Scientists here have identified a new pathway in the progression of chronic myelogenous leukemia (CML). They also discovered that an extract from the root of a common ornamental plant can suppress the process.
The findings, appearing in the November issue of Cancer Cell, may yield new treatment options for the estimated 4,600 people in the United States who are expected to develop CML this year – especially those with advanced disease, or those who become resistant to the drug Gleevec.
The promising new extract is forskolin, which comes from the root of the plant coleus forskohlii, a native of India that is used in the United States as an ornamental plant.
Early results on CML patient cells both in culture and in mice showed that forskolin reduced the cancer cells' ability to grow by up to 90 percent.
"We believe these are significant findings," said Danilo Perrotti, a member of the OSU Comprehensive Cancer Center 's Molecular Biology and Cancer Genetics Program and an assistant professor in the department of molecular virology, immunology and medical genetics. "We have uncovered a key process that underlies progression in CML and identified an agent that can block it. We also have shown that forskolin can reinstate normal cell functioning, even in Gleevec-resistant cells that do not respond to any treatment currently available."
CML arises when two chromosomes – 9 and 22 – mistakenly exchange genetic material during cell division. The translocation creates a new, fused gene (called BCR-ABL), that produces a cancer-causing enzyme called Bcr-Abl. Bcr-Abl permanently "turns on" cell growth signals that are normally held in check by molecules called phosphatases, and the result is the uncontrolled production of white blood cells, the hallmark of CML.
Patients with the earliest form of the disease – called the chronic phase – may not even be aware they are sick. If the disease is discovered early, it almost always responds to the drug Gleevec, which puts the brakes on Bcr-Abl activity. The Food and Drug Administration (FDA) approved Gleevec as a treatment for CML about five years ago and it was initially hailed as the first "wonder drug" for cancer.
But since then, a significant minority of patients who initially responded well to Gleevec have acquired additional mutations and developed resistance to the drug. In these patients, white blood cells continue to proliferate. If left unchecked, it leads to the final, acute stage, called the blast crisis, where immature white blood cells infiltrate the blood and the bone marrow.
Clinicians are well-versed in the signs and symptoms of the different stages of CML, but until now, they have had few clues about what actually causes the disease to progress.
Perrotti said his studies show that it may be due to the increased activity of Bcr-Abl itself.