Lab Tour: How Genetics Could Transform Ovarian Cancer Treatment
Dr. R. Stephanie Huang
University of Chicago Department of Medicine
As a pharmacist, Dr. R. Stephanie Huang’s main concern is how drugs affect patients. Currently, Dr. Huang is exploring how genetics determine why some people respond to certain types of chemotherapy while others do not. For example, one-quarter of women with ovarian cancer develop a platinum resistant cancer. The reason that some people, or some tumors, are resistant to platinum therapies may have its roots in genetics. This area of personalized medicine is expanding as genetic sequencing technology becomes faster and cheaper.
When studying the effect of genetics on anti-cancer treatments, two types of genetic variations need to be considered. The first, germline variations, encompass a person’s genetic code including any heritable mutations. The second, somatic variations, are mutations that are not heritable, such as genetic changes caused by exposure to chemicals. Dr. Huang’s research is focusing on the germline genetic variations, since these may predispose an individual to various treatment-related toxicities. Furthermore, since all cancer cells derive from normal cells, certain germline variations could be linked to both the likelihood of developing ovarian cancer and response to treatments.
“One challenge is to differentiate between what we know and what we can do about it. I’m working to make genetics useful in terms of making fully informed decision about what works for each patient,” says Dr. Huang.
Dr. Huang recently published a paper looking for differences among individuals in their normal DNA code, known as germline genetic variations, that predicted platinum sensitivity in women with ovarian cancer. To do this, she utilized hundreds of cell lines (specific cells bred in a laboratory and able to duplicate indefinitely so that they can be used for research purposes) evaluated by the International HapMap Consortium. This international collaboration is aimed at obtaining all common genetic variations in the world’s human populations and making them publicly available for research. Each of the cell lines is derived from an individual’s blood; information about their ethnicity is captured as well.
The cell lines were treated in her lab with various chemotherapeutic agents to determine each individual’s sensitivity to drugs. Dr. Huang then did genetic analyses between each person’s genomic code and his or her sensitivity to the drug. Her goal was to identify germline genetic variations that could be used to predict chemotherapy response. These cell-based findings were then evaluated in 400 women with ovarian cancer who had undergone the related drug treatment. She found that there may be some genetic variations that affect overall survival, progression free survival or response to chemotherapy. Unfortunately, the data was not able to be validated in a larger scale analysis, but leaves the door open for continued research.
The Huang lab is also examining the differences in germline variations and somatic mutations to see which of those are cancer-related. To do so, Dr. Huang and her collaborators are utilizing data from the Cancer Genome Atlas (TCGA).
TCGA is a multi-year, multi-cancer study funded by the National Cancer Institute to understand the genetics of certain cancers, including ovarian. Preliminary ovarian cancer results were released earlier this year, showing that there are multiple genetic mutations in each case of ovarian cancer, and that each tumor may contain a unique combination of mutations. This poses a significant challenge for individualized ovarian cancer management.
Dr. Huang is working with a team to use TCGA’s information in her research. She is looking at the difference between a person’s genetic code and that of their tumor to establish links between germline genetic variation and somatic mutations in the tumor. Then she can determine genome markers. For example, we know that germline mutations in the BRCA mutations increase a woman’s risk for breast and ovarian cancer. Those women are also more responsive to certain drugs, like PARP inhibitors.
There may be other genetic markers that will help providers understand a woman’s sensitivity to drugs. In the future, each woman may receive a personalized cocktail of drugs intended to target her tumor’s specific mix of genetic mutations. Researchers like Dr. Huang are trying to determine which genetic variations respond best to a particular treatment.
In order to validate any treatment protocols, researchers would need to find the exact genetic variation as well as understand the patient’s overall genetic makeup. Then researchers would collect the patient’s blood, establish cell lines and link the patient’s treatment, outcome, genetics and tumor genetics to determine which treatments will work best. Currently, Dr. Huang is doing this for toxicity to chemotherapy in head, neck and ovarian tumors, and is seeing some patterns.
“The technology in genomic sequencing is fairly mature, but it’s going to get faster and cheaper,” says Dr. Huang. “We will soon have the ability to look at every individual’s genome. Our challenge is to translate scientific discovery into implementation, which takes a lot of data, and a lot of patient participation.” As this field evolves, so might treatment options for women with ovarian cancer.
