The route to understanding medical mysteries such as the why of diseases, including cancer, has totally taken new turns since the Human Genome Project was completed over a decade ago, and the results include new therapies and new hope. Advances in the treatment of cancer make huge medical headlines, in part because of the sheer numbers of people directly affected by the disease. According to the American Cancer Society, the estimated number of new cases in the U.S. for 2011 will total 1,596,670. Globally, 12.7 million cases of cancer were diagnosed in 2008. The majority of these cancers occur in persons aged 55 and older, and with the growth of an aging population, the number of new cases is expected to continue to increase.
Genetic Decoding Leading to Advanced Cancer Medications
By Pamela Boaz
Cancer can develop in anyone, and all cancers involve the malfunction of genes that control cell growth and division. Only five percent of all cancers are strongly hereditary; instead, most result from damage (mutation) to genes during one’s lifetime. Genetic damage may result from internal factors such as hormones, metabolism or immune conditions or from external factors such as tobacco use, radiation, or infectious organisms.
It is important to note that cancer is not just one disease, and even under the umbrella of cancers that occur in the same location – lung, breast or skin, for example – multiple expressions of the disease exist. This makes treatment complicated and answers difficult to find. Annual research dollars can be counted in the millions, and major inroads have been made in cancer research, particularly involving the Human Genome Project.
Mapping the Human Genome
A genome is all of the DNA in an organism, including its genes. DNA is made up of four similar chemicals (called bases and abbreviated A, T, C, and G) that are repeated millions or billions of times throughout a genome. The human genome, for example, has 3 billion pairs of bases. The particular order of A’s, T’s, C’s, and G’s in DNA dictates everything down to whether an organism is human or another species such as yeast, rice, or fruit fly. Genes are sections of DNA strands that provide the code for making all proteins required by all organisms. Each gene serves as a recipe on how to build a protein molecule. Proteins perform important tasks for the cell functions or serve as building blocks. These proteins determine, among other things, how the organism looks, how well its body metabolizes food or fights infection, and sometimes even how it behaves.
Beginning in 1989, the Human Genome Project set out to map the sequence of the 3 billion DNA subunits (or chemical base pairs of A’s, T’s, C’s, and G’s), identify all 20,000-25,000 human genes, and make them accessible for further research. The project began in 1989 and was initially headed by Ari Patrinos, head of the Office of Biological and Environmental Research in the U.S. Department of Energy’s Office of Science. Also working on the project was Francis Collins who directed the NIH (National Institutes of Health) National Human Genome Research Institute efforts. A parallel project was conducted outside of the government by the Celera Corporation, which was formally launched in 1998. In 2000, founder of the Celera Corporation Craig Venter along with Francis Collins jointly made the announcement of the mapping of the human genome, a full three years ahead of the government project.
Dr. Larry Schlabach, a medical oncologist with University Oncology and Hematology in Chattanooga, says, “In the 1970s, the National Institutes of Health got federal funding to ‘figure out cancer.’ In science the answers aren’t simple, and it takes years or even someone’s entire career to figure out one little thing. But the money that the federal government has spent over the past 40 years is now reaping the results of understanding what these diseases are.”
Finding the single marker that puts a person at risk for a particular cancer or identifying the protein that produces a cancer is what makes diagnosing and treating cancer so difficult. Dr. Schlabach explains, “This speaks to the heterogeneity of the disease. Heterogeneity on a pathologic level is the different genetic make-up. In all these cancers, what’s being done now is to look at their genetic profile and why certain treatments work or why they behave so differently.”
Linking Genome Mapping and Cancer Therapies
Completion of the sequencing of the human genome made way for understanding the unique aspects of many diseases, including cancers. Identifying specific mutations in genes, in other words, finding the root cause of the cancer, has and will continue to improve both diagnosis and treatment. Dr. Schlabach explains, “In the past we have lumped all lung cancers together, but they’re not all the same. The question was always ‘Why does Patient A behave so differently from Patient B when they both have the same diagnosis?’ Now we know that the genetic makeup of cancers is not the same.”
While news of breakthroughs in cancer diagnosis and treatment hold great promise, Dr. Schlabach cautions that these are first steps and that this road is long and complex. Enabling researchers and doctors to create therapies that target specific cancers is an important goal of the genome project. Using genetic information to develop and match drugs to treat what is actually causing the cancer makes the creation of “personalized medicine” closer to reality. Clinical studies and drug trials are important in moving this work forward. Dr. Brooke Daniel, a medical oncologist with Chattanooga Oncology and Hematology Associates, says, “Clinical trials bring new drugs to the community, and patients who participate in them are watched very closely.”
Dr. Schlabach explains, “What you hope to find is specific genes in common cancers in order to have a more tailored treatment for the genetic profile of the patient’s cancer. That’s where this is going. Eventually you’ll get a genetic profile of the cancer, which is far, far more important than saying this is lung cancer or this is breast cancer. This is the genetic makeup of this cancer, and this is what will turn this switch off. It’s very, very complicated, but this is the principal.”
Targeted Therapies in the News
Headlines from the American Society of Clinical Oncologists (ASCO) conference held in Chicago this past June featured targeted therapies. Drugs most often identified as “target drugs” work by turning off a protein that causes the cancer or by inhibiting a protein that has allowed a cancer to grow. Targeted therapies may also include drugs that target hormones or the immune system.
Treatment for Advanced Melanoma
Melanoma is a particularly deadly form of skin cancer, especially if it is not diagnosed and treated in the early stages and particularly once it metastasizes. Genetic therapy has revealed that approximately 50 percent of people with melanoma have a mutation of the B-RAF protein. That discovery led to the creation of a drug which targets the B-RAF protein, essentially turning it off. This drug, Vemurafenib, is still in the investigational stages, awaiting FDA approval. Its impact on patients with advanced melanoma is impressive, giving hope where there had been little before. Again, Dr. Schlabach advises caution in how this news is interpreted. The results of the study “show that when you find the right target and you know how to manipulate it, you get dramatic results. We are starting to achieve remission, but 6-12 months later, it’s back. There’s a lot more work to be done,” he adds.
Revving up the Immune System
Another drug getting attention in therapies associated with advanced melanoma is FDA-approved Yervoy. Yervoy is a biologic therapy. It’s a kind of man-made antibody that blocks a crucial switch on immune cells called CTLA-4. Cancers use this switch to turn off the body’s anticancer immune responses, but Yervoy turns the anti-cancer immune response back on. Dr. Daniel finds this drug exciting. “Traditional chemotherapy not only kills cancer cells, but also compromises the patient’s immune system. Yervoy enhances the body’s own ability to fight cancer, and it is available now in Chattanooga,” she says. Yervoy has shown to increase life-expectancy in metastatic melanoma specifically, but Yervoy’s cost and side effects are considerable.
Targeting Prevention of Breast Cancer
A recent study of Aromasin, published in the New England Journal of Medicine and presented at the ASCO conference, focused on targeting the hormone that fuels tumor growth. That means it is not targeting the cancer, but rather a hormone that promotes the growth of the disease. Many breast cancers are sensitive to the estrogen hormone, meaning that the tumor grows with the help of estrogen. When a tumor is sensitive to estrogen, it has receptors on the outer surface of its cells. Estrogen fits into these receptors like a key opening a lock. When this connection is made, the cancer grows. Breast cancers that have estrogen receptors are known as hormone receptor-positive tumors. By decreasing estrogen production, Aromasin can help decrease the growth of these breast cancers.
In the case of post-menopausal breast cancers, Aromasin has been shown effective in reducing the risk of invasive breast cancer by 65 percent. Two other anti-estrogen drugs, tamoxifen and raloxifene, are also approved for this purpose. All three drugs come with side effects, although this most recent study suggests that those associated with Aromasin may be less dramatic.
Breakthroughs come every year. Ultimately, targeted therapies will exist for the treatment of all cancers, providing the best hope for extending the lives of those who are diagnosed. “The hope of all this is prevention,” says Dr. Schlabach. “We’re an aging population. As our cells turn over, DNA is damaged and has to be repaired. If it isn’t repaired correctly, we have more of these diseases later in our lives.” For example, we may be more aware of a young woman who is diagnosed with breast cancer, but the peak incidence occurs in a woman’s late 60s and early 70s.
Both Dr. Daniel and Dr. Schlabach agree that taking care of ourselves by staying out of the sun, eating the right foods, and avoiding other known cancer triggers is a huge part of prevention. There is no doubt that more and more targeted or personalized medicines will become part of the treatment for cancer, and someday, part of the cure. “It’s progress,” says Dr. Schlabach, “but it’s one small step in the big picture. Keep things in perspective. It is a step, and it offers hope. You always want to offer hope.”
Pamela Boaz, a writer and editor, earned a B.S. degree from the University of North Florida and an M. Ed. from UTC. During her more than 30-year career in education, she has served as faculty advisor for student publications and written curricula for a variety of courses. Pam also works as Professor-in Residence for UTC, supervising student teachers.