The fact that treating cancer patients with multiple drugs often results in better outcomes than a single drug treatment is long been known amongst the medical profession. However, a MIT study published in the May 11 issue of Cell has just demonstrated that the order and timing of administering drugs may also have a dramatic impact.
The study revealed that staggering doses of erlotinib and doxorubicin, two approved medicines for the treatment of cancer, resulted in a dramatic improvement of killing a particular malignant type of breast cancer cells. Research leader Michael Yaffe, the David H. Koch professor of Biology and Biological Engineering at MIT is currently collaborating with researchers at the Dana-Farber Cancer Institute to conduct future clinical trials of a staggered drug therapy using both drugs.
The researchers concentrated their study on a triple negative type of breast cancer cells, i.e. the cells have neither overactive estrogen, nor progesterone or HER2 receptors. About 16% of breast cancer cases are triple-negative tumors, which are far more aggressive compared with other types of cancer and predominantly affect younger women.
Yaffe, who studied the complex cell-signaling pathways that control the dynamics of cells for almost a decade, declares:
“For triple-negative breast cancer cells, there is no good treatment. The standard of care is combination chemotherapy, and although it has a good initial response rate, a significant number of patients develop recurrent cancer.”
Yaffe’s research had involved investigating cell growth, cell division and cell death, as these pathways often become erratic in cancer cells, causing cell growth even without the presence of any stimulus and ignoring signals when they should undergo cell suicide. Yaffe hypothesized that staggering drug-induced changes in the signaling pathways could switch a cancerous cell into a less malignant state.
He says:
“Our previous systems-biology work had primed us to the idea that you could potentially drive a cell from a state in which only a fraction of the tumor cells were responsive to chemotherapy into a state where many more of them were responsive by therapeutically rewiring their signaling networks in a very time-dependent way.”
Yaffe and his colleague Michael Lee, a postdoc and leading author of the study, decided to investigate whether cancer cells could be sensitized to DN-damaging drugs, which are the basis of most chemotherapies, by first administering another drug, which blocks one of the erratic pathways that promotes uncontrollable cell growth. They used different timing schedules analyzing various combinations of 10 DNA-damaging drugs together with about a dozen other different cancerous pathway inhibiting drugs.
Lee explains:
”We thought we would retest a series of drugs that everyone else had already tested, but we would put in wrinkles – like time delays – that, for biological reasons, we thought were important. I think had it not worked, we would have gotten a lot of pushback, but we were pretty convinced that there was a lot of information being left on the table by everyone else.”
The best results from all combinations were achieved with a pretreatment of erlotinib followed by doxorubicin, a common chemotherapy agent. Erlotinib has been FDA approved for the treatment of pancreatic cancer and some types of lung cancer, and operates by blocking the epidermal growth factor (EGF) receptor, a protein found on the surface of cells. If the EGF receptor is constantly active, like in many cancer cells, it stimulates a signaling pathway, which promotes uncontrolled cell growth and division.
They discovered that by administering erlotinib between 4 and 48 hours prior to administering doxorubicin dramatically increased cancer-cell death. Up to 50% of triple-negative cells were killed by staggering the doses of the two drugs, as compared with 20% when both drugs were administered simultaneously. They discovered that pretreatment with erlotinib affected about 2,000 genes, which lead to the shutdown of pathways involved in uncontrolled growth.
Lee explains:
”Instead of looking like this classic triple-negative type of tumor, which is very aggressive and fast-growing and metastatic, they lose their tumorigenic quality and become a different type of tumor that is actually quite unaggressive, and very easy to kill.”
They also found that doxorubicin became less effective than a stand-alone drug, if the drugs were administered in reverse order.
The treatment was observed to work in cancer cells grown in a lab dish, as well as in mice with tumors. When treated first with erlotinib followed by docorubicin, the results demonstrated a decrease in tumors, with no re-growth during the 2-week duration of the experiment, unlike chemotherapy alone or both drugs being administered simultaneously, when the tumors decreased initially but then grew back.
To reveal the dynamics of the increased tumor killing and for identifying a biomarker for drug response, the team used a combination of high-throughput measurements and computer modeling. They observed the treatment proved most effective in a subset of triple-negative breast cancer cells with the highest levels of EGF receptor activity. Doctors should therefore be able to screen patients’ tumors in order to establish which patients would potentially have the best response to this novel treatment.
According to Yaffe, the concept of staggering drug treatments to achieve a maximum impact could be applied across a broad range of therapies. The team discovered similar boosts in tumor killing by pre-treating HER2-positive breast cancer cells with a HER2 inhibitor, followed by a DNA-damaging drug, and also observed good results with erlotinib and doxorubicin in some types of lung cancer.
Lee states:
”The drugs are going to be different for each cancer case, but the concept that time-staggered inhibition will be a strong determinant of efficacy has been universally true. It’s just a matter of finding the right combinations.”
Yaffe says t he discovery also underlines the significance of systems biology in studying cancer, and concludes:
“Our findings illustrate how systems engineering approaches to cell signaling can have large potential impact on disease treatment.”
Written By Petra Rattue