Dr. Scott A. Waldman received the Reynold Spector Award in Clinical Pharmacology at this year’s national ASPET meeting at Experimental Biology. Dr. Waldman gave a presentation regarding his award-winning scientific achievements titled, “Bench-to-Bedside Translation in Clinical Pharmacology: From Knowledge Generation to Healthcare Delivery.” Dr. Waldman outlined the history of his research on the gastrointestinal receptor guanylyl cyclase C, or GCC, from the initial characterization of its overexpression in colorectal cancer to its use as a biomarker and therapeutic target for the disease.
Colorectal cancer is the 4th leading cause of cancer in the United States and the 2nd cause of cancer-related death. It is typically caused by the sequential accumulation of mutations that cause normal intestinal epithelial cells to transition to a hyperproliferative state, followed by the formation of adenoma and final progression to carcinoma.
Guanylyl cyclase C is a receptor localized to the intestine. The molecules which bind the GCC receptor include the hormones guanylin and uroguanylin. Interestingly, this receptor also mediates the symptoms of Traveler’s Diarrhea by binding to the enterotoxin released by harmful bacteria.
One theory behind the initiation of colorectal cancer is that of paracrine hormone insufficiency. The hormones guanylin and uroguanylin are the most commonly lost gene products in colorectal cancer. This reduction occurs during the early phases of cancer. When these hormones are lost, the receptor GCC is silenced. Studies have shown that loss of GCC results in an increased incidence of colorectal cancer in rodents, leading to its identification as a tumor suppressor. Therefore, Waldman hypothesized that hormonal replacement therapy could prevent the occurrence of colorectal cancer recurrence. By maintaining homeostatic levels of guanylin and uroguanylin, perhaps the silencing of the receptor could be avoided and carcinogenesis prevented. Fortuitously, since the GCC receptor is exposed to the lumen of the small intestine, hormone therapy can be delivered orally, making it amenable to clinical use. When tested in mice, hormone replacement therapy eliminated tumorigenesis. Currently, Dr. Waldman is collaborating with the NCI Division of Chemoprevention, Ironwood Pharmaceuticals, and the Mayo Clinic to test paracrine hormone replacement therapy in humans.
Dr. Waldman’s lab then investigated the use of GCC as a biomarker for colorectal cancer. GCC is only found in the small intestine and colorectum normally. However, they found that it can also be detected in colorectal cancer cells. Could GCC be used as a marker to test for colorectal cancer metastasis? Indeed, upon further research his lab proved that RT-PCR analysis of extraintestinal tissues can indicate the presence of metastatic cancer cells, as well as the harder to detect micrometastases. Dr. Waldman is also investigating the use of GCC as a biomarker to differentiate tumor stage and risk of recurrence. Currently, clinical trials are underway to determine whether chemotherapy, a treatment typically reserved for metastatic cancer, will be effective for patients who are not categorized with metastatic cancer by current staging guidelines, yet have extraintestinal sites of GCC-positive cells, indicating micrometastases.
The third area of research which Dr. Waldman has pursued is the development of GCC-based vaccines to prevent colorectal cancer recurrence. He hopes to direct the immune system to metastatic cells expressing GCC. The mucosal and systemic systems have different lymphoid organs and separate effectors, providing a dual immune system with minimal cross talk. Waldman is taking advantage of this to immunize the systemic compartment against GCC-expressing cancer cells, without inducing a response in the mucosal compartment where GCC is normally localized. In fact, a vaccine containing GCC elicited antibody and killer T cell responses in mice, preventing metastatic tumor formation without creating or exacerbating inflammation. Currently, Dr. Waldman is testing a GCC-based vaccine in a Phase 1 trial of stage I and II colorectal cancer patients. So far, positive antibody and killer T-cell responses have been observed.
The advances in cancer research that Dr. Waldman has accomplished is the dream of many scientists. To discover the basic mechanisms of a disease and use that information to not only diagnose, but also treat the disease is a feat that few scientists ever accomplish, and Dr. Waldman is indeed worthy of the Reynold Spector Award in Clinical Pharmacology for his research. Throughout his presentation, Dr. Waldman also took the time to highlight scientists who have acted as mentors and friends, supporting him throughout his career. “I think it’s a rare opportunity that we get to thank our mentors in public,” Waldman said. “These are the people that set our feet on the path for our careers and shaped us… For me these are the people on whose shoulders I’m standing, trying to catch a brief glimpse of the horizon in the distance.”
During his doctoral training at Thomas Jefferson University, Dr. Waldman worked in the lab of Dr. Ken Chepenik. “He is the one that instilled in me a love of science and research,” said Waldman. He also expressed appreciation for the friendship he has maintained with Dr. Chepenik through the years. “While he taught me many things scientifically, the more important gift that he gave me was his enduring friendship.”
In 1979, Dr. Waldman began a postdoctoral fellowship in the lab of Ferid Murad, co-winner of the 1998 Nobel Prize in Physiology or Medicine. “He taught me how to do big science,” stated Waldman. “The most important thing that he taught me was actually a passion for translational research. He is the quintessential physician-investigator. Every day it was, ‘What are we going to discover today that we can translate to better manage a patient tomorrow?’” In addition to the science he taught Waldman, their families have remained close friends for 35 years.
Dr. Waldman also thanked his colleague Dr. Andre Terzic, whom he met as a junior faculty member at Thomas Jefferson University. Waldman expressed gratitude for several lessons in personal and professional development. “There’s no ‘I’ in team,” said Waldman of advice gained from Dr. Terzic. “When you are working on something, you are doing it for the betterment of the institution and organization, not for the betterment of the individual. In every interaction, always take the high road, and I’ve tried to do this throughout my career.” Waldman and Terzic have produced a textbook together in basic and clinical pharmacology, and have been the co-editors of Clinical Pharmacology and Therapeutics for ten years. “While scientifically and professionally he’s given me a lot, more importantly he’s given me his friendship, which is of paramount importance,” said Waldman.
Lastly, but most importantly, Dr. Waldman credited his success to his loving family. “All the mentors and all the science is great, but at the end of the day there’s got to be something that inspires you. My inspiration, the thing that gets me up every day, is my family,” said Waldman. “Of all the things that I’ve ever done, of all the cool science that I’ve done and the projects that I’ve been a part of and the people who I’ve met, it’s all wonderful, but truly my family is probably the most important thing I’ll ever do in my life.”
The Reynold Spector Award in Clinical Pharmacology was established in 2014 by ASPET in recognition of Dr. Spector’s dedication and contributions to clinical pharmacology. The award recognizes excellence in research and/or teaching in clinical pharmacology. This award is made possible by an endowment to ASPET from Dr. Reynold and Mrs. Michiko Spector.