Therapies that specifically target mutations in a person’s cancer have been much heralded in recent years, yet cancer cells often find a way around them. To address this, researchers identified a promising combinatorial approach to treating glioblastomas, the most common form of primary brain cancer. Their findings were published in Oncotarget (May 5, 2015; 5).
The study demonstrated that a mouse model of glioblastoma and human glioblastoma tissue removed from patients and cultured in the lab can be effectively treated by combining three classes of anticancer drugs: a drug that targets a cancer mutation in the epidermal growth factor receptor (EGFR) gene, a drug that increases stress in cancer cells, and a drug that damages cancer cell DNA.
“Developing therapies against glioblastoma is like a chess game. For each therapy administered, or move, by the physician, the cancer makes a counter-move,” said senior author Clark Chen, MD, PhD, associate professor of neurosurgery and vice-chair of Research and Academic Development at Moores Cancer Center at the University of California San Diego.
In up to 50% of glioblastomas, mutations in the EGFR gene render cancer cells insensitive to growth regulation by environmental cues, allowing them to grow uncontrollably. Yet highly specific EGFR inhibitors are not particularly effective against glioblastomas with EGFR mutations.
“When glioblastoma cells are treated with EGFR inhibitors, they turn on another receptor to bypass the need for EGFR,” said Chen. “Any hope of an effective treatment requires a combination of moves strategically designed for a checkmate.”
To develop such a strategy, Chen and his group turned to PLK1, a protein that regulates stress levels within glioblastoma cells and is essential for their survival. Chen and his group found that glioblastoma cells that developed resistance to EGFR inhibitors remain universally dependent on this protein.
In mouse models of glioblastoma and in explants of human glioblastoma, singular treatment with an EGFR inhibitor, a PLK1 inhibitor, or the current standard of care drug (a DNA-damaging agent), each temporarily halted glioblastoma growth. But, like the human disease, the tumor eventually grew back. However, no detectable tumor recurrence was observed when a combination of drugs from all three classes was administered. The treated mice tolerated this combination regimen without showing significant side effects.
“It is often assumed that if we find the cancer-causing mutation and inhibit the function of that mutation, we will be able to cure cancer,” said study co-author Bob S. Carter, MD, PhD, chief of neurosurgery at UC San Diego. “Our study demonstrates that the reality is far more complex. Our results provide a blueprint for how to leverage fundamental biologic concepts to tackle this challenging complexity.”
The three drugs administered to mice in this study were: BI2536, a PLK1 inhibitor; gefitnib, an EGFR inhibitor; and TMZ, the standard-of-care chemotherapy for glioblastoma. The study authors noted, that while the safety or side effects of treating human patients with all three drugs is unknown, all are individually well tolerated in humans. The clinical safety profiles of gefitinib and TMZ are well-established for patients with glioblastoma and PLK1 inhibitors have so far been well-tolerated in clinical trials (including one for acute myeloid leukemia that has advanced to phase III).
This research was funded, in part, by the Sontag Foundation, Burroughs Wellcome Foundation, Kimmel Foundation, Doris Duke Foundation, and Forbeck Foundation.