The National Cancer Institute (NCI) has awarded Susan Kane, Ph.D., professor in the Division of Tumor Cell Biology, a five-year, $1.7 million grant to investigate one genetic piece of the puzzle behind multidrug resistance in breast cancer patients.
The funding will enable Kane and her laboratory to answer critical questions about the regulation of the multidrug resistance gene (MDR1). These answers may ultimately result in improved treatments.
|Susan Kane studies genes that help breast cancer survive chemotherapy. (Photo by Markie Ramirez)|
Multidrug resistance in cancer patients is a process in which tumor cells develop resistance to chemotherapy or other drugs, blocking successful treatment and allowing cancer to return, usually with a different susceptibility to drugs.
Cancers developing from tissues that normally express MDR1, such as the colon, liver and kidney, tend to be inherently drug-resistant. About half of breast cancers overexpress the MDR1 gene, although normal mammary tissue does not.
Scientists know that other factors beyond MDR1 also influence drug resistance. “Not every drug-resistant tumor type expresses MDR1, and not every patient with a particular tumor type will express MDR1,” Kane explained. “Therefore, MDR1 is one of many mechanisms of drug resistance that patients may develop.”
Unfortunately, the many mechanisms of drug resistance and the variety of different cell types within the same tumor make it difficult to tease out MDR1’s specific role in resistance.
If researchers could monitor changes in MDR1 expression in patients during treatment, the results could illuminate MDR1’s role. But doctors cannot repeatedly take tumor samples for study while patients are undergoing therapy.
Kane and Long Gu, Ph.D., an assistant research professor working in Kane’s lab, may have solved this problem in the lab by developing a promising model to study MDR1 gene regulation in mice. They connected the firefly luciferase gene to the mouse version of MDR1, called mdr1a. The luciferase gene causes the mouse’s body to glow wherever the mdr1a gene is active. Now researchers can visualize changes in mdr1a expression in live mice via a real-time imaging technology that shows glowing “hotspots” as mdr1a gene expression increases in the animal.
The NCI grant supports research based on this animal model.
The study addresses the regulation of mdr1a gene expression in normal tissues, as well as during tumor progression and long-term treatment with common chemotherapy drugs. The team aims to shed light on the conditions during tumor development and treatment that activate MDR1. With this understanding, doctors could avoid using drugs that may stimulate MDR1, reducing the risk of developing drug resistance. Using this model, researchers could also screen new drugs to determine their effect on MDR1 expression.
Kane and colleagues are investigating other applications for their imaging model in the realm of gene expression, as well.
By coupling their current model with other luminescent markers for multiple drug resistance genes, they will investigate the co-regulation of several genes — how they are regulated at the same time. This model could allow them to determine the different genetic “switches” in tumor tissues that are turned on and off as cancer begins and develops, as well as during treatment.
“We would like to apply what we learn to patients,” Kane said, “either to look for the emergence of MDR1 resistance during long term-treatment or to identify novel targets for potential drug development.”