Oxygen-Focused Treatment and Careful Scheduling May Overcome Drug Resistance in Lung Cancer and Mesothelioma


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X-ray result of Lungs with Cancer

Cancer research is often focused on developing cancer treatments that target a specific gene or biomarker responsible for a particular cancer. Now, researchers report that by focusing on tumor oxygen levels and a treatment schedule using a combination of existing anti-cancer treatments survival in lung cancer patients may be improved. Mesothelioma patients, who often follow the same treatment protocol, could also benefit from this approach.

A team of scientists from the University of Minnesota and the University of Southern California realize that low levels of oxygen in cancer can lead to drug resistance and uncontrollable tumor growth in many cancers. The condition, known as hypoxia, is treated with hypoxia-activated prodrugs, or HAPs. HAPs can penetrate into the oxygen-starved areas of tumors that other cancer drugs cannot. But, HAPs are not effective as a single treatment, so the researchers turned their attention to finding a way to increase the success of them.

The researchers developed a mathematical model to assess the effectiveness of using a HAP (evofosfamide) in combination with standard cancer therapy to prevent the resistance to erlotinib in EGFR-positive non-small cell lung cancer (NSCLC). EGFR is a protein found on the surface of some cells which causes the cells to divide and spread. It is found at abnormally high levels on the surface of lung cancer and mesothelioma. The researchers report that nearly all EGFR NSCLC patients will develop a resistance to erlotinib within a year, making the drug ineffective.

Erlotinib is in a class of drugs called kinase inhibitors that is used to treat NSCLC that has metastasized in patients previously treated with at least one other chemotherapy medication and have not gotten better.

After testing a multitude of treatment schedules combined with differing dosages, the team found that ultimately the best combination to prevent resistance to erlotinib was achieved by alternating the treatment of evofosfamide and erlotinib while limiting the down time between the dosages. By alternating between the two drugs, the researchers report, “the entire population of cancer cells in the tumor microenvironment” is constantly controlled by the drugs.”

“Alternating between these two drugs allows each one to provide the necessary control over the cancer cell population the other one is lacking,” the authors wrote in the study. “These results demonstrate that incorporating HAPs in combination with targeted therapies may be an effective tool in preventing resistance, and suggest an alternative use for HAPs.”

Nearly 3,000 Americans are diagnosed with the incurable cancer, mesothelioma, each year. While recent advances in treatment for mesothelioma patients have improved survival for some patients, continued research is critically important to ensure existing treatments become even more effective. Each breakthrough or promising result from a study increases hope that mesothelioma patients can live longer, higher quality lives with the disease.

“These findings highlight the importance of designing combination therapies with drugs whose strengths complement each other in order to maximize the therapeutic benefits,” concluded the authors.

The study can be found in the Aug. 25 issue of PLOS Computational Biology.

Photo Credit: RxList.com

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