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September 29, 2011

New Prostate Cancer Vaccine Searches And Destroys

Cancer Treatment: Two-headed molecule labels tumor cells and summons immune-system attack

Laura Cassiday

Adapted from ACS Chem. Biol.
NEW VACCINE STRATEGY A small molecule injected into a mouse can bind to cancer cells and spark the immune system to attack the tumor.
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A two-headed small molecule could marshal a cancer patient's immune system to seek out and destroy prostate tumor cells (ACS Chem. Biol., DOI: 10.1021/cb200222s). This new immunotherapy strategy also could treat other cancers with few side effects, researchers say.

Prostate cancer cells produce high levels of unique proteins that sit on the cells' surface, such as the prostate-specific membrane antigen (PSMA). Researchers have targeted these proteins to kill cancer cells by chemically linking PSMA-specific antibodies with chemotherapy drugs or radionuclides. Although the antibodies shuttle most of these toxic agents to cancer cells, the drugs can still hit healthy cells, leading to unpleasant side effects. Also, chemotherapy drugs and radionuclides can be expensive.

View Enlarged Image ACS Chem. Biol.
DOUBLE DUTY This small molecule consists of DUPA (left end), which can bind to a prostate cancer cell antigen, and DNP (right end), a chemical group recognized by human antibodies.

"We wanted to develop a strategy in which a patient's own immune system, rather than a toxic compound, kills prostate cancer cells," says David Spiegel, a chemist at Yale University. For their so-called chemically induced vaccine strategy, Spiegel and his collaborators, including Peter Schultz at the Scripps Research Institute and Charles Cho at the Genomics Institute of the Novartis Research Foundation, designed an inexpensive molecule that would direct a patient's immune system to attack only prostate cancer cells.

It consists of two chemical groups linked together: 2-[3-(1, 3-dicarboxypropyl)-ureido]pentanedioic acid (DUPA) and 2,4-dinitrophenyl (DNP). Other researchers have shown that DUPA recognizes and binds to PSMA on the surface of prostate cancer cells (Mol. Pharm., DOI: 10.1021/mp900069d). DNP is used in manufacturing and is a well-known environmental contaminant. For reasons that are unclear, most people already have antibodies against this chemical group. The team speculated that if the DUPA end of the molecule selectively grabbed onto prostate cancer cells, the DNP end would attract these circulating antibodies and trigger an immune response that would destroy the cells.

The researchers tested their hypothesis in mice that had human prostate tumors grafted under the skin of their right flanks. The mice were a special breed that lacks a complete immune system. The researchers made the mouse immune system more human-like by injecting human lymphocytes that multiplied and produced human antibodies. The researchers then injected their two-headed molecule into the mice.

After three treatments per week for two weeks, tumors in mice injected with the small-molecule vaccine were about 80% smaller than those in mice treated with DUPA alone. When the researchers analyzed tumor tissue samples from mice treated with the two-headed molecule, they discovered that lymphocytes called natural killer cells had infiltrated the tumor. The scientists think that these cells killed the tumor cells after binding to the DNP antibodies.

Spiegel says the team hopes to eventually test the compound in human clinical trials. He notes that the researchers can synthesize large amounts of the small-molecule vaccine cheaply and easily, which should make the treatment cost effective for prostate cancer therapy.

Laura Kiessling, a biochemist at the University of Wisconsin, Madison, says that, because the small molecule is modular, the new approach "lays the groundwork" for targeting not only prostate cancer, but also other cancer types. "In principle, any cell-targeting agent can be combined with an antibody recruitment agent," she says.

Chemical & Engineering News
ISSN 0009-2347
Copyright © 2011 American Chemical Society
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