| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Perspectives |
1 From the Department of Radiology, Massachusetts General Hospital, Harvard Medical School, 14 Fruit St, FND-216, Boston, MA 02114. Received February 18, 2004; accepted February 19. Address correspondence to the author (e-mail: thrall.james@mgh.harvard.edu).
Index terms: Genes and genetics • Perspectives
With the mapping of the human genome, mankind stands on the threshold of understanding the molecular basis of life. Mapping of the genome has captured the imagination of the public and has stimulated scientists, industries, and governments around the world to accelerate investigations of human disease (1–4). Completion of the Human Genome Project was accomplished just 50 years after the description of the double helix of DNA by Watson and Crick, but mapping the genome per se is only the first act in a long drama. Act two will use new information from genomics and other parallel advances in medical science to create better methods for preventing, diagnosing, and treating disease while promoting wellness. There are many pathways to these goals, including the development of gene therapy to correct genetic defects and development of drugs based on targets associated with genes and gene products, such as proteins and peptides.
Among the now projected 30,000 or so genes, the locations and functions are known only for a minority (2,5,6). Among the best characterized genes are those associated with highly penetrated monogenic disorders, such as sickle cell anemia, Huntington Disease, and cystic fibrosis (5). For example, in sickle cell anemia, the exact location of the gene encoding for hemoglobin ß is known on chromosome 11. It is further known that the genetic defect in sickle cell anemia is the result of a single base pair swap, or single nucleotide polymorphism, of adenine for thymine in the chromosomal DNA sequence. The correction of this mutation is a tempting target for gene therapy (7).
Likewise, the location of the defective gene for cystic fibrosis—the most common monogenic inherited disorder—is known, but there are at least a dozen different possible mutations (polymorphisms), making genetic screening more challenging. Even so, the gene defect is well enough characterized that gene therapy for cystic fibrosis has been actively investigated for over a decade (8–10). The locations of the mutated genes in the monogenic (mendelian) diseases are typically found by studying gene linkages, or patterns of polymorphism, between people in multiple affected families.
However, many diseases that plague mankind the most, such as diabetes, asthma, atherosclerosis, hypertension, cancer, obesity, and many types of mental illness, are polygenic in nature and highly influenced by patient behaviors and environment, a far more complex situation than monogenic disease (1,5). Presumptively, in polygenic disease, scientists must identify not one but multiple genes and then elucidate their relative importance and mechanisms of interaction while again looking for diagnostic and therapeutic opportunities. This is further complicated by the multiplicity of phenotypes or clinical manifestations encountered in these common conditions.
Determining the location and function of genes is now occurring at a land-rush pace around the world, along with parallel efforts to identify potential targets for new diagnostic and therapeutic agents. Because genes can be patented, there are enormous commercial implications in being first to accomplish a discovery. As an indication of the perceived financial potential from mining the genome, the government of Iceland has contracted with a commercial company for access to the nation’s genealogic records and gene samples from the population of the country (11).
Personalized Medicine
While the significance of mapping and mining the human genome will take decades and more to fully know, it is already clear that access to genetic information will radically and dramatically change the way medicine is practiced, even in the short run. Every person has a unique genetic profile, or genotype, that differs in potentially significant ways from even his or her closest relatives. These differences are highly deterministic of each person’s medical course through life and response to the environment. Ideally, comprehensive information about each patient’s unique genetic makeup will be available to physicians in the future for selection of the best specific diagnostic and therapeutic methods for treating that individual and for the more general purposes of lifestyle and/or wellness counseling and genetic counseling. The term "personalized medicine" is now being used to describe the concept of tailoring medical care on the basis of detectable genetic differences between patients (12). In the genomics era, the nature and treatment of disease are being redefined at a genetic and molecular level unique to each patient.
Genetic differences may never manifest during times of wellness but can be of critical importance in the face of disease. For example, it has long been known that some patients who receive thiopurine medications such as azathioprine, 6-mercaptopurine, and thioguanine develop toxicity and even fatal myelosupression. The relative activity of the enzyme thiopurine S-methyltransferase (TPMT) is the cause for the differing responses between patients (13). Genetic polymorphism is found in 10% of whites, and one in 300 individuals have complete deficiency of TPMT activity. Without exposure to the thiopurine medications, intermediate or completely deficient TPMT activity is clinically unimportant but potentially fatal in patients that have the genetic polymorphisms and are undergoing treatment.
Recognition of drug toxicity associated with low TPMT activity led scientists to invent new assays for it. While they are not direct genetic assays, they allow prediction of the most important mutations. In patients with absent or intermediate levels of TPMT activity, drug dosages are adjusted accordingly to take into account reduced clearance, permitting safe use of the drugs. As McLeod and Siva (13) note, the TPMT polymorphism "is one of the best models for the translation of genomic information to guide patient therapeutics"—in other words, a good example of personalized medicine.
Interestingly, long before the genomics era, the American public became knowledgeable about a drug response issue highlighted by experience in the war in Vietnam. A small percentage of black soldiers with glucose-6-phosphate dehydrogenase, or G6PD, deficiency developed hemolytic toxicity from prophylactic primaquine phosphate antimalarial therapy (14). G6PD protects red cells from oxidizing agents, including oxidant drugs. Although only a small number of soldiers developed severe toxicity, it is standard practice today to test for G6PD deficiency in at-risk armed service personnel stationed in malaria-bearing areas (14). At-risk travelers who visit affected areas should also be tested so that drug dosage can be adjusted to reflect levels of G6PD activity. At least 20 other drugs are now known to cause toxicity in G6PD–deficient patients (14).
A different avenue being investigated for development of personalized care in complex polygenic diseases is study of the relative expression of genes in a disease without the necessity to know genetic functions or interactions. Gene expression mapping is performed by using microarrays that measure downstream products such as complementary DNA, messenger RNA, and proteins and peptides. Sophisticated statistical analysis is applied to the gene expression data to look for signature patterns that allow best prediction of survival or response to therapy. Once these empirical signatures are established in clinical trials, they can be used prospectively to guide therapeutic decisions for patients with newly diagnosed disease.
The potential utility of gene expression profiling is illustrated in a trial of 76 patients with acute myeloid leukemia in which complementary DNA microarrays of 23,040 genes were used to study gene expression (15). The investigators identified 63 overexpressed genes and 373 suppressed genes in the study group. Among the over- and underexpressed genes, 28 were found to have different expression levels between patients who responded to chemotherapy and those who did not respond. On the basis of a "drug response scoring" system, 40 of 44 patients with positive scores achieved complete remission, compared with only three of 20 patients with negative scores. The authors commented, "an ability to predict chemosensitivity should eventually lead to achievement of our goal of personalized therapy" (15). Similar investigations are being undertaken in many other diseases, with the common goal of being able to predict therapeutic response prospectively through genomic methods, thereby allowing physicians to create far more specific and personalized treatment plans.
Cardiac electrophysiologists have described a number of abnormal conduction syndromes associated with ventricular fibrillation and sudden unexpected nocturnal death. One of these syndromes, Brugada syndrome, is characterized in part by complete or incomplete right bundle branch block and increased risk of nocturnal sudden death and is associated with a mutation or mutations of the gene SCN5A, which encodes the cardiac Na(+) channel (16,17). No effective drug therapy is available yet.
Other cardiac arrhythmias and causes of sudden unexpected nocturnal death have also been shown to be associated with genetic mutations. Patients with characteristic electrophysiologic phenotypes, family histories of sudden death, and personal histories of syncopy or "episodes" need to be evaluated in light of the possibility of possessing one of these genotypes. In the absence of effective drug treatment, patients are receiving implantable cardioverter-defibrillator devices (18). In these gene-linked conditions, knowledge of the relationship between phenotype, genotype, and likely clinical outcomes is being used effectively to personalize therapy for affected patients.
Although personalized medicine is not an "official" term and has no consensus definition yet, it is eye opening to see just how many conditions are now being linked to genetic polymorphisms. This linkage is in turn being used to better understand molecular mechanisms of disease and response to therapy. In the past, physicians have simply had to accept variation from patient to patient as an imponderable and frustrating complexity of medical practice. The methods available in the genomics era will now make it possible to understand many of these variations to the benefit of improved patient care.
Pharmacogenomics
The term pharmacogenomics refers to the science of how genes and expression of genes determine drug behavior (19–21). The importance of pharmacogenomics in the development of personalized medicine is clearly illustrated by the examples discussed earlier involving G6PD deficiency and TPMT. Application of pharmacogenomic principles has rapidly extended beyond clinical patient care and is now a major strategy in drug discovery and development. Two journals, the American Journal of Pharmacogenomics and The Pharmacogenomics Journal, have been established to publish research on the topic.
An important approach in pharmacogenomics research is the genotyping of patients with a particular disease to see if there are polymorphisms associated with potential drug targets in a substantial percentage of the study population. It can be advantageous to first do this in a relatively small stable population to reduce the background noise in the genetic data. Obviously, the results in a small homogeneous population must be validated by finding the same or functionally similar polymorphisms in a larger population for the target to be of significant interest for commercial drug development.
An exemplar for the population-based approach to drug target discovery has recently been reported for a study of patients experiencing myocardial infarctions. Associated single nucleotide polymorphisms or haplotypes in the gene ALOX5AP were found in 29% of Icelandic patients, and somewhat different but functionally similar polymorphisms were found in 14% of British patients with heart attacks (22). Patients with the genetic polymorphisms produce high levels of leukotriene B4, which is known to cause inflammation. Since arterial wall inflammation is generally believed to increase the likelihood of clot formation and heart attack, a causal relationship is suggested. A number of antileukotriene drugs have been developed for other purposes, including the treatment of asthma, which is now facilitating rapid testing for use in the potential new application of heart attack prevention. The example of ALOX5AP polymorphism demonstrates the benefit of using a pharmacogenomic approach to move quickly to first unveil mechanisms of disease and to then design new therapies on the basis of that knowledge. This example also illustrates from the differences encountered in Iceland versus England that prevalence of a specific genetic variation can be highly population dependent.
Experience with clinical drug trials makes clear the value and importance of having more information about differences between patients and disease expression. Many drugs fail in clinical trials after having been shown to be safe and effective in experiments with laboratory animals and even in limited human trials. Differences in gene makeup and expression can be the cause of many otherwise inexplicable and perplexing findings among patients with similar clinical phenotypes.
Inclusion criteria for clinical trials typically encompass the diagnosis and the patient’s clinical condition, which includes prior therapies but has not historically included pharmacogenomic considerations, such as genotyping or gene expression profiling. A compelling example of the importance of this comes from the development of trastuzumab (10,23), a humanized monoclonal antibody developed for the treatment of breast cancer. The target protein antigen for trastuzumab is human epidermal growth factor receptor protein (HER2). Theoretically, patients overexpressing the HER2 protein should respond to the drug, while those without HER2 expression would not benefit because of the lack of a target for the therapeutic molecule in the tumor.
Approximately 25%–30% of patients with breast cancer overexpress HER2 (23). Thus, from a purely statistical point of view, a trial with enrollment of both patients with and those without overexpression of HER2 would either have to be much larger to achieve statistical significance or potentially fail to demonstrate statistical significance, thereby incorrectly relegating the drug to failed status. Patients enrolled in the clinical trials of trastuzumab were tested for HER2 expression as part of the inclusion criteria, and patients undergoing clinical treatment are also pretested. It should be noted that the assay developed for HER2 expression does not test directly for a gene but tests the level of expression of the gene’s product, which is the relevant parameter in this case.
The trastuzumab-HER2 example clearly demonstrates the linkage between gene expression and therapeutic efficacy on the one hand and the crucial role that understanding pharmacogenomics can have in designing a successful clinical trial on the other. Use of pharmacogenomic principles offers the promise of not only developing better and more effective drugs but also designing smaller, shorter, and less expensive clinical drug trials that have a higher likelihood of success.
In the past, investigators have just accepted a certain percentage toxicity or variable efficacy for drugs. The insight and the tools were not available to discover if observed differences were due to variations at the genetic molecular level versus other factors, such as anemia, nutritional status, presence of comorbidity, or other differences between patients that can also affect drug behavior.
It is interesting to speculate how many drugs have been abandoned or labeled as problematic in the past because of lack of understanding of pharmacogenomics or the influence of genetic makeup on drug metabolism. The effective broad-spectrum antibiotic chloramphenicol is a good example. A small percentage of patients who take this medication develop irreversible and fatal aplastic anemia, which restricts its use to selected life-threatening situations (24). This is just one of the many drugs that have side effects in a small percentage of patients, which prevents its use entirely, limits use, or makes use more difficult. Optimistically, some of these drugs can be salvaged through identification of gene markers or downstream markers of gene expression that can be applied to patients prospectively. Patients that manifest toxicity-associated profiles, such as an enzyme deficiency, could be treated accordingly; the drugs would then become more reliable, safe, and readily available for patients with compatible genotypes. The science of pharmacogenomics is still new but promises to be one of the keys to unlocking the treasures of the human genome for use in patient care. Pharmacogenomics will be a cornerstone in the development of personalized medicine.
Radiology and Personalized Medicine
Radiology has a number of roles to play in the coming era of personalized medicine. Imaging will play an increasingly important role in the assessment of therapeutic response, especially in cancer. Novel drugs with new targets, such as antiangiogenesis agents, challenge clinicians more than ever to understand which patients are responding and which are not. Oncologists recognize that patients with similar histologic findings often do not respond to treatment the same way for the reasons discussed earlier. Yet, the expense of chemotherapy can be thousands of dollars a week. Patients who do not respond lose precious time and money but still experience side effects, such as immune system suppression and anemia. In some sense, each patient has a lifetime tolerance for total treatment, and to squander that on things that do not work is unacceptable. Just as medicine stands to become more personalized, the use of imaging to assess response will become more tailored to specific drugs for which pharmacogenomics research identifies a likelihood of variability among patients.
Imaging is already being used widely in drug discovery and is being added to the methods used in pharmacogenomics research to identify and evaluate new targets. For example, a molecular imaging probe can be used to determine target occupancy before and after administration of a new drug candidate, which helps to assess binding affinity and to determine correct dosages. This approach has found particular application in studying activity of drugs for the central nervous system (25). Response of tumor metabolism after chemotherapy is already being studied routinely by using positron emission tomography with fluorodeoxyglucose (26). Imaging biomarkers are being used extensively in clinical drug trials as surrogate end points. This approach often allows patients to be their own controls and reduces trial size, shortens time to the study end point, and reduces costs (27,28).
Imaging methods will become increasingly used in clinical phenotyping. Robust clinical phenotyping helps in finding gene mutations by aggregating subjects into groups with higher probabilities of having common genotypes. For example, functional magnetic resonance imaging can be used to study response patterns as a basis for assigning patients with mental illnesses, such as schizophrenia and depression, to subgroups for assessment of genotype. Likewise, imaging of dopamine receptors can help establish phenotypic patterns of involvement in neurodegenerative diseases.
Multiple methods have now been described for the imaging of gene expression (29,30). If gene therapy becomes important, it is easy to imagine "reporter genes" being added to the therapeutic genetic material to allow early assessment of success in the transfection step and continuous monitoring of gene activity and its distribution in the body.
Image-guided interventional methods will be used when personalized therapies need to be delivered locally in the body. This is done in current practice to deliver regional chemotherapy and has been used in attempts at gene therapy.
The age of personalized medicine is underway. Each individual is now an "n" of one. Knowledge of individual genetic variation will allow physicians to tailor treatment and to understand response to treatment better than ever before. However, this potential should also remind everyone that other factors can defeat even the best that medicine will ever have to offer. Powerful factors that also influence health and wellness include personal choice with respect to lifestyle, illegal drugs, alcohol, and diet; exposure to environmental toxins; and limitations on access to care. The potential for misuse of genetic information and outright discrimination are also formidable concerns (1,31). For whatever secrets are mined from the human genome, the pivotal roles of society and individual choice in achieving optimum health outcomes will in no way be diminished.
REFERENCES
This article has been cited by other articles:
|
|
 |
|
  A. Orlova, V. Tolmachev, R. Pehrson, M. Lindborg, T. Tran, M. Sandstrom, F. Y. Nilsson, A. Wennborg, L. Abrahmsen, and J. Feldwisch Synthetic Affibody Molecules: A Novel Class of Affinity Ligands for Molecular Imaging of HER2-Expressing Malignant Tumors Cancer Res., March 1, 2007; 67(5): 2178 - 2186. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. V. Proto Radiology 2004: James H. Thrall Appointed Perspectives Editor Radiology, August 1, 2004; 232(2): 317 - 318. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| RADIOLOGY | RADIOGRAPHICS | RSNA JOURNALS ONLINE |
