SAIC-Frederick Research Starves Cancer Cells
Winter 2004/2005
When the Indians of ancient Peru used cinchona bark - which yields quinine - to treat fevers such as malaria, they were among the first practitioners of chemotherapy.
Distinct from other ways to treat disease - such as surgery - chemotherapy, today, uses drugs to fight cancer by impairing fast-dividing cells. But such drugs have had a varying rate of success and are often cytotoxic - they damage healthy cells as well as cancerous ones. This can make things very rough on the patient. (Side effects may include nausea and vomiting and depression of the immune system, which can lead to lethal infections.)
Our researchers at SAIC-Frederick, however, are using a relatively new drug development model - molecular targeted screens - that enables researchers to focus on the most vulnerable areas of cancer cells. In fact, (SAIC-Frederick researcher) Dr. Giovanni Melillo has designed an assay for screening more than 200,000 compounds to find drugs that block a key survival mechanism of cancer cells - the ability to thrive in a low-oxygen environment. When cells lack oxygen, they compensate by generating new blood vessels, which makes a cancer tumor more aggressive. (The subsequent treatment also promises less toxicity for patients.)
Such drugs would target hypoxia-inducible factor (HIF-1), the substance essential for increased blood vessel growth - known as angiogenesis. By blocking HIF-1, the tumor would not receive blood and would "starve." (In fact, over expression of HIF-1 has been demonstrated in many cancers, including prostate cancer and breast cancer.)
In addition, you could use the drugs in a different way compared to cytotoxic chemotherapy, which usually requires drugs to be taken at high doses in cycles of one to three days (followed by a three-week break to let the patient's bone marrow and healthy cells recover.)
For example, our researchers found several potentially active compounds, including the clinically approved drug topotecan, and realized that lower daily doses of these drugs would be more appropriate in disabling HIF-1. (In a very low, nontoxic dose, topotecan affects cell signaling in a low-oxygen environment.) In fact, SAIC-Frederick recently received permission from the Cancer Therapy Evaluation Program for a clinical trial of topotecan.
"We'll do a clinical trial with anti-angiogenic intent," said Dr. Robert Shoemaker, who heads SAIC-Frederick's Screening Technology Branch. "Dr. Melillo will look at … HIF-1 alpha in biopsy material (as a pharmacodynamic marker); and we'll combine that small molecular inhibitor with a monoclonal antibody that blocks VEGF (vascular endothelial growth factor) receptors, creating a combination therapy aimed at inhibiting angiogenesis. It's not a Phase 1 trial; it's simply a new schedule for topotecan that's never been tried before because this knowledge of hypoxic cell signaling didn't exist. That will be the first example of a translational project that comes out of a molecular-targeted, in vitro screen."
SAIC-Frederick has already done a preclinical validation of this concept, which Dr. Anna Maria Rapisarda and colleagues published recently in Cancer Research (vol. 64, no. 19, pp. 6845-6848, Nov. 2004.) In fact, Rapisarda reported that daily administration of topotecan blocks gliobastoma (brain tumor) growth.
"Concomitant with HIF-1 alpha inhibition, topotecan caused a significant tumor growth inhibition associated with a marked decrease of angiogenesis and expression of HIF-1 target genes in tumor tissues," according to the report.
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