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• Co-administration phenoxodiol with doxorubicin synergistically inhibit the activity of sphingosine kinase-1 (SphK1), a potential oncogene of osteosarcoma, to suppress osteosarcoma cell growth both in vivo and in vitro.

  Authors: Chen Yao, Sujia Wu, Dong Li, Huimin Ding, Zuyu Wang, Yongjiang Yang, Shichang Yan, Zhangping Gu

  Molecular oncology.

  Elucidation of the mechanisms of chemo-resistance and implementation of strategies to overcome it will be pivotal to improve the survival for osteosarcoma (OS) patients. We here suggest thatElucidation of the mechanisms of chemo-resistance and implementation of strategies to overcome it will be pivotal to improve the survival for osteosarcoma (OS) patients. We here suggest that sphingosine kinase-1 (SphK1) might be the key factor contributing to chemo-resistance in OS. Our Western-blots and immunohistochemistry results showed that SphK1 is over-expressed in multiple clinical OS tissues. Over-expression of SphK1 in OS cell line U2OS promoted its growth and endorsed its resistance against doxorubicin, while knocking-down of SphK1 by shRNA inhibited U2OS cell growth and increased its sensitivity to doxorubicin. Co-administration phenoxodiol with doxorubicin synergistically inhibited SphK1 activity to trigger cellular ceramide accumulation, and achieved synergistic anti-OS growth effect, accompanied with a significant increased of apoptosis and cytotoxicity. Increased cellular level of ceramide by the co-administration induced the association between Akt and Protein Phosphatase 1 (PP1) to dephosphorylate Akt, and to introduce a constitutively active Akt (CA-Akt) restored Akt activation and diminished cell growth inhibition. Further, phenoxodiol and doxorubicin synergistically activated apoptosis signal-regulating kinase 1(ASK1)/c-jun-NH2-kinase (JNK) signaling, which also contributed to cell growth inhibition. Significantly, the role of SphK1 in OS cell growth and the synergistic anti-OS effect of phenoxodiol and doxorubicin were also seen in a mice OS xenograft model. In conclusion, our data suggest that SphK1 might be a critical oncogene of OS and co-administration phenoxodiol with doxorubicin synergistically inhibited the activity of SphK1 to suppress osteosarcoma cell growth both in vivo and in vitro.

• Oncosuppressive role of p53-induced miR-205 in triple negative breast cancer.

  Authors: Claudia Piovan, Dario Palmieri, Gianpiero Di Leva, Luca Braccioli, Patrizia Casalini, Gerard Nuovo, Monica Tortoreto, Marianna Sasso, Ilaria Plantamura, Tiziana Triulzi, Cristian Taccioli, Elda Tagliabue, Marilena V Iorio, Carlo M Croce

  Molecular oncology.

  An increasing body of evidence highlights an intriguing interaction between microRNAs and transcriptional factors involved in determining cell fate, including the well known "genome guardian" p53.An increasing body of evidence highlights an intriguing interaction between microRNAs and transcriptional factors involved in determining cell fate, including the well known "genome guardian" p53. Here we show that miR-205, oncosuppressive microRNA lost in breast cancer, is directly transactivated by oncosuppressor p53. Moreover, evaluating miR-205 expression in a panel of cell lines belonging to the highly aggressive triple negative breast cancer (TNBC) subtype, which still lacks an effective targeted therapy and characterized by an extremely undifferentiated and mesenchymal phenotype, we demonstrated that this microRNA is critically down-expressed compared to a normal-like cell line. Re-expression of miR-205 where absent strongly reduces cell proliferation, cell cycle progression and clonogenic potential in vitro, and inhibits tumor growth in vivo, and this tumor suppressor activity is at least partially exerted through targeting of E2F1, master regulator of cell cycle progression, and LAMC1, component of extracellular matrix involved in cell adhesion, proliferation and migration.

• Identification of recurrence-related microRNAs in hepatocellular carcinoma following liver transplantation.

  Authors: Zhong-Bo Han, Lin Zhong, Mu-Jian Teng, Jun-Wei Fan, Hua-Mei Tang, Jun-Yi Wu, Hong-Yuan Chen, Zhao-Wen Wang, Guo-Qiang Qiu, Zhi-Hai Peng

  Molecular oncology.

  Tumor recurrence-related microRNAs (miRNAs) in hepatocellular carcinoma (HCC) following orthotopic liver transplantation (OLT) are not clear yet. This study was designed to determine whether alteredTumor recurrence-related microRNAs (miRNAs) in hepatocellular carcinoma (HCC) following orthotopic liver transplantation (OLT) are not clear yet. This study was designed to determine whether altered miRNA expression is associated with HCC recurrence and prognosis following OLT. 18 miRNAs, including 6 up-regulated and 12 down-regulated miRNAs were identified by microarray in primary HCC samples of patients who had developed HCC recurrence (n = 5) compared to those with non-recurrence (n = 5) following OLT by using p < 0.05 as cutoff value. The six most significantly altered miRNAs (fold change ≥ 2: miR-19a, miR-886-5p, miR-126, miR-223, miR-24 and miR-147) were further confirmed by qRT-PCR in the remaining 105 HCC samples. In receiver-operating characteristic curve analysis, this six miRNAs were of high sensitivity and specificity in predicting HCC recurrence. Using Cox regression and risk score analysis, we built a six-miRNA signature based on their qRT-PCR readings for the prediction of outcome of HCC following OLT. Kaplan-Meier and Cox proportional regression revealed this six-miRNA signature was a significant independent predictor of overall survival (log-rank p = 0.020) and recurrence-free survival (log-rank p < 0.001). Finally, the data were further reconfirmed in an independent cohort of 50 patients from another transplant center. In addition, bioinformatics Gene Ontology and pathway analysis were also performed to better understand the critical roles of these miRNAs in HCC recurrence. Our study, in addition to suggesting a different miRNA expression pattern between HCC samples of patients with recurrence and those with non-recurrence, proposes that this six-miRNA signature may serve as biomarker for prognosis of HCC patients following OLT.

• Curcumin inhibits tumor proliferation induced by neutrophil elastase through the upregulation of α1-antitrypsin in lung cancer.

  Authors: Yan Xu, Jingjie Zhang, Jing Han, Xueyang Pan, Yajun Cao, Hao Guo, Yan Pan, Yu An, Xuejun Li

  Molecular oncology.

  Lung carcinogenesis is a complex process in an unregulated inflammatory environment. Curcumin has been extensively investigated as a multi-target anti-tumor and anti-inflammation compound. In thisLung carcinogenesis is a complex process in an unregulated inflammatory environment. Curcumin has been extensively investigated as a multi-target anti-tumor and anti-inflammation compound. In this paper, we demonstrate a novel inflammation-related mechanism for curcumin-induced inhibition of lung tumor growth. We found that neutrophil elastase, an important regulator of inflammatory processes, directly triggered tumor cell proliferation in human lung adenocarcinoma A549 cells, and curcumin could completely suppress the excess tumor proliferation induced by neutrophil elastase. α1-antitrypsin is synthesized by tumor cells and is the natural inhibitor of neutrophil elastase. We found that curcumin counteracted the decrease of α1-antitrypsin induced by neutrophil elastase by inducing the promoter activity of α1-antitrypsin and promoting its expression in A549 cells. The inhibition of neutrophil elastase-induced proliferation by curcumin was dependent on the PI3K/Akt pathway. Knockdown of α1-antitrypsin by siRNA further enhanced the tumor cell proliferation induced by neutrophil elastase and significantly blocked the anti-proliferation effect of curcumin against neutrophil elastase. Curcumin remarkably inhibited the primary tumor growth of Lewis lung carcinoma (LLC) in C57BL/6 mice. We further showed that curcumin upregulated the level of α1-antitrypsin in primary tumor tissue by promoting its local expression, and the protein level of neutrophil elastase in tumor tissue was obviously decreased in mice treated with curcumin. Overall, our results suggest that neutrophil elastase and α1-antitrypsin play important roles in modulating lung tumor proliferation in inflammatory microenvironment and curcumin inhibits neutrophil elastase-induced tumor proliferation via upregulating α1-antitrypsin expression in vitro and in vivo.

• Effect of antiangiogenic therapy on tumor growth, vasculature and kinase activity in basal- and luminal-like breast cancer xenografts.

  Authors: Evita M Lindholm, Alexandr Kristian, Hawa Nalwoga, Kristi Krüger, Ståle Nygård, Lars A Akslen, Gunhild M Mælandsmo, Olav Engebraaten

  Molecular oncology.

  Several clinical trials have investigated the efficacy of bevacizumab in breast cancer, and even if growth inhibiting effects have been registered when antiangiogenic treatment is given inSeveral clinical trials have investigated the efficacy of bevacizumab in breast cancer, and even if growth inhibiting effects have been registered when antiangiogenic treatment is given in combination with chemotherapy no gain in overall survival has been observed. One reason for the lack of overall survival benefit might be that appropriate criteria for selection of patients likely to respond to antiangiogenic therapy in combination with chemotherapy, are not available. To determine factors of importance for antiangiogenic treatment response and/or resistance, two representative human basal- and luminal-like breast cancer xenografts were treated with bevacizumab and doxorubicin alone or in combination. In vivo growth inhibition, microvessel density (MVD) and proliferating tumor vessels (pMVD = proliferative microvessel density) were analysed, while kinase activity was determined using the PamChip Tyrosine kinase microarray system. Results showed that both doxorubicin and bevacizumab inhibited basal-like tumor growth significantly, but with a superior effect when given in combination. In contrast, doxorubicin inhibited luminal-like tumor growth most effectively, and with no additional benefit of adding antiangiogenic therapy. In agreement with the growth inhibition data, vascular characterization verified a more pronounced effect of the antiangiogenic treatment in the basal-like compared to the luminal-like tumors, demonstrating total inhibition of pMVD and a significant reduction in MVD at early time points (three days after treatment) and sustained inhibitory effects until the end of the experiment (day 18). In contrast, luminal-like tumors only showed significant effect on the vasculature at day 10 in the tumors having received both doxorubicin and bevacizumab. Kinase activity profiling in both tumor models demonstrated that the most effective treatment in vivo was accompanied with increased phosphorylation of kinase substrates of growth control and angiogenesis, like EGFR, VEGFR2 and PLCγ1. This may be a result of regulatory feedback mechanisms contributing to treatment resistance, and may suggest response markers of value for the prediction of antiangiogenic treatment efficacy.

• ALDH(+) tumor-initiating cells exhibiting gain in NOTCH1 gene copy number have enhanced regrowth sensitivity to a γ-secretase inhibitor and irinotecan in colorectal cancer.

  Authors: John J Arcaroli, Rebecca W Powell, Marileila Varella-Garcia, Martine McManus, Aik Choon Tan, Kevin S Quackenbush, Todd M Pitts, Dexiang Gao, Anna Spreafico, Arvind Dasari, Basel M Touban, Wells A Messersmith

  Molecular oncology.

  The Notch signaling pathway has been shown to be upregulated in colorectal cancer (CRC) and important for the self-renewal of cancer stem cells. In this study, we evaluated the efficacy ofThe Notch signaling pathway has been shown to be upregulated in colorectal cancer (CRC) and important for the self-renewal of cancer stem cells. In this study, we evaluated the efficacy of PF-03084014, a γ-secretase inhibitor, in combination with irinotecan to identify the effects of treatment on tumor recurrence and the tumor-initiating population in our CRC preclinical explant model. The combination of PF-03084014 and irinotecan had the greatest effect at reducing tumor growth on four CRC tumors when compared with treatment with PF-03084014 or irinotecan alone. The combination significantly reduced tumor recurrence in two CRC explants (CRC001 and CRC036) after treatment was discontinued. Both of these tumors exhibited elevated baseline levels of Notch pathway activation as well as an increase in NOTCH1 gene copy number when compared with the two CRC explants (CRC026 and CRC027) where tumors reappeared quickly after termination of treatment. Isolation and injection of aldehyde dehydrogenase (ALDH(+) and ALDH(-)) cells in an in vivo explant model demonstrated that the ALDH(+) cell population were tumorigenic. Evaluation of the ALDH(+) cells after 28 days of treatment showed that the combination reduced the ALDH(+) population in the tumors that did not regrow. Furthermore, ALDH(+) cells from CRC001 and CRC027 were injected in vivo and treated immediately for 28 days. Two months after treatment, tumors were evident in the combination treatment group for CRC027 but not for CRC036. These results indicate the combination of PF-03084014 and irinotecan may be effective in reducing tumor recurrence in CRC patients whose tumors exhibit elevated levels of the Notch pathway.

• Molecular pathology.

  Authors: Stanley R Hamilton

  Molecular oncology.

  Molecular pathology as applied to neoplasia is a rapidly expanding component of the discipline of pathology that uses molecular biology tools in addition to conventional morphologic,Molecular pathology as applied to neoplasia is a rapidly expanding component of the discipline of pathology that uses molecular biology tools in addition to conventional morphologic, immunohistochemical and chemical analyses of abnormalities in tissues and cells to understand the etiology and pathogenesis of tumors, establish their diagnosis, and contribute to prognostication and therapeutic decisions for cancer patient care. Biomarkers are a fundamental component of personalized cancer care, and the discipline of molecular pathology therefore contributes throughout the continuum from biomarker research to use in standard-of-care personalized cancer therapy. This brief review addresses some of the specific roles of molecular pathology in that continuum.

• Hematopoietic growth factors: Personalization of risks and benefits.

  Authors: Shannon Puhalla, Saveri Bhattacharya, Nancy E Davidson

  Molecular oncology.

  A common side effect of cancer treatment is bone marrow suppression. The resulting myelosuppression and anemia can cause significant morbidity and mortality for patients. Agents such as granulocyteA common side effect of cancer treatment is bone marrow suppression. The resulting myelosuppression and anemia can cause significant morbidity and mortality for patients. Agents such as granulocyte colony stimulating factors (GCSF) and erythropoietin stimulating agents (ESAs) may be helpful to ameliorate this depression of blood counts; however these agents have risks which also need to be carefully weighed.

• The challenge to bring personalized cancer medicine from clinical trials into routine clinical practice: The case of the Institut Gustave Roussy.

  Authors: Monica Arnedos, Fabrice André, Françoise Farace, Ludovic Lacroix, Benjamin Besse, Caroline Robert, Jean Charles Soria, Alexander M M Eggermont

  Molecular oncology.

  Research with high throughput technologies has propitiated the segmentation of different types of tumors into very small subgroups characterized by the presence of very rare molecular alterations.Research with high throughput technologies has propitiated the segmentation of different types of tumors into very small subgroups characterized by the presence of very rare molecular alterations. The identification of these subgroups and the apparition of new agents targeting these infrequent alterations are already affecting the way in which clinical trials are being conducted with an increased need to identify those patients harboring specific molecular alterations. In this review we describe some of the currently ongoing and future studies at the Institut Gustave Roussy that aim for the identification of potential therapeutic targets for cancer patients with the incorporation of high throughput technologies into daily practice including aCGH, next generation sequencing and the creation of a software that allows for target identification specific for each tumor. The initial intention is to enrich clinical trials with cancer patients carrying certain molecular alterations in order to increase the possibility of demonstrating benefit from a targeted agent. Mid and long term aims are to facilitate and speed up the process of drug development as well as to implement the concept of personalized medicine.

• Personalized cancer medicine - A strategy to counteract an increasing cancer challenge.

  Authors: John Mendelsohn, Ulrik Ringborg, Richard L Schilsky

  Molecular oncology.

• Molecular imaging for personalized cancer care.

  Authors: Moritz F Kircher, Hedvig Hricak, Steven M Larson

  Molecular oncology.

  Molecular imaging is rapidly gaining recognition as a tool with the capacity to improve every facet of cancer care. Molecular imaging in oncology can be defined as in vivo characterization andMolecular imaging is rapidly gaining recognition as a tool with the capacity to improve every facet of cancer care. Molecular imaging in oncology can be defined as in vivo characterization and measurement of the key biomolecules and molecularly based events that are fundamental to the malignant state. This article outlines the basic principles of molecular imaging as applied in oncology with both established and emerging techniques. It provides examples of the advantages that current molecular imaging techniques offer for improving clinical cancer care as well as drug development. It also discusses the importance of molecular imaging for the emerging field of theranostics and offers a vision of how molecular imaging may one day be integrated with other diagnostic techniques to dramatically increase the efficiency and effectiveness of cancer care.

• Omics and therapy - A basis for precision medicine.

  Authors: Joseph P Garay, Joe W Gray

  Molecular oncology.

  A founding premise of the human genome project was that knowledge of the spectrum of abnormalities that comprise cancers and other human diseases would lead to improved disease management byA founding premise of the human genome project was that knowledge of the spectrum of abnormalities that comprise cancers and other human diseases would lead to improved disease management by identifying molecular abnormalities that could guide disease detection and diagnosis, suggest new therapeutic strategies and be developed as markers to predict response to therapy. This project led to elucidation of a reference normal human genome sequence and normal polymorphisms therein against which sequences from diseased tissues can be compared to enable identification of causal abnormalities. It also stimulated development of an array of computational tools for genomic analysis and catalyzed public and private sector development of revolutionary tools for genome analysis that transformed analysis of whole genomes from an enterprise that required international teams and hundreds of millions of dollars to a process that can be carried out in core facilities for only a few thousand dollars per sample. Indeed, the $1000 genome is nearly upon us. Applications of these technologies to human cancers in international cancer genome projects are now revealing the spectra of abnormalities that comprise thousands of individual cancers. Analyses of these data are leading to the promised improvements in disease management. We review several aspects of cancer genomics with emphasis on aspects that are relevant to improving cancer therapy.

• Paying for personalized care: Cancer biomarkers and comparative effectiveness.

  Authors: Rahber Thariani, David L Veenstra, Josh J Carlson, Louis P Garrison, Scott Ramsey

  Molecular oncology.

  Genomic-based diagnostics can play a key role in creating a more efficient healthcare system by directing patients toward beneficial therapies and away from therapies that pose substantial risk orGenomic-based diagnostics can play a key role in creating a more efficient healthcare system by directing patients toward beneficial therapies and away from therapies that pose substantial risk or are unlikely to improve outcomes for the patient. We outline how the value provided by diagnostics is closely linked to a range of factors including magnitude of health outcome improvement, avoiding adverse effect, diagnostic parameters, process of care, resource utilization, and costs. Comparative effectiveness approaches to evidence generation, including health outcome measurements, quality of life, economic analyses, decision modeling, and pragmatic clinical trials, can be used to provide stakeholders with a range of information to inform treatment, guidelines, coverage, and reimbursement decisions. Evidence of comparative effectiveness can also help support value-based reimbursement of cancer biomarkers and treatment strategies as means of paying for personalized medicine.

• Discovery of small molecule cancer drugs: Successes, challenges and opportunities.

  Authors: Swen Hoelder, Paul A Clarke, Paul Workman

  Molecular oncology.

  The discovery and development of small molecule cancer drugs has been revolutionised over the last decade. Most notably, we have moved from a one-size-fits-all approach that emphasized cytotoxicThe discovery and development of small molecule cancer drugs has been revolutionised over the last decade. Most notably, we have moved from a one-size-fits-all approach that emphasized cytotoxic chemotherapy to a personalised medicine strategy that focuses on the discovery and development of molecularly targeted drugs that exploit the particular genetic addictions, dependencies and vulnerabilities of cancer cells. These exploitable characteristics are increasingly being revealed by our expanding understanding of the abnormal biology and genetics of cancer cells, accelerated by cancer genome sequencing and other high-throughput genome-wide campaigns, including functional screens using RNA interference. In this review we provide an overview of contemporary approaches to the discovery of small molecule cancer drugs, highlighting successes, current challenges and future opportunities. We focus in particular on four key steps: Target validation and selection; chemical hit and lead generation; lead optimization to identify a clinical drug candidate; and finally hypothesis-driven, biomarker-led clinical trials. Although all of these steps are critical, we view target validation and selection and the conduct of biology-directed clinical trials as especially important areas upon which to focus to speed progress from gene to drug and to reduce the unacceptably high attrition rate during clinical development. Other challenges include expanding the envelope of druggability for less tractable targets, understanding and overcoming drug resistance, and designing intelligent and effective drug combinations. We discuss not only scientific and technical challenges, but also the assessment and mitigation of risks as well as organizational, cultural and funding problems for cancer drug discovery and development, together with solutions to overcome the 'Valley of Death' between basic research and approved medicines. We envisage a future in which addressing these challenges will enhance our rapid progress towards truly personalised medicine for cancer patients.

• Hormonal therapy in breast cancer: A model disease for the personalization of cancer care.

  Authors: Shannon Puhalla, Saveri Bhattacharya, Nancy E Davidson

  Molecular oncology.

  The treatment of breast cancer is driven by subtype classification, of which the assessment of hormone receptor status is one of the important determinants of therapy. The use of hormonal therapy toThe treatment of breast cancer is driven by subtype classification, of which the assessment of hormone receptor status is one of the important determinants of therapy. The use of hormonal therapy to treat estrogen-receptor positive breast cancer has been studied for over a century and is one of the well-described uses of personalized medicine. In this review, we will describe the classification of hormone receptor status and the various endocrine treatment strategies. Opportunities for personalization of care are illustrated.

• Bioinformatics and systems biology.

  Authors: Prahlad T Ram, John Mendelsohn, Gordon B Mills

  Molecular oncology.

  Delivering personalized therapeutic options to cancer patients based on the genetic and molecular aberrations of the tumor offers great promise to improve the outcomes of cancer therapy. SignificantDelivering personalized therapeutic options to cancer patients based on the genetic and molecular aberrations of the tumor offers great promise to improve the outcomes of cancer therapy. Significant progress in biotechnology has allowed the measurement of tens of thousands of "omic" data points across multiple levels (DNA, RNA protein, metabolomics) from a single tumor biopsy sample in a reasonable time frame for making clinical decisions. With this data in hand, the challenge from the bioinformatics and systems biology point of view is how does one convert data into information and knowledge that can improve the delivery of personalized therapy to the patient.

• Indirubin derivatives induce apoptosis of chronic myelogenous leukemia cells involving inhibition of Stat5 signaling.

  Authors: Sangkil Nam, Anna Scuto, Fan Yang, Wenyong Chen, Sungman Park, Hwa-Seung Yoo, Heiko Konig, Ravi Bhatia, Xinlai Cheng, Karl-Heinz Merz, Gerhard Eisenbrand, Richard Jove

  Molecular oncology.

  Indirubin is the major active anti-tumor component of a traditional Chinese herbal medicine used for treatment of chronic myelogenous leukemia (CML). While previous studies indicate that indirubin isIndirubin is the major active anti-tumor component of a traditional Chinese herbal medicine used for treatment of chronic myelogenous leukemia (CML). While previous studies indicate that indirubin is a promising therapeutic agent for CML, the molecular mechanism of action of indirubin is not fully understood. We report here that indirubin derivatives (IRDs) potently inhibit Signal Transducer and Activator of Transcription 5 (Stat5) protein in CML cells. Compound E804, which is the most potent in this series of IRDs, blocked Stat5 signaling in human K562 CML cells, imatinib-resistant human KCL-22 CML cells expressing the T315I mutant Bcr-Abl (KCL-22M), and CD34-positive primary CML cells from patients. Autophosphorylation of Src family kinases (SFKs) was strongly inhibited in K562 and KCL-22M cells at 5 μM E804, and in primary CML cells at 10 μM E804, although higher concentrations partially inhibited autophosphorylation of Bcr-Abl. Previous studies indicate that SFKs cooperate with Bcr-Abl to activate downstream Stat5 signaling. Activation of Stat5 was strongly blocked by E804 in CML cells. E804 down-regulated expression of Stat5 target proteins Bcl-x(L) and Mcl-1, associated with induction of apoptosis. In sum, our findings identify IRDs as potent inhibitors of the SFK/Stat5 signaling pathway downstream of Bcr-Abl, leading to apoptosis of K562, KCL-22M and primary CML cells. IRDs represent a promising structural class for development of new therapeutics for wild type or T315I mutant Bcr-Abl-positive CML patients.

• Moving molecular targeted drug therapy towards personalized medicine: Issues related to clinical trial design.

  Authors: Jaap Verweij, Maja de Jonge, Ferry Eskens, Stefan Sleijfer

  Molecular oncology.

  With the event of new Molecular targets, clinical trial design requirements to perform these trials are changing. This paper discusses some of the considerations that need to be taken into accountWith the event of new Molecular targets, clinical trial design requirements to perform these trials are changing. This paper discusses some of the considerations that need to be taken into account when designing a trial, including those trials that assess combinations of targets.

• EGFR and myosin II inhibitors cooperate to suppress EGFR-T790M-mutant NSCLC cells.

  Authors: Huan-Chih Chiu, Teng-Yuan Chang, Chin-Ting Huang, Yu-Sheng Chao, John T-A Hsu

  Molecular oncology.

  An acquired mutation (T790M) in the epidermal growth factor receptor (EGFR) accounts for half of all relapses in non-small cell lung cancer (NSCLC) patients who initially respond to EGFR kinaseAn acquired mutation (T790M) in the epidermal growth factor receptor (EGFR) accounts for half of all relapses in non-small cell lung cancer (NSCLC) patients who initially respond to EGFR kinase inhibitors. In this study, we demonstrated for the first time that EGFR-T790M interacts with the cytoskeletal components, myosin heavy chain 9 (MYH9) and β-actin, in the nucleus of H1975 cells carrying the T790M-mutant EGFR. The interactions of EGFR with MYH9 and β-actin were reduced in the presence of blebbistatin, a specific inhibitor for the MYH9-β-actin interaction, suggesting that the EGFR interaction with MYH9 and β-actin is affected by the integrity of the cytoskeleton. These physical interactions among MYH9, β-actin, and EGFR were also impaired by CL-387,785, a kinase inhibitor for EGFR-T790M. Furthermore, CL-387,785 and blebbistatin interacted in a synergistic fashion to suppress cell proliferation and induce apoptosis in H1975 cells. The combination of CL-387,785 and blebbistatin enhanced the down-regulation of cyclooxygenase-2 (COX-2), a transcriptional target of nuclear EGFR. Overall, our findings demonstrate that disrupting EGFR interactions with the cytoskeletal components enhanced the anti-cancer effects of CL-387,785 against H1975 cells, suggesting a novel therapeutic approach for NSCLC cells that express the drug-resistant EGFR-T790M.

• Individualization of cancer treatment from radiotherapy perspective.

  Authors: Ala Yaromina, Mechthild Krause, Michael Baumann

  Molecular oncology.

  Radiotherapy is today used in about 50% of all cancer patients, often in multidisciplinary approaches. With major advance in radiotherapy techniques, increasing knowledge on tumor genetics andRadiotherapy is today used in about 50% of all cancer patients, often in multidisciplinary approaches. With major advance in radiotherapy techniques, increasing knowledge on tumor genetics and biology and the continuous introduction of specifically targeted drugs into combined radio-oncological treatment schedules, individualization of radiotherapy is of high priority to further improve treatment outcomes, i.e. to increase long-term tumor cure and/or to reduce chronic treatment toxicity. This review gives an overview on the importance of predictive biomarkers for the field of radiation oncology. The current status of knowledge on potential biomarkers of tumor hypoxia, tumor cell metabolism, DNA repair, cancer stem cells and biomarkers for combining radiotherapy with inhibition of the epidermal growth factor receptor using monoclonal antibodies is described.

• Cancer biomarkers.

  Authors: N Lynn Henry, Daniel F Hayes

  Molecular oncology.

  Biomarkers have many potential applications in oncology, including risk assessment, screening, differential diagnosis, determination of prognosis, prediction of response to treatment, and monitoringBiomarkers have many potential applications in oncology, including risk assessment, screening, differential diagnosis, determination of prognosis, prediction of response to treatment, and monitoring of progression of disease. Because of the critical role that biomarkers play at all stages of disease, it is important that they undergo rigorous evaluation, including analytical validation, clinical validation, and assessment of clinical utility, prior to incorporation into routine clinical care. In this review we address key steps in the development of biomarkers, including ways to avoid introducing bias and guidelines to follow when reporting results of biomarker studies.

• The biology of personalized cancer medicine: Facing individual complexities underlying hallmark capabilities.

  Authors: Michele De Palma, Douglas Hanahan

  Molecular oncology.

  It is a time of great promise and expectation for the applications of knowledge about mechanisms of cancer toward more effective and enduring therapies for human disease. Conceptualizations such asIt is a time of great promise and expectation for the applications of knowledge about mechanisms of cancer toward more effective and enduring therapies for human disease. Conceptualizations such as the hallmarks of cancer are providing an organizing principle with which to distill and rationalize the abject complexities of cancer phenotypes and genotypes across the spectrum of the human disease. A countervailing reality, however, involves the variable and often transitory responses to most mechanism-based targeted therapies, returning full circle to the complexity, arguing that the unique biology and genetics of a patient's tumor will in the future necessarily need to be incorporated into the decisions about optimal treatment strategies, the frontier of personalized cancer medicine. This perspective highlights considerations, metrics, and methods that may prove instrumental in charting the landscape of evaluating individual tumors so to better inform diagnosis, prognosis, and therapy. Integral to the consideration is remarkable heterogeneity and variability, evidently embedded in cancer cells, but likely also in the cell types composing the supportive and interactive stroma of the tumor microenvironment (e.g., leukocytes and fibroblasts), whose diversity in form, regulation, function, and abundance may prove to rival that of the cancer cells themselves. By comprehensively interrogating both parenchyma and stroma of patients' cancers with a suite of parametric tools, the promise of mechanism-based therapy may truly be realized.

• Heterogeneity among RIP-Tag2 insulinomas allows vascular endothelial growth factor-A independent tumor expansion as revealed by studies in Shb mutant mice: Implications for tumor angiogenesis.

  Authors: Björn Akerblom, Guangxiang Zang, Zhen W Zhuang, Gabriela Calounova, Michael Simons, Michael Welsh

  Molecular oncology.

  The Shb adapter protein is a signaling intermediate that operates downstream of vascular endothelial growth factor receptor-2 (VEGFR-2) in endothelial cells. The Shb knockout mouse displays aThe Shb adapter protein is a signaling intermediate that operates downstream of vascular endothelial growth factor receptor-2 (VEGFR-2) in endothelial cells. The Shb knockout mouse displays a dysfunctional microvasculature and impaired growth of subcutaneously implanted tumor cells. We decided to investigate tumor growth and angiogenesis in the absence of Shb in an inheritable tumor model, the RIP-Tag2 mouse, which produces insulinomas in a manner highly dependent on de novo angiogenesis. We observed a reduced tumor incidence and burden in both RIP-Tag2 Shb-/- and RIP-Tag2 Shb+/- mice. This correlated with a reduced microvascular density, measured as a percentage of insulinoma area positive for CD31 staining, and altered vascular morphology. However, treatment with a VEGF-A blocking antibody was without effect on the Shb mutant tumor volume whereas it significantly inhibited tumor volume in the wild-type mice, suggesting that in mice with reduced Shb expression tumor angiogenesis was primarily sustained by VEGF-A independent pathway(s). This notion was further substantiated by gene expression analysis of angiogenic markers showing reduced VEGF-A expression in Shb-deficient tumors. Considerable heterogeneity with respect to the gene expression profiles of other angiogenic markers and the signal-transduction characteristics was observed between different tumors, suggesting that multiple "rescue" pathways could be operating. The numbers of invasive tumors or metastases were unchanged in the Shb mutant. It is concluded that the Shb mutant background reduces tumor frequency by chronically suppressing VEGF-A dependent angiogenesis. However, VEGF-A independent angiogenesis supports a significant degree of tumor expansion in Shb-deficient mice, indicating heterogeneity in the mechanisms by which tumor expansion is promoted. Interference with Shb signaling may provide novel means for future cancer therapy.

• The toxin component of targeted anti-tumor toxins determines their efficacy increase by saponins.

  Authors: Alexander Weng, Mayank Thakur, Figen Beceren-Braun, Diana Bachran, Christopher Bachran, Sebastian B Riese, Kristina Jenett-Siems, Roger Gilabert-Oriol, Matthias F Melzig, Hendrik Fuchs

  Molecular oncology.

  Tumor-targeting protein toxins are composed of a toxic enzyme coupled to a specific cell binding domain that targets cancer-associated antigens. The anti-tumor treatment by targeted toxins isTumor-targeting protein toxins are composed of a toxic enzyme coupled to a specific cell binding domain that targets cancer-associated antigens. The anti-tumor treatment by targeted toxins is accompanied by dose-limiting side effects. The future prospects of targeted toxins for therapeutic use in humans will be determined by reduce side effects. Certain plant secondary metabolites (saponins) were shown to increase the efficacy of a particular epidermal growth factor receptor (EGFR)-targeted toxin, paralleled by a tremendous decrease of side effects. This study was conducted in order to investigate the effects of substituting different toxin moieties fused to an EGF ligand binding domain on the augmentative ability of saponins for each against therapeutic potential of the saponin-mediated efficacy increase for different anti-tumor toxins targeting the EGFR. We designed several EGFR-targeted toxins varying in the toxic moiety. Each targeted toxin was used in combination with a purified saponin (SA1641), isolated from the ornamental plant Gypsophila paniculata L. SA1641 was characterized and the SA1641-mediated efficacy increase was investigated on EGFR-transfected NIH-3T3 cells. We observed a high dependency of the SA1641-mediated efficacy increase on the nature of toxin used for the construction of the targeted toxin, indicating high specificity. Structural alignments revealed a high homology between saporin and dianthin-30, the two toxic moieties that benefit most from the combination with SA1641. We further demonstrate that SA1641 did not influence the plasma membrane permeability, indicating an intracellular interaction of SA1641 and the toxin components of targeted toxins. Surface plasmon resonance measurements point to a transient binding of SA1641 to the toxin components of targeted toxins.

• Inhibition of NEDD8-conjugation pathway by novel molecules: Potential approaches to anticancer therapy.

  Authors: Tomoaki Tanaka, Tatsuya Nakatani, Tetsu Kamitani

  Molecular oncology.

  Cancer cells can survive through the upregulation of cell cycle and the escape from apoptosis induced by numerous cellular stresses. In the normal cells, these biological cascades depend on scheduledCancer cells can survive through the upregulation of cell cycle and the escape from apoptosis induced by numerous cellular stresses. In the normal cells, these biological cascades depend on scheduled proteolytic degradation of regulatory proteins via the ubiquitin-proteasome pathway. Therefore, interruption of regulated proteolytic pathways leads to abnormal cell-proliferation. Ubiquitin ligases called SCF complex (consisting of Skp-1, cullin, and F-box protein) or CRL (cullin-RING ubiquitin ligase) are predominant in a family of E3 ubiquitin ligases that control a final step in ubiquitination of diverse substrates. To a great extent, the ubiquitin ligase activity of the SCF complex requires the conjugation of NEDD8 to cullins, i.e. scaffold proteins. This review is anticipated to review the downregulation system of NEDD8 conjugation by several factors including a chemical compound such as MLN4924 and protein molecules (e.g. COP9 signalosome, inactive mutant of Ubc12, and NUB1/NUB1L). Since the downregulation of NEDD8 conjugation affects cell-cycle progression by inhibiting the ligase activity of SCF complexes, such knowledge in the NEDD8-conjugation pathway will contribute to the more magnificent therapies that selectively suppress tumorigenesis.

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