Novel modulators of the polo-like kinase 1 (Plk1) pathway targeting the cell cycle may be effective as anticancer agents.
LOS ANGELESNovel modulators of the polo-like kinase 1 (Plk1) pathway targeting the cell cycle may be effective as anticancer agents. Several of these new compounds, which work by arresting cancer cells in the G2/M phase, are in preclinical and early clinical development, according to reports at the 2007 American Association for Cancer Research annual meeting.
The Plk1s are evolutionarily conserved serine/threonine kinases that are expressed primarily during late G2 and M phases, where they appear to regulate many processes involved in mitotic entry and progression.
Plk1 overexpression is strongly associated with cancer and has been correlated with poor prognosis in a broad range of human tumor types.
ON 01910.Na (Onconova Therapeutics, Inc, Princeton, New Jersey) is a mitotic modulator that arrests cancer cells in G2/M by affecting the action of several regulatory proteins, including Plk1 (abstract LB-7). The agent is a non-ATP-binding inhibitor of multiple kinases and has shown broad-spectrum preclinical activity against many types of cancer.
At the AACR meeting, Antonio Jimeno, MD, PhD, instructor in oncology, Johns Hopkins University School of Medicine, and colleagues reported the first-in-man phase I dose-escalation study of this agent in solid tumors refractory to standard therapy. The drug was given by 2-hour infusion on days 1, 4, 8, 11, 15, and 18, followed by a 10-day rest period for a total of 28 days per cycle. The initial dose of 80 mg was escalated, with one patient treated per cohort until grade 2 toxicity was documented.
Twenty patients entered the study at dose levels of 80, 160, 320, 480, 800, 1,280, 2,080, and 3,120 mg, up to a dose level of 4,370 mg. At the end of the study, most patients received 3,120 mg (n = 7) or 4,370 mg (n = 6). Dose-limiting toxicity was observed in one patient receiving 3,120 mg and one receiving 4,370 mg. The toxicity profile is characterized by abdominal and skeletal pain, nausea, and fatigue, with minor hematological toxicity. The recommended phase II dose will be 3,120 mg, Dr. Jimeno said.
ON 01910.Na showed preliminary signs of clinical activity, Dr. Jimeno said. He described the activity seen in an ovarian cancer patient with prior treatment involving surgery, eight cycles of standard chemotherapy, then topotecan (Hycamtin) upon progression (no response).
"The patient received four cycles of ON 01910.Na and has been progression free since January 2006," he said.
In addition to the dose-finding study, Dr. Jimeno and colleagues tested a number of potential biomarkers in in vitro and ex vivo models of pancreatic cancer, and found cyclin B1 mRNA to be valuable (abstract 5391). Cyclin B1 predicted response to ON 01910.Na in eight of nine cases prospectively evaluated, correctly predicting two cases as sensitive and six of seven that were resistant. Phase II trials in pancreatic cancer this year will incorporate this biomarker, he said.
GlaxoSmithKline (GSK) investigators also reported findings for their Plk1 inhibitor GSK461364A (abstract 5389). In their study, reported by Sylvie Laquerre, of GSK, inhibition of cell cycle progression was concentration dependent, with delay at G2 phase at high compound concentrations and arrest at M phase at lower concentrations. They also showed that GSK461364A appears to have limited effects on nonproliferating cells. It caused net cell death in 45% of the 120 cell lines tested and cytostatic cell cycle arrest without apparent net cell death in 39% of cell lines. "In vitro activity and selectivity of GSK461364A support the advancement of this compound for the treatment of cancer," they concluded.