A protein that sneaks into the cell nucleus and sets off two separate cancer-promoting processes vital to the development of malignant brain tumors makes itself an enticing target for therapy.
Having exposed that dangerous behavior by pyruvate kinase M2 (PKM2) in a series of major publications, MD Anderson scientist Zhimin Lu, M.D., Ph.D., has uncovered a vulnerability that he thinks could turn the metabolic protein into "an Achilles' heel for cancer."
In a paper this week in Nature Cell Biology, Lu and colleagues identified a drug that inhibits growth of brain tumors in mice by thwarting PKM2.
Lu, an associate professor in MD Anderson's Department of Neuro-Oncology, and colleagues have discovered:
- The cellular mechanism that overexpresses PKM2 in cancer cells.
- The complex pathway that smuggles PKM2 into the cell nucleus.
- How in the nucleus PKM2 activates genes involved in cell division and in a glucose metabolism pathway that nourishes brain tumors and other types of cancer called the Warburg effect.
"For tumors to form, PKM2 must get to the nucleus to activate genes involved in cell proliferation and the Warburg effect," Lu said. "If we can keep it out of the nucleus, we can block both of those cancer-promoting pathways."
MEK inhibitors for glioblastoma
A key step in the protein's journey to the nucleus identified by the researchers is attachment of a phosphate group to PKM2 by a protein called ERK, which is activated by another protein, MEK.
Injecting tumors with the MEK inhibitor selumetinib inhibited tumor growth in mice.
"MEK/ERK inhibitors have not been tried yet in glioblastoma multiforme," Lu said. Phosporylated PKM2 is a potential biomarker to identify patients who are candidates for MEK/ERK inhibitors once those drugs are developed.
Lu and colleagues have conducted experiments mainly in human cancer cell lines and mouse models of glioblastoma. However, analysis of human tumors supports the importance of PKM2 in glioblastoma development.
PKM2 levels were measured in tumor samples from 55 glioblastoma patients treated with standard of care -- surgery, radiation and chemotherapy. The 20 with low PKM2 expression had a median survival of 34.5 months, compared to 13.6 months for the 35 patients with high levels of PKM2.
Level of PKM2 expression in 27 low-grade astrocytomas was about half of the expression found in higher grade glioblastomas.
Lu is collaborating with other scientists at MD Anderson to develop a drug to thwart PKM2. Lu and collaborators have characterized the cancer-promoting activity of the protein in four major scientific papers, linked below.
Nature Cell Biology paper
Molecular Cell paper
MD Anderson news release
Previous papers in Cell with release and Nature with news release.