Abstract # 4546:
Karmanos Cancer Institute researchers study novel folate transporter to customize chemotherapy
Tuesday, April 20, 2010
Scientists at the Barbara Ann Karmanos Cancer Institute in Detroit today presented a poster at the American Association for Cancer Research’s 101st Annual Meeting 2010 that details their novel study of molecules that use a tumor’s acidic microenvironment to help them tailor chemotherapeutic agents to kill the tumor.
The study is entitled, “Expression profiling of the major folate facilitative transporters in human tumors and normal tissues.” Karmanos researchers, with the help of colleagues at Duquesne University in Pittsburgh, discovered that low extracellular pH levels within tumors are critical in the effective delivery of novel cytotoxic antifolates – drugs that kill those tumors. They identified that the proton-coupled folate transporter (PCFT), which functions at an acidic pH level, may help in effectively targeting cytotoxic antifolates to 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 (RFC). The cytotoxic effects of those drugs are determined by the levels of PCFT and the RFC in tumors and regular tissues.
PCFT and RFC transport folate into normal cells. Folate, a component of Vitamin B, is critical for cell and tissue regeneration.
Research was supervised by Larry Matherly, Ph.D., professor of Pharmacology and director of the Graduate Program in Cancer Biology and a member of the Developmental Therapeutics Program at Karmanos and Wayne State University School of Medicine. Sita Kugel Desmoulin, a Ph.D. candidate in the Cancer Biology graduate program at Karmanos and Wayne State University School of Medicine, presented the findings.
Researchers determined expression levels for PCFT and RFC in human malignancies and normal tissues. They also identified PCFT and RFC transcript levels in 57 human solid tumor and 27 leukemia lines. Both RFC and PCFT transcripts were highly expressed in the majority of solid tumor cell lines. Only RFC was expressed appreciably in leukemia cell lines.
“PCFT’s presence in a multitude of tumors allows for a much broader scope in identifying therapeutic targets within the tumors,” said Desmoulin. “We’re not just looking at one solid tumor, like breast or prostate. PCFT’s presence in many types of tumors allows for that potential to have significant and widespread therapeutic implications. That is definitely very exciting.”
This study represents the first comprehensive analysis of PCFT expression in tumors and normal tissues and how this expression relates to RFC. Researchers believe the discovery of widespread PCFT expression in human solid tumors offers exciting new therapeutic possibilities for selectively targeting chemotherapy to tumors based on their acidic microenvironments.
“We’ve had a big focus here at Karmanos for the last few years in discovering agents that are specific to PCFT but not RFC,” said Dr. Matherly. “You’re not only playing with the microenvironment and acidic pH levels, you’re also working with therapeutics that are specific to that mechanism and that’s going to give you two opportunities for selectivity of drugs.”
Karmanos researchers say their work is preclinical but mention they are doing in vivo laboratory trials in mouse models. They are also 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, according to Dr. Matherly.
“It’s great to take drugs that are completely unknown, to work them up and find out their characteristics, and to come up with a promising, novel therapy,” said Desmoulin. “The drugs’ potential could be very good.”