NEW YORK (Reuters Health) - Results of a phase I trial indicate that the investigational antisense oligonucleotide OGX-011 (OncoGenex Technologies) inhibits production of the secretory protein clusterin in prostate tumors. This may enhance the effects of chemotherapy, radiation therapy, and hormone therapy.
Dr. Kim Chi of the University of British Columbia, Vancouver, noted at a cancer conference in Geneva today that “clusterin has emerged as an attractive target for cancer because it prevents cell death or promotes cell survival and it does this by protecting cells during times of stress.”
“Clusterin,” he added, “has been shown to be overexpressed in a number of cancers and it has also been shown to be prognostic -- increased expression of clusterin results in worse prognosis -- and it is also associated with cancer progression and resistance to cancer treatment.”
Confirming in vitro observations, “results of this phase I trial show that OGX-011 binds to clusterin messenger RNA to inhibit production of the clusterin protein.”
In the dose-escalation trial, 25 men with localized prostate cancer and high risk features who were scheduled for radical prostatectomy were first treated with hormone therapy, buserelin and flutamide, “which caused an upregulation of clusterin as a survival response,” Dr. Chi said.
The men were then treated with up to 640 milligrams OGX-011 on days 1, 3 and 5 initially and then weekly. Radical prostatectomy was performed on day 30 to 36.
OGX-011 was “very well tolerated and produced dose-dependent decreases in prostate cancer cell clusterin expression,” Dr. Chi reported.
At the 640-mg dose, clusterin mRNA was decreased to a mean of 8% compared with lower dose levels and with historical controls. By immunohistochemistry, the mean percentage of cancer cells staining zero intensity for clusterin protein at the highest dose was 54% compared with 2 to 15% for lower doses and historical controls.
“With this study, we were able to define a biologically active dose of OGX-011, 640 milligrams, and we confirmed that it is doing what it is supposed to be doing - inhibiting clusterin,” Dr. Chi concluded. “Therefore, we can move forward with phase II trials to see if this translates into a benefit for patients.”
The findings were presented at the EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, sponsored by the European Organization for Research and Treatment of Cancer, the U.S. National Cancer Institute, and the American Association for Cancer Research.
MeSH Headings:Genital Neoplasms, Male: Specialty Chemicals and Products: Neoplasms: Neoplasms by Site: Nucleic Acids, Nucleotides, and Nucleosides: Prostatic Neoplasms: Urogenital Neoplasms: Molecular Probes: Nucleic Acid Probes: RNA, Antisense: Antisense Elements (Genetics): Oligonucleotides, Antisense: Laboratory Chemicals: Chemical Actions and Uses: Uses of Chemicals and Drugs: Chemicals and Drugs: DiseasesCopyright © 2002 Reuters Limited. All rights reserved. Republication or redistribution of Reuters content, including by framing or similar means, is expressly prohibited without the prior written consent of Reuters. Reuters shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. Reuters and the Reuters sphere logo are registered trademarks and trademarks of the Reuters group of companies around the world.
