Cancer Genomics

After a quarter of century of express technological advances, research has publicized the convolution of cancer, a disease confidentially related to the dynamic transformation of the genome. It is here that Nanotechnology enters the fray offering a wealth of tools to diagnose and treat cancer. Nanotechnology offers numerous tools to diagnose and treat cancer, such as new imaging agents, multifunctional devices capable of overcome biological barriers to deliver therapeutic agents directly to cells and tissues involved in cancer growth and metastasis, and devices capable of predicting molecular changes to prevent action against precancerous cells. Nanomaterials-based delivery systems in Theranostics (Diagnostics & Therapy) provide better penetration of therapeutic and diagnostic substances within the body at a reduced risk in comparison to conventional therapies. At the present time, there is a growing need to enhance the capability of theranostics procedures where nanomaterials-based sensors may provide for the simultaneous detection of several gene-associated conditions and nanodevices with the ability to monitor real-time drug action. These innovative multifunctional nanocarriers for cancer theranostics may allow the development of diagnostics systems such as colorimetric and immunoassays, and in therapy approaches through gene therapy, drug delivery and tumor targeting systems in cancer. 
 

The advance of whole genome sequencing technology accelerates the identification of key genetic trait or alteration leading to disease development. The major function of current massively parallel genome sequencers is to perform de novo assembly or resequencing of euchromatic regions, about 94% of entire human genome and representing the reference genome firstly obtained after completion of Human Genome Project.  Massively parallel short or medium reads of tens to few thousands with sufficient coverage are able to piece together contiguous euchromatic sequences tolerating 1-4% error rate primarily from inherited DNA polymerase infidelity. However, these short- or medium-read sequencers are not suitable for determining heterochromatic sequences, which cover the yet-to-be completed 6% human genome and contain long repetitive nuclear elements, including the 45S rDNA , about 45-kb per copy and estimated 400 copies distributed across short arms of five human acrocentric chromosomes, and satellite DNAs in centromere. The tandemly repeated 45S rDNA and satellite DNAs are recombinational hot spots and are sealed throughout eukaryotes. Recent evidence further suggests that 45S rDNA rearrangement and concurrent epigenetic changes play a role in mammalian ontogeny and tissue differentiation, and are associated with speciation, aging, cancers, psychological disorders, and neurodegenerative diseases. 

The need to develop sequencing platforms capable of reading continuously a single long-stretch DNA/RNA strand with high accuracy is urgent. Several newly proposed approaches show a potential to achieve long-reads of 50 kb or more, and are at various stages of development toward commercialization. These include new version of single molecule real time (SMRT) technology, biological and solid-state nanopore, nanogap, nanoribbon, nanochannel, and electron microscopy, which are moving away from fluorescence-based detection to electronic sensing or imaging. 

One of the most exciting recent developments in the field of cancer biology is the recognition that lineage progression continues to occur in tumours. In particular, there is an increasing body of evidence that like normal tissues, tumor cells that have the potential for unlimited self-renewal give rise in large numbers to cells that lack this potential - the so-called cancer stem cell hypothesis. By focusing for so many years on the majority cell populations in tumours, and not on the rarer cancer stem cells (cancer initiating cells), scientists and clinicians may have missed out on opportunities to understand, diagnose and treat the processes in cancer that matter most. Existing cancer treatments have mostly been developed based on animal models, where therapies able to promote tumor shrinkage were deemed effective. The existence of cancer stem cells (CSCs) has several implications in terms of future cancer treatment and therapies. These include disease identification, selective drug targets, prevention of metastasis, and development of new intervention strategies. Moreover, according to “individualised cancer immunotherapy”- which is the new frontier in cancer treatment is getting a person’s own immune system to eliminate tumours, rather than targeting the cancer cells with chemotherapy. In contrast to conventional cancer treatments, immunotherapies can lead to long-lasting clinical responses.

The Cancer Cell Map Initiative: Defining the Hallmark Networks of Cancer- Progress in DNA sequencing has revealed the startling complexity of cancer genomes, which typically carry thousands of somatic mutations. However, it remains unclear which are the key driver mutations or dependencies in a given cancer and how these influence pathogenesis and response to therapy. Although tumors of similar types and clinical outcomes can have patterns of mutations that are strikingly different, it is becoming apparent that these mutations recurrently hijack the same hallmark molecular pathways and networks. For this reason, it is likely that successful interpretation of cancer genomes will require comprehensive knowledge of the molecular networks under selective pressure in oncogenesis. he Cancer Cell Map Initiative (CCMI), aimed at systematically detailing these complex interactions among cancer genes and how they differ between diseased and healthy states. New Biologic Frontiers in Ovarian Cancer: Olaparib and PARP Inhibition. Systems Biology Approaches to the Study of Biological Networks Underlying Alzheimer’s Disease: Role of miRNAs. Cancer Immunology. Genomics will also impact our understanding of the immune system's interaction with tumors, leading to the development of personalized vaccine strategies that may provide more durable responses. The combination of next-generation sequencing and analysis as applied to experiments studying the cancer genome has revolutionized our understanding of cancer biology. Large-scale cancer genomics has further established a baseline that is now poised to effect the translation of cancer genomics into the clinical setting, effectively transforming patient care. The barriers and challenges to translation are significant, not the least of which involves the transition of research-grade computational and interpretational analysis to clinical-grade analysis. Assays must be highly refined, validated and accurate. How the use of genomic approaches to monitor patient response to therapy, the onset of acquired resistance to therapy and other aspects of patient care will be accepted as a more sensitive partner with conventional imaging approaches must be addressed.

Cancer is a heterogeneous genetic disease, and excisional biopsies provide only a snapshot in time of some of the rapid, dynamic genetic changes occurring in tumours. In addition, excisional biopsies are invasive, can’t be used repeatedly, and are ineffective in understanding the dynamics of tumor progression and metastasis. However, liquid biopsy, or blood-sample tests, under development by Epic Sciences can generate actionable information for oncologists by analysing circulating tumor cells (CTCs) and fragments of tumor-cell DNA that are continuously shed by tumours into the bloodstream. Highly sensitive analysis of individual CTCs have demonstrated a high level of heterogeneity seen at the single cell level for both protein expression and protein localization and the CTCs reflected both the primary biopsy and the changes seen in the metastatic sites. By detecting and quantifying genomic alterations in CTCs and cell-free DNA in blood, liquid biopsy can provide real-time information on the stage of tumor progression, treatment effectiveness, and cancer metastasis risk. This technological development could make it possible to diagnose and manage cancer from repeated blood tests rather than from a traditional biopsy. Building on the positive results from exploratory whole genome sequencing the analysis is narrowed down to specific bladder cancer-related genomic regions to enable both accurate and cost-efficient detection of bladder cancer from urine.

Numerous recent studies have demonstrated the use of genomic data, particularly gene expression signatures, as clinical prognostic factors in cancer and other complex diseases. These studies highlight the opportunity for strategies to achieve truly personalized cancer treatment. Particularly important has been the use of genome-scale gene expression analyses to identify discrete disease classes not previously recognized. Genomic techniques are transforming biology from an observational molecular science to a data-intensive quantitative genomic science. Most successful applications of genomic technology have been in the study of human cancer, in which gene expression patterns can be identified that provide phenotypic detail not previously obtainable by traditional methods of analysis: profiles and patterns that identify new subclasses of tumors, such as the distinction between acute myeloid leukemia and acute lymphoblastic leukemia. Indeed, much of the activity in employing genomic technologies to achieve the goal of personalized cancer therapy has been directed at the identification of targets for new drug development that uniquely attack a given tumor. Genomic techniques may also be useful in determining more targeted applications for existing cancer therapeutics, many of which are very effective for subsets of cancer patients.

The field of cancer epigenetics is evolving rapidly on several fronts. Advances in our understanding of chromatin structure, histone modification, transcriptional activity and DNA methylation have resulted in an increasingly integrated view of epigenetics. In response to these insights, epigenetic therapy is expanding to include combinations of histone deacetylase inhibitors and DNA methyltransferase inhibitors. Zebularine, an orally administerable DNA methyltransferase inhibitor, has been a very promising recent addition to our arsenal of potentially useful drugs for epigenetic therapy. Epigenetics refers to alternate phenotypic states that are not based in differences in genotype, and are potentially reversible, but are generally stably maintained during cell division. The narrow interpretation of this concept is that of stable differential states of gene expression. 

The potential reversibility of epigenetic states offers exciting opportunities for novel cancer drugs that can reactivate epigenetically silenced tumor-suppressor genes. Epigenetic changes in cancer cells not only provide novel targets for drug therapy but also offer unique prospects for cancer diagnostics  The major interest in cancer epigenetics as a diagnostic tool is in localized epigenetic silencing. It is clear from this bird's-eye overview that the field of cancer epigeneticsis in flux. We can expect to see clinical implementation of both epigeneticcancer therapy and epigenetic cancer diagnostics in the next decade. Epigenetic control defects in cancer cells represent an emerging new area of investigation, where significant breakthroughs in the identification of the underlying molecular defects are anticipated in the next few years.

International Conference on Genetics Counseling and Genomics Medicine, Aug 11-12, 2016, Birmingham, UK; Biotechnology World Convention, Aug 15-17, 2016, Sao Paulo, Brazil; International Conference on Synthetic Biology, Aug 18-19, 2016, London, UK, Annual Conference on Bio Science, Sept 12-13, 2016, Berlin, Germany; Noncoding RNAs in Health and Disease, February 21-24, 2016, Santa Fe, USA; Maintenance of Genome Stability March 7- 10, 2016, Panama, South America; Chromatin and Epigenetics, March 20-24, 2016 Whistler, Canada; Chromatin, Non-Coding RNAs and RNAP II Regulation in Development and Disease, March 29, 2016, Austin, USA; Chromatin Structure & Function, May 22-27, 2016, Les Diablerets, Switzerland

Nanotechnology is increasingly finding use in the management of cancer. Nanoscale devices have impacted cancer biology at three levels: early detection using, for example, Nano cantilevers or nanoparticles; tumour imaging using radio contrast nanoparticles or quantum dots; and drug delivery using nanovectors and hybrid nanoparticles. This review addresses some of the major milestones in the integration of nanotechnology and cancer biology, and the future of nanoscale approaches for cancer management. The drivers for advances in nanotechnology have been the development of tools that enable us to manipulate at an atomic scale, and materials and chemistry that allow the constructions of novel structures. Although it is not the focus of this review to address these tools in details, it is important to realise potentials of these analytical and fabrication tools, which if integrated with fundamental biology can provide essential breakthroughs in the fight against cancer. Nanotechnology platforms can provide the unique niche within this space by enabling multimodal delivery with a single application. Another emerging direction in the application of nanotechnology in cancer is the use of self-assembly techniques, such as to design monodisperse delivery vehicles like polymerosomes or to develop sensors.

Hormones influence not only breast and prostate cancer, the two most common hormone-dependent cancers, but also have a major impact on less common hormone-sensitive malignancies (e.g. ovary, testes, endometrium) as well as human cancers recently discovered to be hormone sensitive (e.g. lung, liver). Developing a means to more specifically treat and ideally prevent hormone-dependent cancers is of critical importance given the significant impact these malignancies have on human health and the economic burden of disease. An in depth understanding of hormone action in regulating diverse cellular processes, cancer phenotypes and drug responsiveness is essential for the development of effective and well tolerated treatment strategies.

Gene editing is rapidly progressing from being a research/ screening tool to one that promises important applications downstream in drug development, cell therapy and bioprocessing. • Genome editing (e.g., CRISPRs technology to replace defective DNA with “good” DNA) is now a new trend in 2016. The engineered editing system makes use of an enzyme that nicks together DNA with a piece of small RNA that guides the tool to where researchers want to introduce cuts or other changes in the genome.

They’re scientists. They’re miners. They dig deep through seemingly endless streams of numbers and terabytes of data to discover hidden gems of understanding about how and why cancer forms. Several recently announced collaborations between academic research institutions and big data analytics vendors powering advanced discovery technologies will bring the power of big data to new studies that may have significant impacts on future therapies and treatments.  With oncology and genomics in the spotlight, personalized medicine is poised to take a leap forward as researchers dive into complex diseases. By analysing data from multiple cancer types, we could evaluate prognostic models and identify gene alterations that led to tumor formation. This wouldn’t have been obtained by looking at tumor data from just one cancer type.