Why Cancer Research?
Cancer Progress Report 2012: Contents
Research is our best defense against cancer. The Nation’s investments in cancer research and biomedical science during the past four-plus decades have produced remarkable progress in our understanding of the events which initiate a number of cancers at the molecular, cellular and tissue levels. Advances in cancer research are now transforming patient care. We would not be on our current path to revolutionizing cancer care if not for the extraordinary endeavors of individuals working in numerous research disciplines and technologies.
Today, we know that because cancer is extremely heterogeneous, it is in fact not a single disease but rather consists of over 200 diseases. Further, we are beginning to understand that due to this heterogeneity, nearly all cancers are comprised of a number of different cancer subtypes, meaning that every person’s cancer is unique in its composition. Despite the apparent complexity that this diversity brings, decades of research have established that there are a number of basic biological principles that underpin cancer initiation, growth and spread to other sites in the body.
One of the most fundamental traits of cancer cells is their ability to multiply uncontrollably. Normal cells only proliferate when the balance of numerous factors instructs them to do so, by progressing through a process called the cell cycle. Various inputs determine whether or not a cell will enter this cycle; these include the balance of growth-stimulating and growth-suppressing factors; the energy state of the cell, including nutrient and oxygen levels; and the status of the environment that surrounds the cell, called the microenvironment. This biological system is dysfunctional in cancer cells.
A second characteristic central to cancer cells is their ability to invade and destroy normal tissue surrounding them and to move to and grow in other areas of the body, called metastasis. Metastasis is the most lethal attribute of cancer cells. It is responsible for more than 90% of the morbidity and mortality associated with cancer (see sidebar on
Metastasis). Local invasion and metastasis are complex processes, fueled by changes in the cancer cells and in their interactions with their environments.
The development of cancer is largely due to the accumulation of genetic changes that lead to malfunctions in the molecular machinery of cells, permitting them to survive when normal cells would die and to multiply uncontrollably and metastasize. In addition, interactions between cancer cells and their microenvironment profoundly affect these same processes. Cancer-influencing factors that comprise the tumor microenvironment include the matrix of proteins outside the cancer cell that support the structure and function of the tissue in which the cancer is growing; the creation of new blood and lymphatic vessels; hormones; nutrients; and the immune system.
Insight into the importance of inflammation, established by certain cells of the immune system, in promoting cancer progression has increased dramatically in the past few years. Persistent inflammation—for example, that driven by infection with hepatitis B virus (HBV) or hepatitis C virus (HCV), or by continual exposure to toxins like alcohol or asbestos—has been known for some time to create an environment that fosters cancer cell survival, proliferation, local invasion and metastasis. More recently, it has become apparent that chronic inflammation in an organ or a region of the body enables cells in that area to acquire the characteristics needed for cancer formation.
In addition to better understanding the concept of tumor-promoting inflammation, the last several decades of research have also established the importance of the components of the immune system that participate in antitumor defense. That knowledge has stimulated developments of drugs designed to boost patients’ antitumor immunity.
Although we have learned a great deal about the unifying principles that underpin cancer, translating this knowledge into cures remains challenging because of the diversity of cancer types. Currently, many areas of research are rapidly evolving, in part as a result of technological advancements that are increasing our ability to probe the genetic and molecular defects that drive cancer. With continued federal investments, these endeavors will yield new discoveries that improve the ways we prevent, detect, diagnose and treat cancer.
Cancer Research: From Concept to Patient and Back Again
If cancer research is to be truly successful, it must be an iterative cycle, with observations flowing from the bench to the bedside and back again. The participation of patients and their health care providers is essential to this cycle because observations made in clinical trials also help define areas for future study, including the identification of new drug targets and the refinement of treatment. Finally, cancer research does not operate in isolation from other fields of research. Insights into the biology of cancer and the identification of ways to prevent, detect, diagnose and treat its many forms offer new ideas for the conquest of other diseases.
The concept of taking an observation, making a discovery, turning it into a tangible tool, drug or agent to be studied in the clinic, testing the discovery in the clinic and ending up with a viable approach for cancer prevention, detection, diagnosis or treatment is sometimes called target-based discovery. It is not the only strategy for developing new ways to reduce the tremendous burden of cancer, but increasingly the advances reaching the clinic are the result of target-based discovery programs (see
Making Research Count for Patients). The following focuses on some of the more frequently used ways in which those involved in basic and clinical cancer research take an idea all the way to the patient.
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Experimental Models of Cancer
In the laboratory, researchers study patient samples as well as cells and animals that mimic what happens in healthy and cancerous conditions.
A wide variety of cell types are used in cancer research. Some cells can be grown continuously in the lab in such a way that each is genetically identical, and these are called cell lines. Others are primary cells, which are genetically diverse because they are obtained directly from tissues. The tissues can be healthy or cancerous and isolated from a human or animal. Cells can be studied in dishes in the laboratory or after having been transferred into animals.
Mice constitute the most commonly utilized animal models in all areas of cancer research. Zebrafish have recently emerged as a useful model for melanoma, the most deadly form of skin cancer, and for leukemias. Other animals are also used, but largely for specific cancer types. For example, because some dog breeds naturally develop certain cancers, they are good models for studying the equivalent human diseases.
Probing Cancer Models: Generating and Testing Ideas
The study and manipulation of these models—for example, exposing them to a potential new drug—can help identify useful approaches for cancer prevention, detection, diagnosis or treatment that can then be tested in the clinic. Various techniques are used to probe cancer models, including but not limited to: genetic, biochemical and cellular analyses.
The genetic code carries a blueprint that is deciphered by the cell to produce the various proteins that it uses to function. Some genetic alterations result in the generation of abnormal proteins that can fuel the development of cancer. Alternatively, they may lead to the loss of other critical proteins that usually maintain normal cellular functions (see sidebar on the
Genetic Basis of Cancer). Tremendous technological advances in recent years have made it possible to rapidly sequence the entire genome of a cancer to reveal which genetic alterations are present. Furthermore, these technologies can also detect changes in the cancer’s epigenome, which is how the DNA is modified and packaged into chromosomes.
Whether or not the observed genetic and epigenetic changes contribute to cancer can be examined further by engineering cells or animals to express the modification and by observing the resultant changes in cell or animal behaviors. Previously, researchers studied individual pieces of DNA, proteins and cell metabolites as they pertain to cell function. Now, as a result of innovative large-scale approaches, researchers can study the entire set of DNA, proteins and metabolites in a sample. These new approaches complement more traditional biochemical methods to rapidly enhance our understanding of the structure and function of cancer-associated proteins and their effects on cell behavior.
Laboratory studies enable researchers to identify changes in genes and proteins linked to cancer. Converting these discoveries into a tool, drug or agent to be tested in the clinic can take many different forms. Some of these validated discoveries identify biological indicators, or biomarkers, which may be clinically useful , while others can be developed into a potential drug.
Moving Cancer Research into the Clinic
Before a tool, drug or agent developed through many years of work in the laboratory can be used routinely in patient care, it must be rigorously tested in clinical trials, which provide each patient with the best care available. This step from the bench to the bedside involves a vast array of approaches. The discussion here only highlights some examples of how this step toward reducing the burden of cancer is implemented.
In the case of a potential therapeutic for cancer treatment, clinical trials with increasing numbers of patients are undertaken to determine the safety and effectiveness of the potential therapy. Individuals participating in clinical trials are monitored extremely closely. For example, levels of known cancer markers in the urine or blood can be regularly checked to provide information as to whether or not the drug is effective. Currently, however, the predominant criteria used to determine whether a new drug for cancer treatment benefits patients are: Does it stop tumor growth or reduce its size? Does it increase the length of time to renewed growth or spread, as assessed by tumor imaging? And does it increase patient survival time?
In many clinical trials, tumor imaging is done using computed tomography (CT) scanning, but other technologies can be used, such as magnetic resonance imaging (MRI) and positron emission tomography (PET) using a radiolabeled tracer called 18fluorodeoxyglucose (FDG). As progress is made in enhancing imaging capabilities, these scans can be incorporated into clinical trials. It is hoped that as advances are made, they can be used to shorten the process of drug development, with significant reductions in tumor burden visible by imaging techniques being used as a measure of drug effectiveness. This is a very active area of cancer research, with multiple other approaches being actively assessed for their utility in the same context.
Clinical Outcomes Go Back to the Laboratory
It is vital that what happens at the bedside is not the end of the cancer research trail. Even if clinical studies indicate that the agent, drug or tool can help reduce the burden of cancer and it is adopted into routine clinical practice, continued monitoring of its safety and benefits provides important information for improved use and further innovation (see sidebar on
Learning Healthcare Systems). For example, some tumors learn to bypass initially efficacious treatments, and how that happens needs to be determined in order to develop new and improved therapies. In cases where there is no immediate gain observed in the clinic, the knowledge amassed during the trial can be probed for insights into why and how the treatment failed to have the expected effects and how to improve upon it.
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Progress Report 2012 Contents