U.S. National Institute of Health www.cancer.gov National Cancer Institute
National Cancer Institute
Skip Header Navigation
Skip Navigation

Research News

Using Evolution to Prolong Progression-Free Survival in Breast Cancer

One of the driving forces of evolution is the competition for scarce resources. Researchers at the H. Lee Moffitt Cancer Center Physical Sciences-Oncology Center (Moffitt PS-OC) have taken advantage of this principle to design a novel course of therapy that may be able to suppress the growth of the drug-resistant tumor cells that come to dominate a tumor during standard high-dose chemotherapy. This strategy combined with lower-dose therapy, could increase the time to tumor recurrence in breast cancer patients by 4- to 10-fold.

This new approach to therapy, developed by a team led by Robert Gatenby, principal investigator of the Moffitt PS-OC, and Robert Gillies, the senior scientific investigator, builds on earlier work that showed that promoting the survival of drug-sensitive cells in a tumor will reduce the number of drug-resistant cells and prolong survival while at the same time reducing drug use and improving quality of life. The results of the current study appear in the journal Cancer Research.

Drug resistance in breast cancer, as well as in many other types of cancer, develops in much the same way as drug resistance does in bacteria. Under assault from drug, cells adaptively respond by producing a membrane-bound pump that rids the cell of the drug. Producing and operating this pump requires energy, however, leaving drug-resistant cells at an evolutionary disadvantage compared to drug-sensitive cells under energy limited conditions.

Rather than try to extinguish every last cancer cell in a tumor, an approach that fails a majority of the time because the development of resistance is inevitable, the strategy that the Moffitt PS-OC team came up with is designed explicitly to maintain a residual population of drug-sensitive cells that can outcompete drug-resistant cells. Using computational models that start with experimental data, the investigators determined that low-dose chemotherapy combined with low doses of the high blood pressure medication verapamil, which competes with chemotherapy drugs for the membrane pump, and 2-deoxyglucose, a sugar derivative that cells cannot metabolize to produce energy, should magnify the selective advantage that drug-sensitive cells have over drug-resistant cells.

In high-dose chemotherapy, virtually every drug-sensitive cell dies, leaving a dominant population of drug-resistant cells that allow the tumor to progress. In low-dose, or adaptive chemotherapy, the purpose of treatment is to maintain tumor burden below a clinically relevant level. Verapamil at a sub-toxic level (completely inhibiting the membrane pump would require toxic levels of this drug) increases the metabolic cost of drug resistance. Adding 2-deoxyglucose depletes the amount of energy source available to the cells, putting the drug resistant cells at huge disadvantage compared to drug sensitive cells.

Computational simulations of hypothetical patients with breast cancer show the potential advantage of this evolutionarily driven combination therapy compared to standard high-dose chemotherapy. In patients where 10 percent of tumor cells are drug resistant, the combination of adaptive chemotherapy plus verapamil and 2-deoxyglucose increases the time of progression-free survival by a factor of four. If the initial population of drug-resistant cells is only five percent, the time for progression-free survival increases 10-fold.

The researchers note that instead of using 2-deoxyglucose, which could have toxic effects in patients, the same effect could be produced by reducing dietary carbohydrate intake. The next step for the Moffitt team will be to test this therapeutic approach in mouse models of breast cancer.

This work, which is detailed in a paper titled, “Evolutionary approaches to prolong progression-free survival in breast cancer,” was supported by the National Cancer Institute's Physical Sciences in Oncology initiative, a program that aims to foster the development of innovative ideas and new fields of study based on knowledge of the biological and physical laws and principles that define both normal and tumor systems. An abstract of this paper is available at the journal's Web site.
View abstract

Funding Opportunities
Find out more about funding opportunities available in physical sciences. More
Purple border
Think Tanks
Learn about the Physical Sciences in Oncology Workshops and Think Tanks. More

 

 

Skip Footer Navigation