Ward Rounds

What’s your genotype? If this seems like a personal question, it is and it is one that’s central to the rapidly advancing area of genome-based, or as it has been coined, “personalized” medicine. In the past decade alone, advances in technology have brought the cost of whole-genome sequencing down from millions to thousands of dollars and improved the efficiency of what was once an extremely slow and labor-intensive process. As knowledge expands about genetic connections to common, complex health conditions – ranging from heart disease and diabetes to cancer – the practice of medicine continues to forge ahead into a new frontier of highly individualized health care.

“In my view, good medicine has always been personal and taken into account the needs of individual patients,” says Peter A. Kopp, MD, interim director of Northwestern University Feinberg School of Medicine’s Center for Genetic Medicine. “Personalized medicine just takes advantage of the differences – and similarities – in our genomes to make more precise diagnoses, tailor specific therapies, choose appropriate medications, and potentially provide preventive measures against disease.”

Northwestern has access to tools that enable the sequencing of a whole genome to define therapy choices. Peter Kopp, MD, interim director of the Center for Genetic Medicine, stands in front of a Next-Gen Sequencer, which was purchased through the philanthropic support of donor Ann Lurie.

While personalized medicine encompasses genetics – the study of heredity – it’s much more than addressing disease-causing genes passed down through generations of families. This burgeoning new medical model melds details gleaned from genetic, genomic, environmental, and lifestyle information to better predict an individual’s susceptibility for a given disease. The ability to identify biomarkers known to cause harm can lead to more targeted screening and care.

While one drug may function well in one patient, in another that same drug could be toxic

In the area of pharmacogenomics, genetic tests reveal critical data and help fine-tune the selection of effective drug therapies. Already standard in clinical practice, for instance, physicians treating women for breast cancer routinely collect genetic information to determine if certain drugs will work for specific patients. A widely known example of a pharmaceutical agent that works wonders for some and not at all for others is the drug trastuzumab (Herceptin). Targeting breast tumors that express excessive HER2 protein, Herceptin primarily benefits women battling HER2-positive breast cancer. With genotyping, doctors caring for HER2-negative cancer patients immediately know they should turn to other drug therapies.

“Gene variations can make a significant difference,” adds Dr. Kopp. “While one drug may function well in one patient, in another that same drug could be toxic due to genetic differences that affect how the drug is metabolized.” Studies have shown, for example, that the HIV drug abacavir (Ziagen) can be fatal for a small subset of patients with the gene variant HLA-B*5701, making genetic testing for this allele a necessity.

Personalized medicine offers potential applications in almost every medical specialty. At Northwestern, faculty members in a variety of specialties have embarked on genetic – and genomic-based studies to enhance all aspects of health care from prevention to outcomes. In particular, investigators have made important inroads in oncology, since by its very nature all cancers start with genes – generally “behaving badly” and causing highly irregular and damaging cell growth.

Dr. Jonathon Licht, chief of hematology/oncology, and his colleagues have taken a personalized medicine approach to developing new therapeutics for a particular form of multiple myeloma.

Developing Targeted Therapeutics

“Genetic technologies are helping us to understand in detail the molecular basis of cancers and the many different forms of what may seem like the same tumor,” explains Jonathan D. Licht, MD, Johanna Dobe Professor and chief of hematology/oncology at Northwestern. “There are forms of lymphoma that may look morphologically the same under the microscope; however, if one examines the underlying patterns of gene expression, one can find distinct subsets of disease. Now, with personalized medicine, clinical trials are being designed to place patients in one category or another and to treat these subsets of disease in distinct ways.”

For example, Dr. Licht and his colleagues have taken a personalized medicine approach to developing new therapeutics for a particular form of multiple myeloma. This cancer of the plasma cells can lead to tumors in the bone marrow and elsewhere in the body. Up to 20 percent of myeloma cases are associated with abnormal high-level expression of a gene called MMSET, which yields an enzyme critical for the control of other genes. MMSET appears to be required for normal growth and development in humans and seems to have no ill effects when expressed at low levels. According to findings of the Licht laboratory, when expressed at high levels, MMSET chemically modifies and causes widespread changes to chromatin – the mixture of DNA and surrounding proteins that help pack DNA into its tidy chromosomal structure. This sets off a process that turns on and off large numbers of genes – still to be identified – and stimulates abnormal myeloma cell growth.

“We think MMSET is the Achilles’ heel. When depleted from myeloma cells, those cells die,” says Dr. Licht. “With a collaborator, we’ve been screening thousands of chemical compounds and looking for an MMSET inhibitor. If we can prevent the enzyme from turning normal cells into abnormal ones, we might have a therapy specific for this subset of patients, which are often the toughest, most chemotherapy-resistant cases.”

Virginia Kaklamani, MD, director of translational breast cancer research at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, has studied the influence of two genes on breast cancer risk.

Connecting the Dots

Inherited genetic mutations account for 20 to 30 percent of breast cancers

Inherited genetic mutations account for 20 to 30 percent of breast cancers. In recent years, BRCA1 and BRCA2 (breast cancer susceptibility genes 1 and 2) have become commonly known abbreviations for biomarkers that increase the risks of developing breast cancer by as much as 87 percent. Yet for all of its notoriety, this inherited gene only shows up in one in 500 individuals and not all variations of it result in cancer. In fact, many genetic variants can contribute to breast cancer risk as well as link to other diseases through interrelated pathways.

Director of translational breast cancer research at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, oncologist Virginia Kaklamani, MD, has studied two genes – TGF-beta and adiponectin – and their influence on breast cancer risk. For TGF-beta, she and her research team discovered that one change in the gene’s receptor can boost an individual’s chances for breast cancer. Adiponectin is a protein secreted by adipose tissue or body fat. Dr. Kaklamani’s group not only examined changes in this gene and its link to breast cancer risk but also started connecting the dots with other cancers and made several novel discoveries. Says Dr. Kaklamani, “Looking at specific gene pathways related to obesity and diabetes as well as breast cancer, we found that mutations in adiponectin – along with interactions with other genes – can increase or decrease risks for developing breast, colon, and prostate cancers.”

Dr. Kaklamani, an associate professor in the Division of Hematology/Oncology, recently embarked on a study to identify possible genetic changes that can predispose women with breast cancer to gaining weight. Research has shown an adverse relationship between obesity and breast cancer. Obese women with breast cancer, as well as patients who gain weight after a breast cancer diagnosis, tend to have a worse prognosis than their normal-weight counterparts, according to Dr. Kaklamani. Experts speculate that carrying additional body fat may thwart the effectiveness of chemotherapy or cause higher levels of estrogen known to fuel some breast cancers and contribute to their recurrence. However, much is still unknown about obesity’s influence. Following 150 women with breast cancer, Dr. Kaklamani will examine genetic backgrounds as well as treatment factors with the end-goal of developing personalized medicine strategies.

“If we can find a genetic connection, then perhaps we can intervene with those who are at most risk for gaining weight,” she says. “That way we can offer individualized exercise and diet plans that specifically fit the needs of each patient.”

William Catalona, MD, professor of urology at Northwestern, was among the pioneers who helped develop the PSA test as an early screening tool for prostate cancer.

Optimizing Patient Care

In November, 69 top human genetics researchers convened in Washington, D.C., for the first NCI Prostate Cancer Genetics Working Group Workshop, headed by William J. Catalona, MD, professor of urology at Northwestern’s Feinberg School of Medicine. Dr. Catalona brought together these experts to develop plans for a large consortium to expand research in the genetic determinants of prostate cancer aggressiveness. By leveraging resources around the country, this proposed collaborative effort would lead to the creation of a large, multi-institutional, virtual biobank of clinical and genetic data. This mega-storehouse of information could vastly improve patient care by accelerating the ability to accurately identify the deadliest forms of this second leading cause of cancer death in men. To date, genome-wide association studies – which compare genetic variants or single nucleotide polymorphisms (SNPs) that occur in people with a certain disease versus those without – have zeroed in on some 30 SNPs associated with prostate cancer susceptibility. But the question still remains: What is the cause of prostate cancer aggressiveness?

Since prostate-specific antigen (PSA) testing was introduced in the early 1990s, the U.S. death rate due to prostate cancer has dropped by 40 percent. PSA testing allows for earlier detection and treatment that saves lives. Yet not every patient necessarily benefits from a prostate cancer diagnosis. “The recent concern is that the test identifies men who have prostate cancers that will never cause them suffering or death. So why put them through unnecessary biopsy and treatment?” says Dr. Catalona. A renowned prostate cancer expert, he has been studying the genetics of prostate cancer – considered to be one of the most hereditary of cancers – for the past 10 years. “The ability to genetically identify people who are susceptible to the most harmful forms of prostate cancer would allow us to not only target them for screening but also selectively treat them for specific genetic abnormalities of the cancer.”

I believe the 21st century will be the era of big discoveries in our understanding of the relationship between genes and diseases

No one knows better than Dr. Catalona the importance of early screening for prostate cancer: he was among the pioneers who helped develop the PSA test. In 1991 he published the first paper, which appeared in The New England Journal of Medicine, showing that a simple blood test that measured levels of PSA was the most accurate method for detecting prostate cancer. Since that time, his work studying the genetics of the disease has yielded promising results. Dr. Catalona contributed to the discovery of the first genetic marker of prostate cancer risk in the region of chromosome 8 – a finding that was described in the June 2006 issue of Nature Genetics. Dr. Catalona’s work has led to other novel gene discoveries that he and his fellow investigators are currently assessing in regard to their association with aggressive vs. non-aggressive forms of the disease. These biomarkers have the potential to significantly enhance the next generation of prostate cancer screening tests.

“I believe the 21st century will be the era of big discoveries in our understanding of the relationship between genes and diseases,” remarks Dr. Catalona. “Thanks to advancements in technology, we will have more and more tools to analyze people’s genetic make-ups, link that information to their susceptibility to certain diseases, and tailor treatments to those individuals. In the very near future, we will have great opportunities to access information unlike any that has come before.”