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The mechanics of anti-tumor activity outlined


Inhibiting the growth and the angiogenic properties of cancer is an important modality for cancer treatment and research. Angiogenesis, the development of new blood vessels from pre-existing vasculature, supports the development of many diseases including cancer, rheumatoid arthritis and others. In the case of cancer, angiogenesis is essential for the growth, progression and metastasis of a tumor and thus, agents that inhibit angiogenesis are attractive therapeutic options.

In an article published today in the April issue of Cancer Cell (Vol. 3, No. 4, pg. 363), Winship Cancer Institute (WCI) researchers report that 2-methoxyestradiol (2ME2) inhibits tumor growth and angiogenesis by suppressing hypoxia-inducible factor-1 (HIF). HIF is a factor that is over-expressed in more than 70% of human cancers and their metastases, including breast, prostate, brain, lung, and head and neck cancers.

Besides cancer, HIF is also associated with diseases of the bone and diseases that are mediated by inflammation such as rheumatoid arthritis.

The paper, "2ME2 Inhibits Tumor Growth and Angiogenesis by Disrupting Microtubules and Dysregulating HIF," was authored by WCI and EmoryUniversity scientists Nicola J. Mabjeesh, MD, PhD, Daniel Escuin, and Paraskevi Giannakakou, PhD. The paper was co-authored with scientists Theresa LaVallee, PhD, Victor Pribluda, PhD, and Glenn Swartz from EntreMed, a biopharmaceutical leader in angiogenesis research and product development.

2ME2 is a well-tolerated, orally active small molecule with anti-angiogenic and anti-tumor activity currently in Phase I/II clinical trials under the name PanzemÒ The trials are being conducted by EntreMed.

"This report contributes to the body of knowledge that will help us better understand the basic mechanism by which 2ME2 inhibits cancer cell growth and tumor angiogenesis," says Dr. Giannakakou.

Drs. Mabjeesh and Giannakakou report that 2ME2 inhibits tumor growth and angiogenesis by targeting microtubules, or a cell’s skeleton, and suppressing HIF activity.

"The study is the first to demonstrate that an agent, 2ME2, inhibits the assembly of microtubules in the tumors of treated animals," says Dr. Giannakakou. "Microtubule disruption results in the down regulation of HIF-1a. While this effect is not unique to 2ME2 when compared to Taxol or vincristine in preclinical models, it is the most more potent HIF inhibitor of all the microtubule-targeting chemotherapeutic agents tested that are used to treat cancer."

The paper outlines the mechanism by which 2ME2 downregulates HIF; a finding that had not been previously discovered. Utilizing a pharmacological approach and xenograft models, which are mouse models of human cancer, investigators showed that 2ME2 depolymerizes microtubules and blocks HIF-1a nuclear accumulation and HIF-transcriptional activity, or the transfer of genetic code information from one kind of nucleic acid to another.

"This research is important because we see for the first time a mechanistic link between targeting of the microtubule cytoskeleton and inhibition of angiogenesis," says Dr. Giannakakou. "This work will provide a new framework to study and develop novel compounds for the treatment of cancer."

In addition to Drs. Mabjeesh, and Giannakakou and PhD-candidate Daniel Escuin, WCI investigators Margaret T. Willard, PhD, Hua Zhong, PhD, and Jonathan Simons, MD contributed to the paper.

Vincent Dollard | EurekAlert!
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