An innovative cancer agent called PHA-739358, which inhibits one of the aurora proteins, has shown indications of potential benefit in 7 of 36 patients (19.4%) with advanced or metastatic solid tumors who participated in a phase I dosing and toxicity study, Dutch researchers reported at the EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics
PRAGUE, Czech RepublicAn innovative cancer agent called PHA-739358, which inhibits one of the aurora proteins, has shown indications of potential benefit in 7 of 36 patients (19.4%) with advanced or metastatic solid tumors who participated in a phase I dosing and toxicity study, Dutch researchers reported at the EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics (abstract 27).
The study population included patients with a variety of different solid tumors, including nine with colorectal cancer, five with sarcoma, three with pancreatic cancer, and the rest with other malignancies including ovarian, kidney, prostate, and bile duct cancers.
"All the patients had advanced solid cancers that were progressing at the time they entered the trial," said Maja de Jonge, MD, a medical oncologist at the Erasmus University Medical Center Rotterdam, The Netherlands. "However, in seven of these patients, the disease stabilized and has remained stable in four of the patients for 7 months or more."
Aurora proteins belong to a family of serine/threonine kinases that play key roles in regulating different steps in mitosis. Aurora B, the enzyme targeted by PHA-739358, helps dividing cells share their genetic material between the daughter cells. Aurora proteins are overexpressed in cancer, which results in an unequal distribution of the genetic material and the creation of abnormal cells. [See box,The Science Behind the Study.] Only recently, however, have researchers begun investigating aurora proteins as targets for cancer therapies.
Dr. de Jonge and her colleagues' study is one of the first trials to investigate an aurora kinase inhibitor in patients. PHA-739358 was discovered and characterized by scientists at Nerviano Medical Sciences in Milan, Italy.
The scientists tested seven doses45, 90, 135, 190, 250, 330, and 400 mg/m2. They gave the drug as a continuous infusion administered over 6 hours on days 1, 8, and 15 of each 4-week cycle. At a dose level of 190 mg/m2, skin biopsies showed that the drug was actively inhibiting the aurora B protein.
"The clinical trial has proved the concept that inhibition of the aurora protein disrupts an important stage of cell division, once the dose level reaches 190 mg/m2," Dr. de Jonge said. "Patients are able to tolerate the drug and dosing schedule, and it is exciting that at this early stage of the drug's development, there is evidence of its ability to stabilize advanced disease." Nerviano plans to initiate a phase II study in late 2006.
Two patients given 400 mg/m
did not tolerate the drug well, and the team concluded that 330 mg/m
appears to be the optimal dose for PHA-739358. Otherwise, drug-associated side effects have proven relatively minor. Adverse events consisted "of a transient hypertensive episode in one patient, nausea, loss of appetite, diarrhea, and temporary neutropenia, which was serious enough at 400 mg/m
in one patient for the drug to be omitted on day 8 and in another patient on day 15," Dr. de Jonge said.
The Science Behind the Study
The aurora B protein is responsible for phosphorylating histone H3, a protein involved in the structure of chromatin (the strands of DNA that make up chromosomes) in cells. Inhibition of aurora B results in the inhibition of phosphorylation of histone H3, thereby blocking that step in cell division.