is essentially involved in the switch from tumor-suppressive to tumor-promoting functions of the TGF-β family leading to enhanced cancer growth and metastatic dissemination of primary tumors. Thus, the interface of these signaling cascades is considered as a promising target for the development of novel cancer therapeutics. The current pharmacological anti-cancer concepts combating the molecular cooperation between RAS and TGF-β family signaling during carcinoma progression are critically discussed.

The small GTP-binding proteins HRAS, KRAS and NRAS belong to a family of oncoproteins associated with many types of human cancer. Signal transduction processes initiated at receptor tyrosine kinases converge on RAS proteins which serve as molecular switches linking upstream signals with the transcriptional machinery. RAS proteins interact with a number of effector proteins that in turn activate the Raf/MEK/ERK pathway, the PI3K/PKB/Akt pathway, the RalGDS/Ral pathway and other downstream pathways. Mutations in RAS lock the protein in its active form. Chronic activation of the KRAS isoform is the basis for resistance toward antibody therapies targeting receptor tyrosine kinases, as an upstream stimulus through growth factor receptor-mediated activation is no longer required. However, the complexity of the RAS signaling system necessitates the search for additional activating mechanisms as well as biomarkers associated with pathway activation. During recent years, several RAS pathway-related gene signatures were identified, mostly by microarray- based gene expression profiling of normal versus RAS-transformed cells. The signatures can serve as a source of common biomarkers indicating functionally relevant downstream effects of the RAS signaling system. In searching for new markers, we compared the gene expression signatures compiled in 24 independent studies. We analyzed differentially regulated genes recovered in microarray studies on human specimens to discriminate paired normal and tumor tissues. Although the overlap between individual studies was low, this meta-analysis revealed Kruppel-like factor 5 (KLF5), the CD44 antigen and members of the epidermal growth factor (EGR)-family as common downstream effectors of RAS.

Activated oncogenes like Ras have traditionally been thought of as promoting unrestrained proliferation; therefore, the concept of oncogene-induced senescence has been, and still is, controversial. The counter-intuitive notion that activation of oncogenes leads to the prevention of cellular proliferation has initially been fueled by in vitro studies using ectopic expression of activated Ras in primary fibroblasts. While these initial studies demonstrated unambiguously the existence of a new type of cellular senescence, induced by oncogenes in an ex-vivo system, questions were raised about the physiological relevance of this process. Indeed, recent technical advances in mouse modeling for cancer have suggested that the occurrence of Ras-induced senescence is highly dependent on the cellular context, as well as the level of expression of activated Ras, and may not be pertinent to the study of human cancer initiation and/or progression. However, our increased knowledge of the molecular basis for cellular senescence has led to a better understanding of the molecular events modulating cancer progression in vivo. Recent studies have not only clearly established the incidence of cellular senescence in preneoplasic lesions, but also its role as a potential tumor-suppressor mechanism in vivo. Here, we review the recent and exciting new findings regarding the physiological relevance of Ras-induced senescence, and discuss their implications in terms of cancer therapy.

Our understanding of the process of tumour vascularization and the consequences of targeting the tumour vasculature to treat cancer has considerably evolved since the seminal hypothesis, formulated by Judah Folkman almost 40 years ago, that tumour growth and metastasis rely on the formation of a new vascular network. As the cellular mechanisms and the molecular pathways involved in tumour angiogenesis have started to unravel, new actors have come into play and new therapeutic targets have emerged. This hot-topic issue of Current Cancer Drug Targets on the “New therapeutic advances and perspectives in tumour angiogenesis” focuses on the current status, future prospects and challenges of anti-vascular therapies. First, the different therapeutic targets that may be exploited to block tumour angiogenesis in childhood cancer patients are explored and their current clinical development is reviewed. Then, the pro-angiogenic functions of two novel therapeutic targets, namely heat shock protein (HSP) 90 and histone deacetylase (HDAC), are outlined and the pre-clinical and clinical development of their specific inhibitors is examined. Finally, the technical challenges associated with the detection and analysis of endothelial progenitor cells (EPCs) are explained to help understand the actual controversy in this research field and highlight the potential of this unique cell population to be used as therapeutic tool in clinical oncology. Can Tumour Vasculature be an Efficacious Target in Paediatric Oncology? Following the first FDA approval of the anti-VEGF antibody, bevacizumab, in 2004, angiogenesis inhibitors have now become part of the standard of care for several types of adult cancer. Numerous clinical studies have been completed in various other tumour types and more trials are currently ongoing. In paediatric oncology, although clinical data remain sparse, anti-angiogenic agents are also being increasingly investigated. Already approved anti-angiogenic agents, such as bevacizumab, are increasingly used for the treatment of advanced and/or highrisk paediatric tumours, such as high-grade glioma, metastatic neuroblastoma and sarcoma. Furthermore, several new targets, including integrins and receptor tyrosine kinases, have emerged and are also increasingly investigated in pre-clinical models of childhood cancer and early clinical trials. Another anti-angiogenic strategy relies on metronomic chemotherapy, which is defined by the frequent administration of chemotherapeutic drugs at concentrations well below the maximum tolerated dose and with no prolonged drug-free break. The review by Andre et al. published in this special issue provides an extensive overview of these different anti-angiogenic strategies and their current clinical development for the treatment of childhood cancer. The authors further discuss a crucial issue that warrants sustained attention, especially in paediatric oncology, which is the long-term safety of anti-angiogenic therapies, since interfering with angiogenesis may hamper normal growth and development of children. So far, anti-angiogenic agents have indeed been used, with relative success, in paediatric patients with advanced and poor-prognosis disease and high-risk of relapse, making it difficult to adequately assess potential long-term side effects due to the low number of long-term survivors. HSP90, a Pivotal Co-Factor in Angiogenic Signalling Pathways As reviewed by Staufer and Stoeltzing in this issue, HSP90 is directly involved, through its chaperone activity, in several pro-angiogenic signalling cascades and especially PI-3K dependent pathways, including HIF-1α, eNOS and MAPK signalling. HSP90 therefore plays an essential role in hypoxia signalling and is also crucial to the activity of various pro-angiogenic receptors, such as VEGFR-2, integrin αvβ3, angiopoietin-1 and neuropilin-1. With such a central position and numerous client proteins involved in angiogenesis signalling, HSP90 appears as an attractive therapeutic target for anti-angiogenic cancer treatment. Although the results of early clinical studies of HSP90 inhibitors as single agents have been quite disappointing, the results of ongoing phase II trials combining HSP90 inhibitors and conventional chemotherapy or proteasome inhibitor are highly anticipated. HDAC Inhibitors, the Next “Big Thing” in Medical Oncology? With more than 1 publication a day for the last 3 years, HDAC inhibitors (HDACi) currently represent one of most active fields of re- search in experimental cancer therapeutics. The contribution of HDACs to tumour angiogenesis was first evidenced less than 10 years ago. However, as explained in this issue, major advances have been made since this initial discovery and our understanding of both the pro- angiogenic functions of HDACs and the anti-angiogenic properties of HDACi has considerably increased. By directly and indirectly regulat- ing the expression of numerous genes involved in angiogenesis, HDACs are at the crossroads of several pro-angiogenic pathways including HIF-1α and VEGF/VEGFR signalling. Therefore, it is not surprising to see the list of HDACi with potent anti-angiogenic properties regu- larly expand. The review by Mottet and Castronovo explains the pro-angiogenic functions of HDACs and provides a snapshot of the current clinical development of HDACi. Endothelial Progenitor Cells, How to Look Beyond the Controversy? For new anti-angiogenic targets such as HSP90 and HDACs, as for any anti-vascular strategy, powerful diagnostic, predictive and surrogate markers are crucially needed. Endothelial progenitor cells (EPCs) were recently shown to be involved in tumour vascularization and response to anti-vascular treatment, and thus represent promising biomarkers. However, the definition, origin and role of EPCs remain controversial. As explained in detail in this issue, the debate surrounding the role of EPCs in tumour vascularization and their potential as reliable biomarkers partially originates from the technical challenges associated with their accurate detection and characterization. In addition, preclinical and clinical studies have reported variable levels of mobilization and recruitment of EPCs, according to the models and settings. Recent findings have shed some light on the mechanisms involved in the recruitment of bone marrow-derived pro-angiogenic cells and provided a possible explanation for this discrepancy of results. One positive aspect of any scientific controversy is the consequent eagerness of researchers to try and solve the puzzle. The actual controversy surrounding EPCs have recently drawn the attention of both scientists and clinicians to this field of research, resulting in significant breakthroughs, detailed in the review article by Pasquier and Dias. The myriad of possibilities offered by the very existence of a cell population that is potentially capable of generating new endothelial cells, promoting de novo formation of blood vessels and healing vascular injury, is likely to lead to major therapeutic advances in cancer and other angiogenesis-related disorders. However, standardization of detection methods and optimization of isolation protocols are crucially needed in order to get better insights into the biology of EPCs and other bone marrow-derived pro-angiogenic cells. The establishment of such powerful biomarkers represents one of the key challenges for the antiangiogenic strategies reviewed in this special issue and the development of global, combinatorial and personalized therapeutic approaches to treat cancer.

Tumor angiogenesis, i.e. the development of neovascularisation in and around solid tumors, plays a key role in the local and distant growth of cancer and anti-angiogenic treatments are now established strategies to treat cancer patients. Specific inhibitors of angiogenesis such as bevacizumab or receptor tyrosine kinase inhibitors targeting VEGFR or PDGFR are now in clinical trials and are being increasingly validated for the treatment of poor prognostic cancers. Other anti-angiogenic strategies such as cilengitide or metronomic chemotherapy (low-dose anti-angiogenic chemotherapy) have been developed to treat certain types of adult cancer. In children, the clinical potential of anti-angiogenic approach is still in an early stage of investigation. This review will focus on the role of angiogenesis in pediatric solid tumors and will describe the pre-clinical and clinical experience with several anti-angiogenic compounds as a potential treatment for children with cancer.

The inhibition of oncogenic signaling pathways has gained great interest for cancer therapy. In this context, the molecular chaperone heat shock protein 90 (HSP90) has emerged as a promising molecular target, since it is critically involved in maintaining stability, integrity and functions of key oncogenic proteins. A variety of HSP90 inhibitors have been developed in the past decade and have shown convincing anti-neoplastic activity in pre-clinical tumor models. Importantly, HSP90 inhibitors are predominantly being recognized as “tumor cell targeting” agents since cancer cells a) overexpress HSP90 protein, b) highly rely on HSP90 function for maintaining oncogenic signaling, and c) HSP90 inhibitors bind with high affinity to HSP90 in tumor cells. Nevertheless, results from recent studies also suggest that HSP90 inhibitors elicit anti-angiogenic properties by affecting the PI-3K/Akt/eNOS signal transduction pathway in endothelial cells, as well as through down-regulation of VEGFR-2 expression, a crucial component of the angiogenic process. In addition, blocking HSP90 may also diminish the secretion and expression of tumor cell-derived pro-angiogenic growth factors and cytokines, thus leading to “indirect” anti-angiogenic effects. This review article focuses on the role of HSP90 in angiogenesis and on delineating the effects of HSP90 inhibitors on angiogenic signaling pathways involved in tumor vascularization.

Judah Folkman was the first in 1971 to observe and report that cancer growth and dissemination were dependent on angiogenesis - the formation of new blood vessels from pre-existing vasculature. For almost 40 years, this concept has inspired generations of researchers to identify anti-angiogenic molecules that could be used therapeutically to stop blood vessels formation and starve tumors of nutrients and oxygen. Tumor angiogenesis requires complex cellular and molecular interactions between endothelial and cancer cells. In response to external stimuli such as hypoxia, cancer cells secrete pro-angiogenic factors into the extracellular matrix that activate the surrounding endothelial cells to proliferate, migrate and form new blood vessels. So, vascularization of malignant lesions depends on the expression of specific genes in both endothelial and tumor cells and accumulating evidence shows that several members of the histone deacetylase (HDAC) family play key roles in the regulation of these genes. Indeed, numerous in vitro and in vivo studies demonstrated that inhibitors of HDAC modulate angiogenic gene expression in both endothelial and cancer cells and disturb the delicate and complex balance between the collective action of pro-angiogenic factors and angiogenesis inhibitors. Thus, HDAC are currently recognized as promising targets for the development of anti-cancer drugs. This review is an effort to present and discuss the role, functions and mechanisms of action of HDAC during tumor-driven angiogenesis as well as a brief summary of the clinical status of the main HDAC inhibitors (HDACi) currently under development in cancer therapy.

The capacity to induce new blood vessel formation or to repair damaged vessels is an attractive idea that has, for a long time, captured the attention and imagination of researchers. Beside the identification of the pro-angiogenic growth factors and their counterpart inhibitors, the discovery of endothelial progenitor cells (EPC) in adults and their putative vascular-promoting and/or vascular-healing properties, has generated some of the biggest fascination and debate in the broad field of vascular biology. The simple concept of a population of undifferentiated cells being able to generate new endothelial cells and the corresponding blood vessels in adults is both intriguing and, as seen in the last 10 years, controversial. Academic rivalry or pure scientific dispute has accompanied the research on EPC for some time. The major issues put forward by opposing groups of scientists regarding the identity and the role of EPCs as well as the optimal isolation and detection techniques are discussed in this review. The clinical relevance of EPCs and their potential applications in cancer treatments are also highlighted.

The efficacy of cancer-immunotherapy with complement-activating monoclonal antibodies is limited by over-expression of one or more membrane-bound complement regulatory proteins (mCRPs: CD46, CD55, CD59) on the surface of neoplastic cells. In this study we designed small interfering RNAs (siRNAs) for posttranscriptional gene knock down of CD46, CD55 and CD59 aiming to sensitize tumor cells to complement attack and thereby to better exploit complement for tumor cell destruction. Tumor cell lines of different origin, such as Du145 (prostate), BT474 (breast) and K562 (erythroleukemia) were selected for the study. FACS-analysis demonstrated that siRNA anti-CD46(301) reduced CD46 protein expression up to 80%, siRNA anti-CD55(255) diminished CD55 protein expression up to 49%, and CD59 protein expression was inhibited up to 82% by siRNA anti-CD59(1339). Time course experiments revealed a long-lasting silencing effect with >50% complement regulator inhibition up to day 13. Upon mCRP knock down, complementdependent cytotoxicity (CDC) was augmented by 20-30% for CD46, by up to 24% for CD55 and by up to 55% for CD59. The combined inhibition of all three inhibitors further enhanced CDC by up to 66%. Dependent on the cell line, CD46 and CD55 downregulation increased significantly C3 ospsonization, which is known to support cell-mediated defense mechanisms. mCRP blocking antibodies were only partly able to further augment the tumor cells' susceptibility to complement lysis. Thus, siRNA-induced inhibition of complement regulator expression clearly sensitizes malignant cells to complement attack and, if specifically targeted to the tumor, appears suited as adjuvant to improve antibody-based cancer immunotherapy.

Pokemon gene has crucial but versatile functions in cell differentiation, proliferation and tumorigenesis. It is a master regulator of the ARF-HDM2-p53 and Rb-E2F pathways. The facts that the expression of Pokemon is essential for tumor formation and many kinds of tumors over-express the Pokemon gene make it an attractive target for therapeutic intervention for cancer treatment. In this study, we used an RNAi strategy to silence the Pokemon gene in a cervical cancer model. To address the issues involving tumor specific delivery and durable expression of siRNA, we applied the Arg-Gly-Asp (RGD) peptide ligand and polylysine (K18) fusion peptide to encapsulate a recombinant retrovirus plasmid expressing a siRNA targeting the Pokemon gene and produced the ‘mimoretrovirus’. At charge ratio 2.0 of fusion peptide/plasmid, the mimoretrovirus formed stable and homogenous nanoparticles, and provided complete DNase I protection and complete gel retardation. This nanoparticle inhibited SiHa cell proliferation and invasion, while it promoted SiHa cell apoptosis. The binding of the nanoparticle to SiHa cells was mediated via the RGD-integrin αvβ3 interaction, as evidenced by the finding that unconjugated RGD peptide inhibited this binding significantly. This tumor-targeting mimoretrovirus exhibited excellent anti-tumor capacity in vivo in a nude mouse model. Moreover, the mimoretrovirus inhibited tumor growth with a much higher efficiency than recombinant retrovirus expressing siRNA or the K18/P4 nanoparticle lacking the RGD peptide. Results suggest that the RNAi/RGD-based mimoretrovirus developed in this study represents a novel anti-tumor strategy that may be applicable to most research involving cancer therapy and, thus, has promising potential as a cervical cancer treatment.