A Biomarker Could Increase Effectiveness of Mesothelioma Chemotherapy

For patients diagnosed with mesothelioma, chemotherapy is the most commonly prescribed treatment for managing symptoms and slowing the growth of the disease. But mesothelioma has been shown to become chemo-resistant, eventually rendering the mesothelioma treatment ineffective. Now, researchers report they have uncovered a biomarker that could effectively eliminate resistance in one chemotherapy agent.

Pemetrexed (Alimta) is the only chemotherapy drug that has been approved in the U.S. for the treatment of patients with malignant pleural mesothelioma, but nearly all patients develop resistance. Researchers from the VU University Medical Center in Amsterdam, The Netherlands, wanted to find a way to halt that resistance and found that the protein PCFT plays a significant role in driving the effectiveness of the drug.

The researchers first looked at thymidylate synthase (TS) which other studies have shown as a  predictive biomarker for mesothelioma in response to pemetrexed. Then they looked at PCFT, or proton-coupled folate-transporter, levels in both frozen mesothelioma lines and in tissue micro-arrays of patients who had previously been treated with pemetrexed to determine if PCFT and TS levels were correlated.

While PCFT plays a role in the absorption of folates, pemetrexed is a folate inhibitor. Research has shown that PCFT is “abundantly expressed in human tumors,” including some mesothelioma patients, making pemetrexed effective in fighting the cancer.

However, the VU researchers found that mesothelioma tumors with low PCFT levels corresponded to shorter overall survival, and patients who had both low PCFT levels and high TS levels had the worst prognosis and overall survival. The researchers determined that PCFT silencing reduced the patients’ response to pemetrexed. Without an abundance of PCFT, pemetrexed was not effective in fighting mesothelioma.

They concluded that if they could find a way to increase PCFT levels, and maintain them during pemetrexed treatment, they could extend overall survival by eliminating the cancers ability to fight off the chemotherapy. This study is the first time scientists have looked at PCFT as a target for fighting mesothelioma.

“…Preclinical data suggest that targeting PCFT -promoter methylation might eradicate pemetrexed-resistant cells characterized by low- PCFT expression,” wrote the authors.

This breakthrough, and others like it, continues to bring hope to the mesothelioma community that the terminal cancer might someday be curable. Nearly 3,000 Americans are diagnosed with the deadly asbestos-caused cancer each year.

Read the full study in the Sept. 1 issue of Annals of Oncology.