May 13, 2010

Researcher wins grant to target chemo in mesothelioma

A Wayne State University School of Medicine researcher has secured a grant from the Mesothelioma Applied Research Foundation to further his work on battling tumors with targeted therapeutics.

The foundation gave Larry Matherly, Ph.D., professor of the Department of Pharmacology, a $100,000 grant for his study, "Targeting malignant pleural mesothelioma with PCFT-targeted therapeutics."

Pleural mesothelioma is the most common form of a rare cancer that occurs in the layer of cells lining internal organs. The pleural form affects the lining of the lungs. At this point, the only recognized cause, according to the MARF, is exposure to asbestos. The cancer can be aggressive, spreading to the chest wall and heart, and is generally fatal. Patients diagnosed with pleural mesothelioma often die within a year. An early diagnosis, and surgery, can extend that window. Other treatments include radiotherapy and chemotherapy.

"Our study is designed to establish the proton-coupled folate transporter as a viable approach for targeting malignant mesothelioma with chemotherapy drugs," said Dr. Matherly, who also serves as associate director of the graduate program in Cancer Biology for the Barbara Ann Karmanos Cancer Institute. "This will lead to the development of new targeted drugs chemically similar to pemetrexed (a chemotherapeutic drug with the brand name Alimta), but with clear advantages, including increased potency and tumor selectivity."

Study of the novel PCFT targeted agents will provide lead drugs that can later be modified for increased potency and tumor selectivity, Dr. Matherly said.

According to the MARF, folate plays a key role in cell division and replication, and is the target of the current established treatment for mesothelioma, Alimta. The PCFT transporter is a vital pathway in delivering Alimta to malignant mesothelioma cells. Developing agents that target the transporter and can be combined with Alimta or related drugs will enhance their transport to the malignant cells, thereby increasing their effect.

"The result will be increased numbers of long-term survivors and reduced toxicity. This should offer new hope to patients diagnosed with this devastating disease, he said.

Last month, School of Medicine and Karmanos Cancer Institute researchers presented their study of molecules that use a tumor's acidic microenvironment to help them tailor chemotherapeutic agents to kill the tumor. They discovered that  low extracellular pH levels within tumors are critical in the effective delivery of novel cytotoxic antifolates -- drugs that kill those tumors. They found that the PCFT transporter, which functions at an acidic pH level, may help those drugs home in on tumors, based on their acid microenvironments.

They identified PCFT molecules in varying levels in breast, colon, kidney, liver, lung, ovary and prostate cancer tumors. Researchers looked at clinically-relevant antifolates such as pemetrexed, methotrexate and raltitrexed, which are transported by PCFT and the reduced folate carrier. The cytotoxic effects of those drugs are determined by the levels of PCFT in tumors and regular tissues.

The research was supervised by Dr. Matherly. Sita Kugel Desmoulin, a Ph.D. candidate in the Cancer Biology graduate program, presented the findings, which represent the first comprehensive analysis of PCFT expression in tumors and normal tissues.

The researchers said their work is preclinical but they are conducting in vivo laboratory trials in mouse models. They also are talking to pharmaceutical companies to license some of the chemotherapeutic agents that are transported by PCFT. Licensing would allow the drugs to be used in human trials, Dr. Matherly said.

For more information about MARF, visit www.curemeso.org