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Drug that interrupts a key stage of cell division shows promise for advanced solid tumors
November 08, 2006Prague, Czech Republic: One of the first studies to investigate the effects of a new anti-cancer drug in patients with advanced or metastatic solid tumours has shown that it is capable of halting progression of the disease, and the study has provided the first proof of the drug's mechanism of action.
The drug works by blocking aurora proteins, which play a key role in cell division and are implicated in the onset and progression of cancer. It was discovered and characterised by scientists at Nerviano Medical Sciences in Italy.
Dr Maja de Jonge, a medical oncologist at the Erasmus University Medical Centre, Rotterdam, The Netherlands, told the EORTC-NCI-AACR [1] Symposium on Molecular Targets and Cancer Therapeutics in Prague today (Wednesday 8 November): "So far we have tested the drug in 36 patients in a phase I clinical trial. All the patients had advanced solid cancers that were progressing at the time they entered the trial. However, in seven of these patients the disease stabilised and has remained stable in four of the patients for seven months or more. Without the drug we would have expected to see their disease continue to progress."
Aurora proteins belong to a family of enzymes that regulate the different steps in mitosis when the cell nucleus divides into two identical cells. The enzymes help the dividing cell to share its genetic material between the daughter cells, and they are essential for cell proliferation. Aurora proteins are over-expressed in cancer and this causes unequal distribution of the genetic material, creating abnormal cells - the hallmark of cancer. However, it is only recently that scientists have started to investigate the proteins as targets for anti-cancer therapies, and this is one of the first studies to investigate an aurora kinase inhibitor in patients.
Dr de Jonge and her colleagues tested an aurora kinase inhibitor PHA-739358. Her patients had a range of solid tumours: colorectal (9), pancreatic (3), sarcoma (5), ovarian (2), kidney (2), prostate (2), cancer of the bile ducts (2), oesophageal (3) and eight others.
They tested seven different dose levels of the drug (measured in milligrams per squared metre of body surface area (mg/m2)). Two patients could not tolerate well a dose of 400 mg/m2, and 330 mg/m2 appeared to be the recommended dose. The drug was infused into the patients' veins over a six-hour period on days 1, 8 and 15 every four weeks.
Dr de Jonge said: "So far adverse effects have been relatively minor, consisting of a transient hypertensive episode in one patient, nausea, loss of appetite, diarrhoea, a temporary shortness of white blood cells (neutropenia), which was serious enough at 400 mg/m2 in one patient for the drug to be omitted on day eight and in another patient on day 15.
"Once the dose levels reached 190 mg/m2, tests on skin biopsies showed that the drug was inhibiting the aurora B protein - in other words it was beginning to do what we expected it to.
"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. This study shows, for the first time, that the aurora kinase inhibitor PHA-739358 inhibits phosphorylation of histone H3 in the skin of patients, and therewith provides a proof for its (or one of its) mechanisms of action."
The researchers are continuing to recruit patients in order to define the safety of the drug and the recommended dose for subsequent studies. However, they believe the results so far are promising.
"The clinical trial has proved the concept that inhibition of the aurora protein disrupts an important stage of cell division, once the dose levels reaches 190m/m2," said Dr de Jonge. "Patients are able to tolerate the drug and dosing schedule, and it is exciting that, at this early stage in the drug's development, there is evidence of its ability to stabilise advanced disease."
European Organisation for Research and Treatment of Cancer
Aurora proteins belong to a family of enzymes that regulate the different steps in mitosis when the cell nucleus divides into two identical cells. The enzymes help the dividing cell to share its genetic material between the daughter cells, and they are essential for cell proliferation. Aurora proteins are over-expressed in cancer and this causes unequal distribution of the genetic material, creating abnormal cells - the hallmark of cancer. However, it is only recently that scientists have started to investigate the proteins as targets for anti-cancer therapies, and this is one of the first studies to investigate an aurora kinase inhibitor in patients.
Dr de Jonge and her colleagues tested an aurora kinase inhibitor PHA-739358. Her patients had a range of solid tumours: colorectal (9), pancreatic (3), sarcoma (5), ovarian (2), kidney (2), prostate (2), cancer of the bile ducts (2), oesophageal (3) and eight others.
They tested seven different dose levels of the drug (measured in milligrams per squared metre of body surface area (mg/m2)). Two patients could not tolerate well a dose of 400 mg/m2, and 330 mg/m2 appeared to be the recommended dose. The drug was infused into the patients' veins over a six-hour period on days 1, 8 and 15 every four weeks.
Dr de Jonge said: "So far adverse effects have been relatively minor, consisting of a transient hypertensive episode in one patient, nausea, loss of appetite, diarrhoea, a temporary shortness of white blood cells (neutropenia), which was serious enough at 400 mg/m2 in one patient for the drug to be omitted on day eight and in another patient on day 15.
"Once the dose levels reached 190 mg/m2, tests on skin biopsies showed that the drug was inhibiting the aurora B protein - in other words it was beginning to do what we expected it to.
"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. This study shows, for the first time, that the aurora kinase inhibitor PHA-739358 inhibits phosphorylation of histone H3 in the skin of patients, and therewith provides a proof for its (or one of its) mechanisms of action."
The researchers are continuing to recruit patients in order to define the safety of the drug and the recommended dose for subsequent studies. However, they believe the results so far are promising.
"The clinical trial has proved the concept that inhibition of the aurora protein disrupts an important stage of cell division, once the dose levels reaches 190m/m2," said Dr de Jonge. "Patients are able to tolerate the drug and dosing schedule, and it is exciting that, at this early stage in the drug's development, there is evidence of its ability to stabilise advanced disease."
European Organisation for Research and Treatment of Cancer
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Boston University scientists first to see RNA network in live bacterial cells
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Texas A&M researchers find new mechanism for circadian rhythm
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Eutrophication affects diversity of algae
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