A rheumatoid arthritis treatment suppresses the growth of PTEN mutant cancer cells — a finding that could lead to targeted therapies against aggressive cancers that have few treatment options, researchers say.
The study, “PTEN Regulates Glutamine Flux to Pyrimidine Synthesis and Sensitivity to Dihydroorotate Dehydrogenase Inhibition,” was published in Cancer Discovery.
The research team was led by Ramon Parsons, MD, PhD, professor and chair of the Department of Oncological Sciences at New York’s Icahn School of Medicine at Mount Sinai.
Parsons’ team, which studies tumor suppression, discovered the PTEN gene. Their work showed that a mutation of the gene regulates a metabolic pathway in a way that causes uncontrolled tumor growth.
Glutamine is the most abundant amino acid in blood and tissues. Changes in the way its metabolizes, or burns energy, are a hallmark of cancer. Parsons’ team observed that PTEN mutations trigger recruitment of glutamine and accelerates production of DNA.
The team found that leflunomide – an oral rheumatoid arthritis drug approved by the U.S. Food and Drug Administration – selectively kills mutant PTEN cancer cells, leaving healthy cells undamaged. Leflunomide blocks an enzyme involved in DNA synthesis that damaged DNA during cell division.
When researchers transplanted human breast cancer cells into mice, leflunomide significantly reduced tumor growth. That included mice with cells from triple-negative breast cancer patients. Similar results were observed when the team treated 3D patient-derived glioblastomas with PTEN deficiency.
PTEN mutation is implicated in aggressive cancers with insufficient treatment options, including prostate cancer, breast cancer, endometrial cancer, and glioblastoma, a brain cancer. Leflunomide’s ability to block tumor growth may lead to targeted, tumor-specific therapies.
“Finding successful targeted therapies for cancer is a challenging but important goal in the face of insufficient treatment options,” Parsons said in a press release. “Targeted therapies that are tumor-specific are much needed, and identifying changes based on specific tumor suppressor or oncogene alterations will facilitate this effort. Due to the high mutation rate of PTEN in cancer, the effects of PTEN could be at the heart of targeted therapy.”
Parsons’s team is planning clinical trials to test leflunomide in patients with breast and colon cancer.