Exploring new frontiers in personalized cancer care

Personalized medicine is turning medical care on its head, and cancer treatment is at the forefront of that revolution. The UAB Comprehensive Cancer Center’s 17th Annual Research Retreat introduced this cutting-edge work to an audience of nearly 400 clinicians and researchers. The topic was timely after this summer’s announcement of major initiatives in genomics and personalized medicine at UAB, including a research consortium between the Cancer Center and Huntsville’s HudsonAlpha Institute for Biotechnology.

“Personalized medicine is the future of cancer care,” noted Eddy Yang, M.D., Ph.D., associate professor in the UAB Department of Radiation Oncology, who organized this year’s symposium. “This is certainly a glimpse of what is to come for the Cancer Center and UAB as a whole.”

The Future: Cancer as a Chronic Disease

“Oncology has been a first mover for personalized medicine,” said invited speaker Mark Boguski, M.D., Ph.D., founder of Genome Health Solutions and a faculty member at Harvard Medical School.

Boguski shared his remarkable vision. With the use of personalized medicine, he said, we can now begin to reimagine cancer as a manageable chronic disease. Subsequent speakers amplified that theme, describing advances, challenges and roadblocks to delivering personalized cancer care to patients across the United States.

Boguski began with three patient case histories.

The first was a patient in 2010 with adenocarcinoma that was EGFR-positive (that is, it contained mutations that activated the EGFR pathway). When treatment with the usual drug failed, genomic and transcriptomic analysis showed why — metastases from the original cancer were no longer EGFR-positive. But biomarkers on those cancer cells successfully identified a target for a different drug that was effective.

The second case was a metastatic squamous cell carcinoma. Genomic analysis showed, surprisingly, that it could be treated with a hematological cancer drug.

“You wouldn’t guess to use that on a solid tumor,” Boguski said.

Similarly, in a case of advanced lymphoblastic leukemia, genomic analysis unexpectedly pointed to using a renal cell carcinoma drug. With this sea change in the way that oncologists can make their treatment decisions, cancer patients are beginning to ask that their genomes be analyzed, Boguski said.

The UAB Cancer Center’s Molecular Tumor Board, initiated last year, identifies patients who could benefit from DNA sequencing of their tumors, said Yang. These tests, usually conducted in patients with rare tumors or tumors that do not respond to typical treatment, can identify off-label uses for cancer drugs. For example, BRAF inhibitors, which are approved for melanoma, have been used to treat patients with other tumor types that nevertheless harbor the BRAF V600E mutation, Yang said. In another important consideration, “treating physicians have been successful in getting third-party payers to pay for these drugs outside the ‘approved’ indications using the profiling results,” he explained.

Cancer Center Honors Research Excellence In addition to talks by leading investigators, the Cancer Center’s research retreat also features the work of a new generation of cancer researchers. Graduate students, postdoctoral fellows and junior faculty members took part in the annual poster competition; the 131 presentations emphasize the breadth of studies ongoing in the Cancer Center, from cancer prevention to bioinformatics. See the award winners here.

But roadblocks prevent the widespread delivery of such personalized, targeted care, Boguski noted in his talk, because:

• 80 percent of cancer care is delivered away from the top 50 cancer centers.
• Most doctors suffer from a knowledge gap; they need accelerated genome training to understand the top molecular biomarkers and how these markers can guide patient therapy.
• Pathologists — who are a key link to alter the delivery of care — need to know not only tissue pathology but also how to test for and report the molecular drivers of cancer.

Genomics Identifies Actionable Targets

Mark Kris, M.D., an attending physician at the Memorial Sloan Kettering Cancer Center and professor at the Weill Cornell Medical College, showed how genomics and personalized care can be harnessed to improve lung cancer survival.

Working with 11 cancer centers, Kris and colleagues tested 1,000 patients who had stage IV lung cancer. While tissue pathology confirmed adenocarcinoma, the cancers also underwent mutational analysis to probe for oncogenic drivers, and these findings were shared with physicians.

Two-thirds of the patients had at least one of 10 known oncogenic drivers. These drivers are “actionable targets” that helped to guide treatment choices, leading to increased median survival for these advanced cancer patients.

The French medical system, Kris noted, has provided genotyping to every lung cancer patient since 2011, at a rate of 20,000 patients a year. This equity of access to innovation does not exist in the United States, Kris said, even though the National Comprehensive Cancer Network clinical practice guidelines for non-small-cell lung cancer already list a set of molecular drivers that should be looked to to classify and guide treatment.

Needed: A New Kind of Trial

Another roadblock is the need for new ways to perform clinical trials of investigational drugs, said Donald Berry, Ph.D., professor of biostatistics at the M.D. Anderson Cancer Center and a co-founder of Berry Consultants.

Berry described how the use of Bayesian biostatistics in an adaptive platform trial can lower the numbers of patients needed for the trial, while simultaneously investigating multiple drugs and targets. He focused on a current study, I-SPY2, which is investigating treatments for breast cancer. (Berry noted that UAB is one of the largest contributors of patients to the trial.)

Data obtained during trials such as I-SPY2 are used to guide changes in the studies midstream, Berry explained. The result is nimble, lean studies that yield a more dependable estimate of the chance that a particular drug will succeed in its subsequent Phase III trial. Such information is crucial, given the cost and the failure rates of conventional Phase III trials.

Predicting Patient Response With Avatars

The final outside speaker, Paul Haluska Jr., M.D., Ph.D., associate professor of oncology at the Mayo Clinic, described an “Ovarian Avatar” model to personalize ovarian cancer treatment. The avatar is created by implanting live cancer tissue from the cancer patient into a mouse within two hours of surgery.

Haluska shared several definitions involved in this model:
• “Xenograft” is a tumor taken from one species and implanted in another;
• “Orthotopic” means the implant is placed in the natural body location for that type of tumor;
• “Patient-derived Xenograft” is a direct implant from the patient into the other species, without any intermediate in vitro growth or manipulation; and
• “Avatar” is thus an orthotopic, treatment-naïve, patient-derived xenograft.

Mayo implanted its first model in March 2010. Through this September, 404 models have been injected and 294 of them successfully engrafted. The avatar responses to a drug, Haluska said, appeared to mirror the patient responses to treatment with the same drug, and the avatars are being used for drug development.

The next step will be to actually use a particular patient’s avatar to direct her therapy. “It will be the first ovarian cancer with xenograft-directed therapy,” Haluska said. “The best predictor of response is response.”

Oncogenic Drivers and Racial Disparities

UAB has its own xenografts that are derived from glioblastoma multiforme tumors, said Christopher Willey, M.D., Ph.D., an associate professor in the Department of Radiation Oncology and director of the UAB Kinome Core (pronounced “k-eye-nome”). But these personal avatars have a problem — they take too much time to establish compared to the rapid and fatal course of glioblastomas. So Willey hopes instead to use “kinomic” profiles of established avatars from other patients to guide the treatment for a new patient; glioblastoma tissue removed from the new patient during surgery can quickly be kinomically profiled.

Kinomics uses substrate arrays to identify which kinase enzymes — often found to be key oncogenic drivers — are active in the cancer cells. This can help select among about 30 cancer chemotherapeutic agents that target kinases.

The other UAB speaker, Phillip Buckhaults, Ph.D., associate professor in the UAB Division of Hematology and Oncology, described his search for genetic mechanisms that lead to earlier onset and higher incidence of breast and colon cancers in African-Americans, as compared to Caucasian-Americans. His trail began with the discovery of a point-mutant variant of the TP53 tumor suppressor gene in African-Americans, and it has led to the variant’s effect on the PRDM1 chromatin-silencing gene.

Translating research insights from the laboratory to the clinic is a major focus of the UAB-HudsonAlpha cancer consortium, noted Cancer Center director Edward Partridge, M.D. “We’re not at the point yet where we can routinely apply genomics information from the tumor to treatment; but we’re clearly learning, and learning at a rapid pace,” Partridge said. “The goal of the consortium is to accelerate that, and we’re excited about what it means for the care we can bring to our patients.”

— Jeff Hansen

Chimerism: not being yourself has medical implications

Science has demolished another idea that researchers once knew to be "true" about genes, the chains of molecules that encode the blueprint for the human body. The consensus a few years back was that every cell in each person's body has the same genetic signature, the same set of DNA unique to that person. It is a pretty important concept if you think about it.

Researchers determine things like paternity, genetic risk for disease and presence at crime scenes by examining just a few of the trillion cells in each a person.This practice is based on the assumption that the few cells taken accurately represent the genes in the rest of that individual.

But what if one person had different sets of genes, or genomes, in different cells? Some people, it turns out, have patches of cells with genetic changes in them not found in other parts of their bodies. Some have cells with genes that came from other people.

Such variety is called chimerism or mosaicism, depending on the details, both of which were the subject of a recent article by writer Carl Zimmer in the New York Times. We used the occasion of the article to ask Bruce Korf, M.D., Ph.D., chair of the UAB Department of Genetics, for his thoughts on the implications of these ideas for medicine. 

Show notes for the conference: 

0:35 To recap, the blueprint for the human body is encoded in genes, many of which hold the information necessary for the building of one or more proteins. Gene expression is the process by which information stored in genes is converted into proteins, the workhorse molecules that make up the body’s structures and carry its signals.

1:38 The dogma for decades in genetics was that all cells in one person, having all come from the same original cell (the embryo), had copies of the same genetic material throughout life. That belief was correct to a point, but did not tell the whole story, said Dr. Korf. Each person does indeed have a unique genome, a set of genetic material made up of about 3 billion bases, the “letters” that make up the DNA code, but changes in that code occur every time anyone our trillions of cells divides and multiplies. So mutations are underway constantly, with different changes building up in different groups of cells. Furthermore, several events, some of them more common that once thought, can inject other people's cells into our bodies.

6:35 Chimerism is the presence of two or more genetically different cells occurring in the same body. While we are taught the a fetus results when one sperm fertilizes one egg, more pregnanices than once thought may result from multiple fertilization events. More than one sperm fertilizes more than one egg in the womb get mixed to form one body. Beyond the number of twins born, researchers now suspect that many single baby pregnancies started as twins. One of the embryos then died early on, but not before sharing blood and cells with its twin. Thus you have one baby with the genomes of two babies mixed together. In other cases, two fertilized eggs may fuse together with no evidence they were once two individuals. Obviously, people who get an organ transplant are chimeras as well, as are most mothers, who absorbed their some of their babies' cells while pregnant.

8:15 Chimerism, which happens during conception, is different from the changes in genes that arise from constant small changes in genetic code underway in every human cell over a person's lifetime, a concept called mosaicism. Most of us have patches of cells in our body that have different genes than patches growing elsewhere. While the overall differences are small, mounting evidence suggests they may be meaningful. In the UAB Medical Genomics lab led by Dr. Korf,  the team studies many genetic orders that proceed from mosaicism. In many cases, a patient will have a genetic change that has caused cancer just in one patch of skin, instead of a change across the entire body.

11:06  When a person has two sets of different DNA in their cells, one set will greatly predominate with the other in relatively few cells. Until recently, DNA technologies often could not capture the less frequently occurring genome, losing it in the vast background of the majority. Next-generation sequencing technologies, however, can now identify rare cells that have a different genotype than most of the cells in a person, a capability which may explain why this topic has been more in the news lately. According to the Times article, recent cases have featured genetic test results that found a mother was not the mother of one of her children, and that a sexual assault suspect did not have the same genetic signature in his sperm as in his saliva. The fact both were chimeras threw the tests off.

12:56 While we don't yet know whether cells with different DNA have a big impact on say hearth disease risk, they are known to have a profound role in cancer. Whether the DNA is atypical from chimerism or mosaicism, it is possible the change may affect a cell's ability to divide and multiply, perhaps leading to abnormal growth. Cancer is a disease of mosaicism, said Dr. Korf, because a cell comes to include a small changes in its DNA that remove normal growth limits to create tumors.

16:45  We don't really know how many different genomes we have in the cells in our body. If you look at it one way, we have as many different sets of genetic material as we have cells, since small, unique and random changes slip in as each cell divides and multiplies into two more. Most of the changes have no impact on healthy function, but some do, and the trick is to pick out trillions the few that do.

17:22  Cells with slightly different DNA sequences obviously play a role in cancer, but the remaining question is whether or not small numbers of cells with differing genomes different play a role in other major diseases, like heart disease or Alzheimer's. Is it possible that chimerism or mosaicism in the heart can cause rhythm disorders or that such changes in the pancreas bring about diabetes?