On the Horizon

Cancer Progress Report 2012: Contents

It is clear that although the altered genomes of cancer cells can have a profound effect on cancer development and spread, factors at all levels—from molecules to cells to humans—are involved. It is critical that we understand all of these influences, assimilate this knowledge and develop new ways to apply this wisdom if we are to develop comprehensive approaches to conquering cancer going forward.

At the cellular level, it will be necessary to integrate advanced genomic information with knowledge generated through the analysis of changes in the way the cancer cell’s DNA is modified and packaged; this is a ripe area of research called epigenetics. The function of regions of the genome that do not encode proteins, but rather generate non-coding RNAs that fine tune the expression of proteins, will also be important to our further understanding of the biology of cancer. This comprehension must, in turn, be combined with information gleaned from studying cancer at a body-wide level through a systems biology approach that integrates our genomic and epigenomic knowledge with an understanding of the importance of metabolism (at a cellular and body-wide level) along with new knowledge of the sum of the genomes of all the microorganisms that live naturally in our bodies, collectively called the “microbiome.” 

While a more comprehensive systemic understanding of cancer is critical to future near-term success, a deeper understanding of the neurological control of risky behaviors is essential to help prevent those cancers that could potentially be avoided through behavioral modification. Although progress is beginning to be made, it will take a concerted effort from all in the cancer research community to deliver on the promise of these and other forthcoming breakthroughs.

Research at the Cellular Level: Epigenetics

The striking diversity of cell types in our body is a result of selective use of distinct parts of the genome in various kinds of cells. Information directing which parts of the DNA should be accessible in different cells of the body is conveyed by special chemical tags on the DNA called methylation. How the DNA is packaged with proteins into chromosomes is noted by other special chemical marks. The science of epigenetics examines how these DNA marks and packaging arise, how they affect cellular function, and how they are changed over time during normal development and in disease states such as cancer.

Most cancer cells exhibit profound abnormalities in the patterns of epigenetic marks across the genome, the sum of which is called the epigenome. In many cases, these defects work in conjunction with genetic mutations to promote the cancerous behaviors of cells. Efforts are currently underway to map these changes in all major types of cancer. We are finding that cancer epigenomes can be used to define new subtypes of cancer and can serve as indicators of patient outcome or predictors of therapeutic response. Early studies indicate that we will be able to develop sensitive assays for abnormal epigenetic marks that can be used for early detection of cancer and for assistance in monitoring drug response.

One of the exciting aspects of this research is that epigenetic abnormalities are reversible. As a result, scientists are exploring whether novel therapies that work by reversing epigenetic defects can be used to treat cancer. This concept has led to an exciting new avenue of attack on cancer, evidenced by some patients who were previously nonresponsive to traditional chemotherapy and who are now showing dramatic responses to the four FDA-approved epigenetic drugs. With cancer epigenomic profiles rapidly being assembled and drugs being developed for an ever-increasing number of epigenetic marks, it seems clear that the relatively new field of cancer epigenetics and epigenomics is destined to have a profoundly positive effect on patients in the near future and for years to come.

Metabolomics: From Molecules to Cells to Humans

Metabolomics is the simultaneous study of hundreds to thousands of small molecules in a biological system of interest, such as the blood, urine or a tissue sample. Metabolomics provides an integrated view of how messages from the genome, epigenome and environment influence the biochemistry of a particular system at one point in time. As such, we can simultaneously measure entire biochemical pathways, such as all of the molecules that comprise the system for energy generation in a cell (and the flux through that pathway); interactive pathways, such as the pathways involved in cell growth; and conceptually linked systems, such as antioxidants and oxidative damage products. Therefore, metabolomics complements other large-scale approaches, such as genomics, epigenomics, transcriptomics and proteomics, for analyzing a cell and an individual’s status at any moment in time.

Because tumor cell physiology can be different from the physiology of normal cells, it is widely anticipated that metabolomics can be used to improve our understanding of the causes of cancer, improve early diagnosis and facilitate cancer drug development. For example, investigators are examining the utility of metabolomics in identifying indicators, or biomarkers, of increased cancer risk and in establishing biomarkers that can help predict a patient’s disease course or treatment response. In addition, metabolomics can be used to determine new potential drug targets and to help understand how a drug works or causes its side effects. This area of research is a rapidly growing field that shows tremendous promise for improving our understanding of cancer as well as its prevention, detection, diagnosis and treatment while simultaneously lowering the costs of both patient care and drug development.

Whole Body Influences: The Microbiome 

It is becoming increasingly clear that the many millions of microorganisms that live naturally inside or on our bodies, in areas such as the skin and the gut, have effects that resonate throughout the body. Most of the time, these microorganisms are our partners in health, contributing to a strong immune system and the digestion of dietary components to produce essential nutrients, among many other things. However, growing evidence indicates that, under certain conditions, some of these microorganisms may, in fact, worsen our health or increase our risk of certain diseases, including cancer.

These are early days in this field, however, and researchers are still trying to fully establish the nature of these microorganisms and their associated effects. One systematic approach to clarify the ambiguity involves cataloging all of the genomes of all of the microorganisms that live in or on healthy humans and those with certain diseases. The sum of all of the genomes of all these microorganisms is called “the microbiome,” and it is hoped that by understanding how it changes over time as we can now do for whole genomes, it might be possible to gain new insight into risk factors for many different human diseases, including cancer. Armed with this knowledge, it would be possible to develop new approaches to cancer prevention, detection, diagnosis and treatment. While the translation of this vision into useful clinical tools will take time, it is important that we continue providing the resources necessary for the large-scale enterprise of defining the human microbiome, given its apparent importance in human health and disease.

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Integrating Everything: Systems Biology

Systems biology is focused on the identification of key networks, pathways within these networks and interactions among networks that cells use to function normally. Likewise, systems biology seeks to define how these same networks are altered in cancer to support its initiation and development.

By allowing us to understand as a whole the complex systems that are created by cancer genomes, epigenomes, microbiomes and metabolomes, systems biology is helping to identify the unique growth and survival dependencies in cancer cells. It is also enabling us to predict the reserve pathways that cancers may use when initially challenged by an effective therapy. All this information is pivotal to identifying new targets for cancer medicines and novel combinations of therapies that can hit both the cancer’s initial point of vulnerability and the pathways that tumor cells may use to develop drug resistance.

Unfortunately, some of the dependencies being revealed by systems biology point to drug targets that are unfamiliar to the traditional drug discovery process. Some people even refer to such targets as “undruggable.” However, this view is beginning to melt away, as advances in the field of chemical biology are revealing new solutions; thus, it is clear that systems biology, in combination with other emerging areas of research, like chemical biology, can produce new approaches to cancer prevention, detection, diagnosis and treatment in the not-too-distant future.

Improving Knowledge Application: Nanotechnology

Nanotechnology refers to the manufacturing of objects with dimensions one million times smaller than a millimeter (the smallest width of a human hair is 0.017 millimeters). Nanomedicine is the application of nanotechnology to the research and practice of medicine. Nanodrugs typically comprise a pharmaceutical agent encapsulated within a nanoparticle, with surface modifications that allow for reduced capture by the body’s defenses. Nanodrugs are often characterized by increased circulatory life and enhanced concentration at the site of a targeted cancer cell to increase effectiveness and/or reduce toxicities. There are now more than a dozen nanodrugs being used for the treatment of cancer, including the breast cancer drug paclitaxel (Abraxane), and it is clear that this approach to drug delivery will become increasingly common in the future. In fact, in August of 2012, the FDA approved the latest cancer nanodrug, vincristine sulfate liposomes (Marqibo), for the treatment of a rare, rapidly progressing form of leukemia.

Nanotechnology is applied not only for cancer treatment, but also for cancer detection and diagnosis. Several nanotechnology based laboratory platforms are emerging; they offer opportunities for novel and improved methods for the early detection of cancer from biological fluids, the identification of novel biomarkers and the development of tests to rapidly determine the effectiveness of therapeutic regimens in individual patients. In addition, nanotechnology can be used to improve the quality of life of cancer patients. For example, there are now nanotechnology based implants that can release cancer treatments in an optimized time-release fashion to maximize the therapeutic effects of a drug, while reducing side effects and without confining patients to the hospital. 

Nanotechnology holds the promise of providing a complete spectrum of tools to improve our approaches to cancer prevention, detection, diagnosis and treatment as well as to enhance quality of life.

Reducing Cancer Risk Through Behavioral Modification

It is clear that approximately 50% of cancers could be prevented by behavioral changes such as quitting smoking, increasing exercising, adopting a more healthful diet and following recommended screening guidelines. Individuals are often aware of the negative consequences of their behaviors, but find it extremely difficult to change them. Research in affective and cognitive neuroscience is beginning to show that this is not the consequence of moral weakness. Neurobiological changes induced by behavioral addictions, such as cigarette smoking and compulsive overeating, can bias our decision-making processes and prevent us from adopting healthier lifestyles. For example, brain-imaging studies have demonstrated that nicotine, like other substances of abuse, hijacks brain circuits underlying emotional and cognitive processes. In fact, recent studies suggest that, for some individuals, cigarette smoking might reduce their ability to enjoy other pleasurable activities, making it more difficult for them to quit.

As our understanding of the neurobiological processes underlying specific behaviors increases, it might be possible, for example, to develop new personalized smoking cessation interventions that will minimize the risk of relapse and will allow smokers to achieve their goal of a smoke-free life. By discovering biomarkers that will refine diagnoses, and by creating interventions that will help individuals adopt and maintain healthy behaviors, continued and increased neuroscience research can significantly contribute to reducing cancer risk, incidence and mortality.

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Cancer Progress Report 2012 Contents

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