Researchers from Thomas Jefferson University have discovered that the protein guanylyl cyclase C (GCC) is expressed in humans solely in the intestines, including the colon and rectum, making it a selective marker for colorectal tumors that metastasize. These findings appear in the December 10th issue of the Proceedings of the National Academy of Sciences.
The research, led by Scott Waldman, MD, PhD, associate professor of medicine, biochemistry and molecular pharmacology and acting director of the division of clinical pharmacology, is groundbreaking because it has the potential to lead to the first effective way of detecting colorectal tumors once they spread beyond the intestines.
"The survival rate for patients who have metastatic colorectal cancer is presently very poor, with only 5% surviving after five years, because there has not been an effective way of tracking its spread to other organs and present chemotherapy does not make an enormous impact," explains Dr. Waldman. "Knowing that GCC is specific to the intestines allows us to use it as a tag or marker to detect where the cancer has spread."
Protein Expressed Only in Normal and Malignant Intestinal Cells
By examining human tissue samples with the reverse transcription-polymerase chain reaction (RT-PCR), researchers discovered that GCC is expressed only by two different cells in the body. It is present in the single layer of cells that lines the normal intestine and continues to be expressed after these cells undergo malignant transformation and migrate out of the intestines into other sites. As a result of this, GCC acts as a marker, demarcating the cancer's spread throughout the body.
Guanylyl cyclase C also is the receptor for the heat-stable enterotoxin (ST) produced by Escherichia coli. With this working knowledge, the Jefferson team exposed preparations of human tissues to ST and discovered that the only tissues that interact with this small protein were those that expressed GCC. Only tissues outside the intestine, containing metastatic colorectal cancer, expressed GCC and interacted with ST.
"We found that ST effectively binds to GCC in all tissues which contained metastatic colorectal cancer, regardless of the type of tissue or its location," says Dr. Waldman. "It is our hope that this research leads to new treatments that use ST as a guided missile to target cancer-fighting poisons directly to metastatic tumor cells, without harming normal surrounding tissues."
Diagnostic Tests and Therapies in the Works
Targeted Diagnostics and Therapeutics, Inc, a biotechnology company that has acquired the worldwide exclusive license to the work from Dr. Waldman's laboratory, is laying the groundwork for the birth of new diagnostic and therapeutic options by developing a tissue biopsy test that will accurately stage patients to determine whether colorectal cancer has spread outside of the intestine. The company is also developing a blood test that will determine whether colorectal cancer has spread beyond the intestine or has recurred after definitive surgery. In addition, work has begun on new therapeutics that will use ST to target and kill metastatic colorectal cancer cells.
"It is our goal to make diagnostic tests available for clinical use in the next two to three years, reducing the number of lives colorectal cancer claims each year, which is currently close to 50,000," says Harry A. Arena, CPA, MBA, President and CEO of Targeted Diagnostics and Therapeutics.
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