If there were a “golden ticket” in the fight against colorectal cancer, it would be guanylyl cyclase C (GCC) – a molecule that plays a critical role in the suppression of colorectal tumors. Most colorectal tumors form or grow larger when GCC is silenced by the hormones that regulate it. Researchers at Jefferson are working to find ways to manipulate these hormones so GCC can get back to work suppressing tumors.
Leading the efforts are clinical pharmacologist Scott A. Waldman, MD, PhD, and immunologist Adam Snook, PhD, of the Waldman-Snook Laboratory. As they study GCC and the associated hormones, Drs. Waldman and Snook collaborate closely with colorectal surgeons Scott D. Goldstein, MD, FACS, Gerald A. Isenberg, MD, FACS, and Benjamin R. Phillips, MD, FACS, FASCRS, as well as physicians from the Division of Gastroenterology.
“The Department of Surgery’s collaboration with the Waldman-Snook Laboratory is helping to improve outcomes and quality of life for those coming to Jefferson for care,” says Dr. Goldstein. “Our team is at the forefront of innovative colorectal cancer research.”
One such project is studying how commercially available gastrointestinal hormones could be deployed to combat colorectal cancer. Funded by the U.S. Department of Defense, the study is using tissue samples gathered by gastroenterologists during colonoscopies and by colorectal surgeons during resections.
“We have mapped the mechanism by which the hormones are lost,” Dr. Waldman explains. “It’s a reflection of the very first mutation in the gene APC, which triggers the cascade of events that leads to tumorigenesis. When APC is mutated, a complicated signaling mechanism shuts off the synthesis of these hormones.” The study’s hypothesis is that dosing patients with commercially available hormone analogs could help turn GCC back on, halting development or progression of colorectal tumors.
In addition to mapping how the hormones are lost, Drs. Waldman and Snook want to understand the precise signaling mechanisms that lead from activation of GCC to the prevention of tumor initiation and progression. Another study is supporting that effort, and again, Drs. Goldstein, Isenberg and Phillips are contributing colon and rectal tissue specimens to be studied in the lab. The team is studying these normal and diseased samples both in animals and in test tubes.
“In the mice, we’re letting the tumors grow to see if we can manipulate the GCC and determine what signaling mechanisms are being turned on or off and what proteins are changing,” Dr. Waldman says. “In the test tubes, we’re literally creating ‘mini guts’ so we can get a good read on what downstream molecular pathways are being activated by the tumorsuppressing system. We couldn’t do any of this without our colleagues in Colorectal Surgery.”
In addition to those studies, the Waldman-Snook Laboratory is working with colorectal surgeons on the second phase of a colorectal cancer vaccine study that showed great promise in Phase 1. Patient enrollment will begin in late summer or early fall. Beyond that, Dr. Waldman says the colorectal surgeons will be highly engaged in an upcoming study involving patients with active metastatic disease.
“With this study, we’ll take ‘killer’ immune cells from the patients’ own bodies and genetically reprogram them outside the body to recognize the specific target – in this case, GCC being expressed on metastatic cancer cells,” Dr. Waldman explains. “We will create billions of those genetically reprogrammed cells, and each one will be a ‘smart bomb’ that ignites when it sees a target on a cancer cell in the lung or liver. In short, these ‘smart bombs’ will home in on the metastatic cancer cells but won’t harm normal lung or liver cells.”
"Innovative Colorectal Research Targets Key Tumor-Suppressing Molecule,"
Jefferson Surgical Solutions: Vol. 14
, Article 6.
Available at: https://jdc.jefferson.edu/jss/vol14/iss1/6