Molecular Oncology RSS feed: Current Issue. Molecular Oncology highlights new discoveries, approaches, as well as technical developments, in basic, clinical and discovery-driven translational research. Topics include: • Key biological processes such as cell cycle; DNA repair; apoptosis; invasion and metastasis; angiogenesis and lymphangiogenesis; cell signalling and interactive networks; immune response. • Emerging technologies (genomics, proteomics, functional genomics, metabolomics, tissue arrays, imaging), and model systems. •Biomarkers: diagnosis, prognosis, stratification and efficacy. • Cancer genetics, epigenetics, and genomic instability. • Minimal residual disease, pre-malignant lesions. • Cancer micro-environment. • Molecular pathology. • Tumour immunology. • Translational research. • Cancer therapy (target discovery, drug design, immunotherapy, combination therapies, resistance, and individualised treatment). • Chemotherapy, radiotherapy and surgery. • Clinical pharmacology. • Clinical trials, integration of basic science into cancer clinical trials. • Epidemiology and prevention. • Infrastructures (biobanks, databases, genomic resources). A main feature of the Journal is to provide an international forum for debating cancer issues, and for integrating the input of all the stakeholders. Coverage: Reviews, original articles, technical notes, editorials, news & views (commentary, science policy issues, ethical and legal issues, patient organisations, industry needs and alliances, regulatory issues, news items), letters to the editor, conference announcements, advertisements. Submitting Authors: Manuscripts can be submitted to Molecular Oncology at: http://ees.elsevier.com/molonc/ http://www.moloncol.org/?rss=yesElsevier Inc.en © 2012 Published by Elsevier Inc. All rights reserved. Molecular Oncology1574-789162April 2012 © 2012 Published by Elsevier Inc. All rights reserved. healthpermissions@elsevier.comhttp://www.moloncol.org/article/PIIS1574789112000324/abstract?rss=yesEditorial Board10.1016/S1574-7891(12)00032-4Molecular Oncology 6, 2 (2012)2012-04-01Molecular Oncology2012-04-0162S1574-7891(12)X0002-4iiiihttp://www.moloncol.org/article/PIIS1574789112000233/abstract?rss=yesThe problem of cancer is increasing annually and will only escalate further in the future, mainly due to the aging population. The number of new cancer cases diagnosed will increase by approximately 60% during the next 20 years and cancer mortality by a similar percentage, unless we can improve cure rates. The number of patients living for 5 or more years with a cancer diagnosis is increasing even more, a challenge for the health care systems all over the world (International Agency for Research on Cancer). Clearly, present preventive, clinical and research strategies have not been sufficient to meet these challenges.Personalized cancer medicine – A strategy to counteract an increasing cancer challengeJohn Mendelsohn, Ulrik Ringborg, Richard L. Schilsky10.1016/j.molonc.2012.03.002Molecular Oncology 6, 2 (2012)2012-03-21Molecular Oncology2012-03-2162S1574-7891(12)X0002-4Preface109110http://www.moloncol.org/article/PIIS1574789112000129/abstract?rss=yesAbstract: 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 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.The biology of personalized cancer medicine: Facing individual complexities underlying hallmark capabilitiesMichele De Palma, Douglas Hanahan10.1016/j.molonc.2012.01.011Molecular Oncology 6, 2 (2012)2012-02-13Molecular Oncology2012-02-1362S1574-7891(12)X0002-4Reviews111127http://www.moloncol.org/article/PIIS157478911200021X/abstract?rss=yesAbstract: 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 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.Highlights: ► Current status of genome-wide analysis of a variety of tumor types. ► How analyses of these above data are shaping our investigation of important therapeutic targets. ► Methodology for development of therapeutically relevant modalities. ► Progress of creating personalized medicine.Omics and therapy – A basis for precision medicineJoseph P. Garay, Joe W. Gray10.1016/j.molonc.2012.02.009Molecular Oncology 6, 2 (2012)2012-03-15Molecular Oncology2012-03-1562S1574-7891(12)X0002-4Reviews128139http://www.moloncol.org/article/PIIS1574789112000117/abstract?rss=yesAbstract: Biomarkers 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.Highlights: ► Cancer biomarkers must undergo rigorous analytic and clinical validation. ► Clinical validity must be established before a biomarker is used in the clinic. ► Guidelines have been established for reporting results of tumor marker studies.Cancer biomarkersN. Lynn Henry, Daniel F. Hayes10.1016/j.molonc.2012.01.010Molecular Oncology 6, 2 (2012)2012-02-10Molecular Oncology2012-02-1062S1574-7891(12)X0002-4Reviews140146http://www.moloncol.org/article/PIIS1574789112000099/abstract?rss=yesAbstract: 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. 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.Bioinformatics and systems biologyPrahlad T. Ram, John Mendelsohn, Gordon B. Mills10.1016/j.molonc.2012.01.008Molecular Oncology 6, 2 (2012)2012-02-22Molecular Oncology2012-02-2262S1574-7891(12)X0002-4Reviews147154http://www.moloncol.org/article/PIIS1574789112000166/abstract?rss=yesAbstract: 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 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.Highlights: ► Here we review small molecule cancer drug discovery and development. ► We focus on Target selection, hit identification, lead optimization and clinical trials. ► A particular emphasis of this article is personalized medicine.Discovery of small molecule cancer drugs: Successes, challenges and opportunitiesSwen Hoelder, Paul A. Clarke, Paul Workman10.1016/j.molonc.2012.02.004Molecular Oncology 6, 2 (2012)2012-03-05Molecular Oncology2012-03-0562S1574-7891(12)X0002-4Reviews155176http://www.moloncol.org/article/PIIS1574789112000191/abstract?rss=yesAbstract: 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.Highlights: ► Diverse laboratory methodologies are available for various analytes, often making test development problematical. ► Integral marker clinical trials and standard-of-care applications must employ regulatory-compliant biomarkers. ► The Institute of Medicine of the National Academies in the United States has produced a comprehensive review of omics-based tests. ► Understanding of aberrations along molecular pathways and of intratumoral heterogeneity are key to successful use of biomarkers.Molecular pathologyStanley R. Hamilton10.1016/j.molonc.2012.02.007Molecular Oncology 6, 2 (2012)2012-04-05Molecular Oncology2012-04-0562S1574-7891(12)X0002-4Reviews177181http://www.moloncol.org/article/PIIS1574789112000178/abstract?rss=yesAbstract: 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 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.Highlights: ► Molecular imaging techniques are vital for personalized medicine. ► PET/CT is currently the predominant clinical molecular imaging modality. ► Novel PET tracers are expected to increase the versatility and accuracy of PET/CT. ► Hyperpolarized MRI has entered the clinical arena and allows in vivo metabolic imaging. ► Multimodal nanoparticles promise to allow combined pre- and intraoperative imaging.Molecular imaging for personalized cancer careMoritz F. Kircher, Hedvig Hricak, Steven M. Larson10.1016/j.molonc.2012.02.005Molecular Oncology 6, 2 (2012)2012-03-19Molecular Oncology2012-03-1962S1574-7891(12)X0002-4Reviews182195http://www.moloncol.org/article/PIIS1574789112000105/abstract?rss=yesAbstract: 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 account when designing a trial, including those trials that assess combinations of targets.Highlights: ► Without certainty on the functionality of an drug target clinical studies should not be started. ► We need to try to predict Drug-Registration in the earliest clinical studies. ► The most important biomarker is the patient selection biomarker. ► Get the pharmacology right before moving on. ► Choices on drug combinations should be based on biological rationales.Moving molecular targeted drug therapy towards personalized medicine: Issues related to clinical trial designJaap Verweij, Maja de Jonge, Ferry Eskens, Stefan Sleijfer10.1016/j.molonc.2012.01.009Molecular Oncology 6, 2 (2012)2012-02-20Molecular Oncology2012-02-2062S1574-7891(12)X0002-4Reviews196203http://www.moloncol.org/article/PIIS1574789112000208/abstract?rss=yesAbstract: 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.Highlights: ► Cancers are divided into very small subgroups carrying a rare molecular alteration. ► Most of the new drugs are targeting these infrequent events. ► Trials are testing the use of high throughput technologies in personalized medicine. ► Circulating tumor cells and virtual cell program could optimize genomic testing. ► Future clinical research will focus in target identification at a patients level.The challenge to bring personalized cancer medicine from clinical trials into routine clinical practice: The case of the Institut Gustave RoussyMonica Arnedos, Fabrice André, Françoise Farace, Ludovic Lacroix, Benjamin Besse, Caroline Robert, Jean Charles Soria, Alexander M.M. Eggermont10.1016/j.molonc.2012.02.008Molecular Oncology 6, 2 (2012)2012-03-26Molecular Oncology2012-03-2662S1574-7891(12)X0002-4Reviews204210http://www.moloncol.org/article/PIIS1574789112000087/abstract?rss=yesAbstract: 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 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.Graphical abstract: Highlights: ► Predictive biomarkers are highly important for personalization in radiation oncology. ► Hypoxia is one of the best investigated biomarkers for hypoxia-specific approaches. ► Other promising markers include PET, DNA repair and stem cell markers. ► markers for combined molecular targeting approaches have to be established.Individualization of cancer treatment from radiotherapy perspectiveAla Yaromina, Mechthild Krause, Michael Baumann10.1016/j.molonc.2012.01.007Molecular Oncology 6, 2 (2012)2012-02-15Molecular Oncology2012-02-1562S1574-7891(12)X0002-4Reviews211221http://www.moloncol.org/article/PIIS1574789112000154/abstract?rss=yesAbstract: 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 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.Highlights: ► There are a number of prognostic assays to predict outcome in ER+ breast cancers. ► Treatments include tamoxifen, ovarian suppression, and aromatase inhibitors. ► Therapy should be individualized with regards to risk and benefit.Hormonal therapy in breast cancer: A model disease for the personalization of cancer careShannon Puhalla, Saveri Bhattacharya, Nancy E. Davidson10.1016/j.molonc.2012.02.003Molecular Oncology 6, 2 (2012)2012-03-02Molecular Oncology2012-03-0262S1574-7891(12)X0002-4Reviews222236http://www.moloncol.org/article/PIIS1574789112000221/abstract?rss=yesAbstract: 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 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.Hematopoietic growth factors: Personalization of risks and benefitsShannon Puhalla, Saveri Bhattacharya, Nancy E. Davidson10.1016/j.molonc.2012.03.001Molecular Oncology 6, 2 (2012)2012-03-29Molecular Oncology2012-03-2962S1574-7891(12)X0002-4Reviews237241http://www.moloncol.org/article/PIIS1574789112000038/abstract?rss=yesAbstract: The remarkable specificity of the immune system through antigen recognition has long attracted investigators to the possibility of immune-based therapy for cancer. Previous cancer immunotherapeutics had been restricted to non-specific immunomodulatory agents, such as the cytokines IL-2 or IFN-α. However, the molecular definition of cancer-associated antigens introduced the possibility of specific vaccines and adoptive T cell approaches aiming to target the tumor cells more specifically. The recent introduction of total exome sequencing has enabled the identification of patient tumor-specific epitopes generated through somatic point mutations, raising the possibility of targeting tumor antigens in individual patients which are even more tumor-specific. Transcriptional profiling and immunohistochemistry analyses have revealed a subset of patients with a pre-existing T cell-inflamed tumor microenvironment. This phenotype may be predictive of clinical outcome to immunotherapies and offers the possibility of a predictive biomarker. Further analysis of these tumors has identified a set of defined immune suppressive factors which themselves are being targeted with new immunotherapeutics, already with interesting early phase clinical trial results. Understanding not only the expression of tumor antigens but also the dynamic between a growing tumor and the host immune response is thus generating a rich set of opportunities for the specific immunotherapy of cancer.Cancer immunotherapyThomas F. Gajewski10.1016/j.molonc.2012.01.002Molecular Oncology 6, 2 (2012)2012-01-13Molecular Oncology2012-01-1362S1574-7891(12)X0002-4Reviews242250http://www.moloncol.org/article/PIIS1574789112000063/abstract?rss=yesAbstract: Pharmacogenomics is the study of genetic factors determining drug response or toxicity. The use of pharmacogenomics is especially desirable in oncology because the therapeutic index of oncology drugs is often narrow, the need for favorable drug response is often acute, and the consequences of drug toxicity can be life-threatening. In this review, we examine the state of pharmacogenomics in oncology, focusing only on germline pharmacogenomic variants. We consider several critical points when assessing the quality of pharmacogenomic findings and their relevance to clinical use, and discuss potential confounding factors limiting interpretation and implementation. Several of the most extensively studied drug–gene pairs (irinotecan and UGT1A1; tamoxifen and CYP2D6; 5-fluorouracil and DPYD) are inspected in depth as illustrations of both the state of advancement—and the current limitations of—present knowledge. We argue that there will likely soon be a critical mass of important germline pharmacogenomic biomarkers in oncology which deserve clinical implementation to provide optimal, personalized oncologic care. We conclude with a vision of how routine clinical testing of such germline markers could one day change the paradigm for cancer care.Germline pharmacogenomics in oncology: Decoding the patient for targeting therapyPeter H. O'Donnell, Mark J. Ratain10.1016/j.molonc.2012.01.005Molecular Oncology 6, 2 (2012)2012-01-25Molecular Oncology2012-01-2562S1574-7891(12)X0002-4Reviews251259http://www.moloncol.org/article/PIIS157478911200018X/abstract?rss=yesAbstract: 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 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.Highlights: ► Effective personalized therapies are being introduced rapidly. ► High costs can make these therapies prohibitive. ► Genomic based diagnostics can direct these therapies effectively. ► Diagnostic value depends on health outcomes, logistics, and resources utilized. ► Comparative effectiveness provides valuable tools for assessing diagnostic value.Paying for personalized care: Cancer biomarkers and comparative effectivenessRahber Thariani, David L. Veenstra, Josh J. Carlson, Louis P. Garrison, Scott Ramsey10.1016/j.molonc.2012.02.006Molecular Oncology 6, 2 (2012)2012-03-09Molecular Oncology2012-03-0962S1574-7891(12)X0002-4Reviews260266