Molecular Basis of Cancer

Peter P. Ruvolo, Ph.D., assistant professor of molecular medicine, Brown Foundation
Institute of Molecular Medicine for the Prevention of Human Diseases and GSBS

Peter P. Ruvolo, Ph.D

A marker is a molecular flag indicating disease (such as three copies of chromosome 21 indicating Down Syndrome). In cancer research, the race is on to identify new genetic markers for cancer and drug resistance. This information will help diagnose certain types of cancer and aid in deciding the course of treatment.

Peter P. Ruvolo, Ph.D., has identified a marker for acute myeloid leukemia. “In some cancer cells, the failure of the normal mechanism by which cells die leads to chemotherapeutic drug resistance. One of the proteins involved in this process is a tumor promoter called Bcl2.” He has dedicated his research to studying how Bcl2 functions, and how this function affects drug resistance of cancer cells.

“Bcl2 protects cells from stress treatments, such as chemotherapy drug treatment, and thus Bcl2 can make cells resistant to therapy,” Ruvolo said.

To examine how a protein works and when it functions, it helps to know how its activity is regulated. One manner of dynamic regulation is through phosphorylation of the protein.

The Bcl2 protein in a cell is constantly having a phosphate group attached and removed from it by two competing processes, phosphorylation and dephosphorylation. In the normal, healthy cell, there is a favorable balance between the two competing processes, in which the majority of the protein is dephosphorylated. In the abnormal cell, the disruption of the dynamics tilts the scales toward a higher amount of phosphorylation.

Ruvolo’s research team has found that phosphorylation enhances the activity of Bcl2, increasing resistance to chemotherapy.

“We were the first group to determine that Bcl2 is phosphorylated in cancer cells derived from patients,” Ruvolo said. “We found phosphorylated Bcl2 in nearly half of patients with acute myeloid leukemia (AML).”

In addition, how much of the Bcl2 was phosphorylated determined prognosis. “AML patients with cells expressing phosphorylated Bcl2 have shorter overall survival compared to patients with cells expressing unphosphorylated Bcl2.” For cancer patients, phosphorylated Bcl2 is bad news.

By determining the role Bcl2 phosphorylation plays in chemotherapeutic drug resistance, Ruvolo’s research may help in future drug design. “We study the mechanism of how new cancer drugs kill cancer cells,” he said. “We have found that dephosphorylation of Bcl2 is an important event in the mechanism of action for many cancer drugs.”