May is National Cancer Research Month, created by Congress in 2007 to recognize the American Association of Cancer Research (AACR) for its contributions to the field. To honor AACR and highlight some of the important cancer research being done at Sanford-Burnham, we will be posting a series of articles on the ongoing work in our National Cancer Institute-designated Cancer Center. The vast majority of this research is made possible by funding from the National Institutes of Health (NIH), which includes the National Cancer Institute (NCI).
Fighting cancer is one of the most difficult problems humans have ever tackled. Cancer is versatile: it grows rapidly, adapts to difficult environments and hides well. Defeating it will not be easy, but scientists are also taking a versatile approach—one that involves collaborations between many disciplines.
One such collaboration combines the talents of Dr. Elena Pasquale, a biologist, Dr. Maurizio Pellecchia, a chemist and Dr. Paul Fisher, who directs the Institute of Molecular Medicine at Virginia Commonwealth University. Dr. Pasquale has spent years studying the interplay between Eph cell surface receptors and ephrin proteins. Eph receptors are like antennae protruding from the surface of a cell. They foster cell communication by binding to ephrin proteins on the surfaces of neighboring cells. Eph receptors also appear more often in cancer cells than normal ones. Dr. Pasquale and Dr. Pellecchia began to wonder if they could use this deep understanding of Eph/ephrin interactions to create a compound that attaches selectively to Eph and combine it with medicine—creating a guided missile with a potent anti-cancer payload.
To build this missile, Dr. Pasquale creates peptides (pieces of proteins) that bind to Eph. Dr. Pellecchia develops methods to link the peptides to chemotherapeutic agents—not an easy task.
“You need to marry the chemistry of a natural product with the chemistry of the peptide,” says Dr. Pellecchia. “The two molecules need to link in one position, and the chemical linker should be robust enough for the peptide and the drug to stick together when administered. Once this combination selectively attaches to cancer cells, the linker needs to be vulnerable to cellular enzymes so that it will be degraded, delivering its cargo – the chemotherapeutic agent – in its original form.”
In other words, the peptides – attached to an anti-cancer medicine – home in on a tumor’s Eph receptors. Once bound, the combined molecule is drawn into the cell, where the peptide is degraded and the intact medicine released. Drs. Pasquale and Pellecchia are also attaching imaging reagents to the peptide. This would give physicians the ability to use MRI or PET scans to locate where the drug is in the body and ensure that it is congregating in the tumor.
New approaches like this will one day make chemotherapy treatments more effective by sending them directly to the cancer, while greatly reducing side effects.