Emerging diagnostic,prognostic and therapeutic biomarkers for ovarian cancer

Background

In spite of various treatment options currently available, ovarian cancer (OC) still remains a leading cause of death in women world-wide. Diagnosis at an early stage is one of the most important factors that determines survival. Current clinical diagnostic tools have, however, a limited efficacy in early OC detection. Therefore, there is a critical need for new (early) diagnostic biomarkers and tools. Through advances in genomic, proteomic and metabolomic techniques, several novel molecular OC biomarkers have recently been identified. These biomarkers are currently subject to validation. In addition, integration of genomic, proteomic and metabolomic data, in conjunction with epidemiologic and clinical data, is considered essential for obtaining useful results. Interesting recent work has already shown that specific diagnostic biomarkers, such as BRCA mutations, may have profound therapeutic implications. Here, we review the current state of OC research through literature and database searches, with a focus on various recently identified biomarkers via different technologies for the (early) diagnosis, prognosis and treatment of OC.

Conclusions

Multi-biomarker panels accompanied by a meticulous determination of their sensitivity and specificity, as well their validation, using multivariate analyses will be critical for its clinical application, including early OC detection and tailor-made OC treatment.

     

组学技术在胶质瘤分子分类方面应用研究进展

胶质瘤传统病理学的分类分级主要基于细胞水平的认识,而缺乏对胶质瘤分子学特征的认识。随着分子生物学的发展,尤其是基因组学和蛋白质组学技术的发展,人们逐渐肯定了髓母细胞瘤起源于小脑颗粒细胞,少枝胶质细胞瘤因按其基因表达谱的差异可进一步进行分类,依据胶质细胞瘤基因或蛋白的表达差异可对胶质细胞瘤进行分级及预后预测,并可对胶质母细胞瘤进行进一步分类。组学技术的发展扩大了检测胶质瘤分子缺陷的数目,推动了胶质瘤分子分类方法的发展。     

Physical oncology: a bench-to-bedside quantitative and predictive approach

Cancer models relating basic science to clinical care in oncology may fail to address the nuances of tumor behavior and therapy, as in the case, discussed herein, of the complex multiscale dynamics leading to the often-observed enhanced invasiveness, paradoxically induced by the very antiangiogenic therapy designed to destroy the tumor. Studies would benefit from approaches that quantitatively link the multiple physical and temporal scales from molecule to tissue in order to offer outcome predictions for individual patients. Physical oncology is an approach that applies fundamental principles from the physical and biological sciences to explain certain cancer behaviors as observable characteristics arising from the underlying physical and biochemical events. For example, the transport of oxygen molecules through tissue affects phenotypic characteristics such as cell proliferation, apoptosis, and adhesion, which in turn underlie the patient-scale tumor growth and invasiveness. Our review of physical oncology illustrates how tumor behavior and treatment response may be a quantifiable function of marginally stable molecular and/or cellular conditions modulated by inhomogeneity. By incorporating patient-specific genomic, proteomic, metabolomic, and cellular data into multiscale physical models, physical oncology could complement current clinical practice through enhanced understanding of cancer behavior, thus potentially improving patient survival.     

Oral squamous cell carcinoma: etiology, pathogenesis and prognostic value of genomic alterations

Tumours of the head and neck comprise an important group of neoplasia, the incidence of which is increasing in many parts of the world. This increase remains high, despite all the advances in modern medicine. This malignancy is more prevalent in the developing world and unfortunately, has not received satisfactory attention as the more prevalent cancers of the developed world, like lung, breast, or colon cancer. Recent advances in diagnosis and therapeutic techniques of these lesions have yielded novel molecular targets, uncovered signal pathway dominance and advanced early cancer detection. This review covers recent advances in our understanding of the etiology, molecular changes and the possible role that genomic and proteomic research might play in the diagnosis and effective cure of this modern-day scourge.     

Clinical trials and biomarker development with molecularly targeted agents and radiotherapy

INTRODUCTION: The conventional paradigm of drug development used for cytotoxic chemotherapeutic agents may not represent the most effective method of assessing the safety and biological activity of molecularly targeted agents, given that the latter may offer improved therapeutic indices with less toxic effects on normal tissues. OBJECTIVES: With the number of novel therapeutics in oncology entering the investigative arena, there is a need to expedite the drug development process by allowing for optimal selection of agents with the greatest likelihood of having clinical benefit over those of lower potential utility. DISCUSSION: The high throughput techniques now available in genomic, proteomic and metabolomic profiling should allow for more effective preclinical investigation with the identification of biomarkers or indicators of treatment response, leading to increased clinical efficacy with appropriate patient selection. CONCLUSION: With this in mind, current investigation should be directed at validating novel endpoints in order to accelerate the drug development and approval process with targeted therapeutics in oncology.     

Technology insight: pharmacoproteomics for cancer--promises of patient-tailored medicine using protein microarrays

Patient-tailored medicine can be defined as the selection of specific therapeutics to treat disease in a particular individual based on genetic, genomic or proteomic information. While individualized treatments have been used in medicine for years, advances in cancer treatment have now generated a need to more precisely define and identify those patients who will derive the most benefit from new-targeted agents. Cellular signaling pathways are a protein-based network, and the intended drug effect is to disrupt aberrant protein phosphorylation-based enzymatic activity and epigenetic phenomena. Pharmacoproteomics, or the tailoring of therapy based on proteomic knowledge, will begin to take a central role in this process. A new type of protein array platform, the reverse-phase protein microarray, shows potential for providing detailed information about the state of the cellular 'circuitry' from small samples such as patient biopsy specimens. Measurements of hundreds of specific phosphorylated proteins that span large classes of important signaling pathways can be obtained at once from only a few thousand cells. Clinical implementation of these new proteomic tools to aid the clinical, medical and surgical oncologist in making decisions about patient care will now require thoughtful communication between practicing clinicians and research scientists.     

Genomics and proteomics in predicting cancer outcomes

Sequencing of the human genome and the acquisition of genomic data combined with advances in genomic and proteomic technologies have fueled a revolution in understanding disease. The combination of genomics and proteomics has provided a unique opportunity to diagnose, classify, and detect malignant disease, to better understand and define the behavior of specific tumors, and to provide direct and targeted therapy. Nevertheless, challenges remain, including integration and standardization of techniques and validation against accepted clinical and pathologic parameters. This article provides a summary of technologies, potential clinical applications, and challenges.     

Head and neck cancer

Tumors of the head and neck comprise an important neoplasia group, the incidence of which is increasing in many parts of the world. Recent advances in diagnostic and therapeutic techniques for these lesions have yielded novel molecular targets, uncovered signal pathway dominance, and advanced early cancer detection. Proteomics is a powerful tool for investigating the distribution of proteins and small molecules within biological systems through the analysis of different types of samples. The proteomic profiles of different types of cancer have been studied, and this has provided remarkable advances in cancer understanding. This review covers recent advances for head and neck cancer; it encompasses the risk factors, pathogenesis, proteomic tools that can help in understanding cancer, and new proteomic findings in this type of cancer. Cancer 2010. © 2010 American Cancer Society.     

Consensus on precision medicine for metastatic cancers: a report from the MAP conference

Recent advances in biotechnologies have led to the development of multiplex genomic and proteomic analyses for clinical use. Nevertheless, guidelines are currently lacking to determine which molecular assays should be implemented in metastatic cancers. The first MAP conference was dedicated to exploring the use of genomics to better select therapies in the treatment of metastatic cancers. Sixteen consensus items were covered. There was a consensus that new technologies like next-generation sequencing of tumors and ddPCR on circulating free DNA have convincing analytical validity. Further work needs to be undertaken to establish the clinical utility of liquid biopsies and the added clinical value of expanding from individual gene tests into large gene panels. Experts agreed that standardized bioinformatics methods for biological interpretation of genomic data are needed and that precision medicine trials should be stratified based on the level of evidence available for the genomic alterations identified.     

MicroRNA ‘signature’ during estrogen-mediated mammary carcinogenesis and its reversal by ellagic acid intervention

Dysregulated miRNA expression has been associated with the development and progression of cancers, including breast cancer. The role of estrogen (E₂) in regulation of cell proliferation and breast carcinogenesis is well-known. Recent reports have associated several miRNAs with estrogen receptors in breast cancers. Investigation of the regulatory role of miRNAs is critical for understanding the effect of E₂ in human breast cancer, as well as developing strategies for cancer chemoprevention. In the present study we used the well-established ACI rat model that develops mammary tumors upon E₂ exposure and identified a ‘signature’ of 33 significantly modulated miRNAs during the process of mammary tumorigenesis. Several of these miRNAs were altered as early as 3 weeks after initial E₂ treatment and their modulation persisted throughout the mammary carcinogenesis process, suggesting that these molecular changes are early events. Furthermore, ellagic acid, which inhibited E₂-induced mammary tumorigenesis in our previous study, reversed the dysregulation of miR-375, miR-206, miR-182, miR-122, miR-127 and miR-183 detected with E₂ treatment and modulated their target proteins (ERα, cyclin D1, RASD1, FoxO3a, FoxO1, cyclin G1, Bcl-w and Bcl-2). This is the first systematic study examining the changes in miRNA expression associated with E₂ treatment in ACI rats as early as 3 week until tumor time point. The effect of a chemopreventive agent, ellagic acid in reversing miRNAs modulated during E₂-mediated mammary tumorigenesis is also established. These observations provide mechanistic insights into the new molecular events behind the chemopreventive action of ellagic acid and treatment of breast cancer.     

Mutation matters in precision medicine: A future to believe in

As a genetic disease [1] cancer dysregulates key oncogenic pathways that influence cell growth, proliferation, survival, angiogenesis, and metastasis. Among the major determinants that enable cancer cells to acquire malignant traits are genomic diversity and instability. In the post human genome project era, cancer-specific genomic maps are redesigning tumor taxonomy. The treatment modalities, as well as the overall management of cancer as a disease in today's clinic, have started depending heavily on the molecular pathology of the individual tumor(s) in addition to the fundamental classification of cancers by histopathology. The enrichment tumor taxonomy by genomic morphology has also opened up the possibilities for genomics-driven drug development. The success of a cancer drug today is fundamentally based on the success in identifying target genes that control tumorigenic pathways. One primary goal of precision cancer medicine is to make clinical decisions based on genomic/proteomic data, which can identify a target or targets for therapy, and subsequent inevitable development of therapeutic resistance to the drug. The ability to exploit tumor genetic information for its full clinical potential has only recently become evident. Over the last decade, the convergence of discovery, technology, and therapeutic development has created an unparalleled opportunity to test the hypothesis that systematic knowledge of genomic and proteomic information from individual tumor(s) may significantly improve clinical outcomes for many patients with unmanageable tumor burden. This review presents the signaling logic behind the ground rules for the rational approach to the genomics-driven precision medicine.     

From oncogene to network addiction: the new frontier of cancer genomics and therapeutics

Recent advances in genomic analysis have provided a comprehensive view of the genetic and epigenetic changes present in cancer cells. While therapies targeting genes causally linked to carcinogenesis have been successful in a subset of tumor types, the hope for treatments tailored on patient genomic profiles seems, for most cancers, still elusive. Cancer genes belong to two clearly defined groups. The first subset of genes is frequently mutated across samples and tumor types, and includes well-studied oncogenes and tumor suppressor genes, such as members of the RAS, AKT and TP53 families, whose direct targeting has so far been largely disappointing. In the other group, the vast majority of putative cancer genes emerging from sequencing and genomic studies show a low incidence (5% or less). The possibility of finding novel selective drugs against such a high number of gene products seems daunting. However, recent genomic and proteomic findings, as well as novel frameworks arising from systems biology approaches, suggest that this apparent discordance may converge towards a more satisfying model. It seems that genetic lesions in cancer tend to cluster around certain pathways, suggesting that the concept of 'network addiction', rather than 'oncogene addiction', would recapitulate more closely what is happening during tumor development and after exposure to therapeutic agents. This new perspective, arising from genomic and systems biology studies, will likely provide a valuable frame for the design of the cancer drugs of the future.     

Integrative Expression,Survival Analysis and Cellular miR-2909 Molecular Interplay in MRN Complex Check Point Sensor Genes (MRN-CSG) Involved in Breast Cancer

BackgroundBreast cancer, an emerging global challenge, is evidenced by recent studies of miRNAs involvement in DNA repair gene variants (MRE11, RAD50, and NBN as checkpoint sensor genes (CSG) – MRN-CSG). The identification of various mutations in MRN-CSG and their interactions with miRNAs is still not understood. The emerging studies of miR-2909 involvement in other cancers led us to explore its role as molecular mechanistic marker in breast cancer.Materials and MethodsThe genomic and proteomic data of MRN-CSG of breast cancer patients (8426 samples) was evaluated to identify the mutation types linked with the patient's survival rate. Additionally, molecular, 3D-structural and functional analysis was performed to identify miR-2909 as regulator of MRN-CSG.ResultsThe genomic and proteomic data analysis shows genetic alterations with majority of missense mutations [RAD50 (0.7%), MRE11 (1.5%), and NBN (11%)], though with highest MRE11 mRNA expression in invasive ductal breast carcinoma as compared to other breast cancer types. The Kaplan–Meier survival curves suggest higher survival rate for unaltered groups as compared to the altered group. Network analysis and disease association of miR-2909 and MRN-CSG shows strong interactions with other partners. The molecular hybridization between miR-2909-RAD50 and miR-2909-MRE11 complexes showed thermodynamically stable structures. Further, argonaute protein, involved in RNA silencing, docking studies with miR-MRE11-mRNA and miR-RAD50-mRNA hybridized complexes showed strong binding affinity.ConclusionThe results suggest that miR-2909 forms strong thermodynamically stable molecular hybridized complexes with MRE11 and RAD50 mRNAs which further strongly interacts with argonaute protein to show potential molecular mechanistic role in breast cancer.     

Genomic profiling of glioblastoma: convergence of fundamental biologic tenets and novel insights

With advances in genomic profiling and sequencing technology, we are beginning to understand the landscape of the genetic events that accumulated during the neoplastic process. The insights gleamed from these genomic profiling studies with regards to glioblastoma etiology has been particularly satisfying because it cemented the clinical pertinence of major concepts in cancer biology—concepts developed over the past three decades. This article will review how the glioblastoma genomic data set serves as an illustrative platform for the concepts put forward by Hanahan and Weinberg on the cancer phenotype. The picture emerging suggests that most glioblastomas evolve along a multitude of pathways rather than a single defined pathway. In this context, the article will further provide a discussion of the subtypes of glioblastoma as they relate to key principles of developmental neurobiology.     

The challenge of drugging undruggable targets in cancer: lessons learned from targeting BCL-2 family members.

The genomic and proteomic revolutions have provided us with an ever-increasing number of mechanistic insights into cancer pathogenesis. Mutated genes and pathologic protein products have emerged as the basis for modern anticancer drug development. With the increasing realization of the importance of disrupting oncogenic protein-protein interaction, new challenges have emerged for classical small molecule and protein-based drug modalities, i.e., the critical need to target flat and extended protein surfaces. Here, we highlight two distinct technologies that are being used to bridge the pharmacologic gap between small molecules and protein therapeutics. With the BCL-2 family of survival proteins as their substrate for intracellular targeting, we conclude that peptide stapling and fragment-based drug discovery show promise to traverse the critical surface features of proteins that drive human cancer.     

Tropomyosins as interpreters of the signalling environment to regulate the local cytoskeleton

A key regulator of cell morphology is the actin cytoskeleton and it has long been appreciated that the cytoskeleton is characteristically altered in cancer. Actin is organized into polymeric structures with distinct dynamics which in turn participate in a wide variety of cell processes including adhesion, migration, cell division and apoptosis. Despite displaying an altered actin cytoskeleton, transformed cells retain--and in many cases increase--their ability to adhere, move, divide and respond to apoptotic stimuli. Thus cancer cells maintain responsive actin cytoskeletons. Actin dynamics are regulated by numerous actin-binding proteins and chief among these are the tropomyosins which are core components of the microfilament. Recent advances in genomic and proteomic profiling confirm that Tm expression profiles are profoundly changed in transformed cells. It is therefore timely to review the role of Tms in the regulation of actin dynamics that pertain to crucial phenotypic changes in cancer. In this review we discuss how actin filaments containing different Tm isoforms respond to the activation of cell signalling pathways and consider the implications of this for cancer progression and therapy.     

New approaches in identifying drugs to inactivate oncogene products

With an information explosion on the molecular mechanism of oncogenesis, the completion of the human genome sequence project, and the advances in genomic and proteomic methods, many therapeutic targets for various cancers have been identified. It is timely that a number of new drug development techniques have been developed in this last decade. Candidate drug targets can now be efficiently validated with RNA interference and transgenic animals studies. Combinatorial chemistry provides large numbers of chemical compounds for drug lead discovery and optimization. High throughput assays and high content cell-based assays, in conjunction with sophisticated robotics, are now available for screening large numbers of compounds. Based on X-ray crystallographic structure data, drug leads can be discovered through in silico screening of virtual libraries. By applying these various drug discovery techniques, it is anticipated that more potent and specific anti-cancer agents will be discovered within the next decade.