May 26, 2023
By Matt Crouch
AUBURN, Alabama – For most academic scientists conducting biomedical research, the possibility of advancing a new medicine to the clinic is, at best, an aspiration. Despite the odds against success, Dr. Gary Piazza and his research team in the Harrison College of Pharmacy discovered a highly potent and selective anticancer drug and are collaborating with investigators at the University of Alabama-Birmingham, or UAB, O’Neal Comprehensive Cancer Center to advance a new drug candidate to clinical trials for patients with the most fatal of cancers.
Piazza joined the Harrison College of Pharmacy, or HCOP, in 2021 as W.W. Walker Professor and head of the Department of Drug Discovery and Development. A highly-respected cancer investigator, Piazza came to Auburn as a UAB graduate with over 35 years of research experience, including 10 years as a professor at the University of South Alabama Mitchell Cancer Institute in Mobile and 10 years as a principal scientist with Southern Research in Birmingham.
Along with his administrative responsibilities, Piazza continues his groundbreaking research as director of the newly-created Cancer Research Center at HCOP.
A team of scientists who started to collaborate while at Southern Research also made the move from MCI to Auburn including Dr. Xi Chen, a medicinal chemist; Dr. Adam Keeton, a cancer biologist; Dr. Yulia Maxuitenko, a pharmacologist; and Kristy Berry, a lab manager with expertise in mouse tumor models.
“We share a common interest in cancer research but have very different skill sets,” said Piazza. “Having a multidisciplinary team with diverse scientific expertise has allowed us to solve many technical problems as we seek to advance our experimental drugs to the clinic.”
Since its inception in 2021, the HCOP Cancer Research Center under Piazza’s leadership has seen rapid expansion that now includes two research assistant professors in Drs. Jacob Valiyaveettil and Younis Abiedalla; two postdoctoral scientists in Drs. Khalda Fadlalla and Sindu Ramesh; and three graduate students, Chung-Hui Huang, Austin Moore, and Thomas Holmes.
The team also has ongoing collaborators with other faculty members in the department, including Dr. Forrest Smith with expertise in drug design and molecular modeling, Dr. Murali Dhanasekaran with expertise in drug biomarkers, and Dr. Amit Mitra with expertise in pharmacogenomics as well as investigators at UAB, Samford, LSU and the Georgia Cancer Center.
Piazza also brought with him to Auburn multiple actively funded research projects, including three R01 projects from the National Institutes of Health National Cancer Institute directed at colorectal and lung cancer and a project from the Breast Cancer Research Foundation of Alabama along with several million dollars in funding.
Selectively targeting cancer cells
As a post-doctoral fellow at the Fox Chase Cancer Center in Philadelphia and then as a research assistant professor at Brown University in Providence, Piazza began to study the behavior of cancer cells. After this training, we made, what he calls a “natural progression” into the field of drug discovery and development as a scientist working in the pharmaceutical industry. He first worked with a large company, Procter & Gamble Co in Cincinnati, and then with a small biotech company in Denver, Cell Pathways Inc.
It was with Cell Pathways as director of research, that Piazza first began researching some novel anticancer properties of a commonly used class of drugs, known as non-steroidal anti-inflammatory drugs, or NSAIDs. He was intrigued with the unique anticancer activity by which one NSAID, sulindac, could selectively kill cancer cells and inhibit tumor growth apparently without affecting normal cells, thus lacking the toxicity associated with conventional chemotherapy.
From his early research, Piazza was the first to publish evidence that sulindac could kill cancer cells by a specific mechanism known as apoptosis, or programmed cell death. This research supported the clinical development of a sulindac derivative called exisulind to treat precancerous colon adenomas (polyps) in patients with familial adenomatous polyposis who are at high risk of developing colorectal cancer.
While Piazza led the preclinical development of exisulind that went from the bench to the completion of Phase 3 clinical trials, the drug unfortunately did not receive FDA approval because of liver toxicity and modest efficacy, forcing Piazza and his team to go back to the drawing board.
"NSAIDs are not considered to have strong anticancer activity and are not FDA approved for long-term use to either prevent or treat cancer because of potentially fatal gastrointestinal and other toxicities,” said Piazza. “Yet, this unusual anticancer activity of NSAIDs commonly used to treat everything from headaches to arthritis inspired me to better understand the underlying mechanism of action.”
After leaving Cell Pathway’s, then located in Philadelphia, Piazza began what he called a long journey back to academic research with a couple of detours along the way. He first served as vice president of research with a biotech company in San Diego, and then as director of pharmacology at the Institute of Drug Development in San Antonio, before finally landing back in Alabama at Southern Research where he was able to apply for NIH funding needed to continue research that he started while at Cell Pathways but which he could do as an independent investigator.
“My early research at Southern Research was focused on understanding how sulindac could selectively induce apoptosis of cancer cells, which I believed could provide insight into new targets to discover safer and more efficacious anticancer drugs,” said Piazza. “From this basic research, which we continued after the team moved from Birmingham to Mobile, a novel series of compounds emerged that displayed ultra-high potency and unusual selectively to induce apoptosis of cancer cells by inhibiting a protein called RAS that is well known to drive cell signaling and is essential for the proliferation of cancer cells, as well as normal cells.”
RAS is a protein in which mutations in RAS genes have been known for decades to be responsible for many human cancers and those that are the most fatal, especially pancreatic, colorectal and lung cancers.
“RAS is the oncogene from hell and most cancer researchers are well aware of RAS and have strong opinions about drugging RAS,” said Piazza. “Many consider RAS to be 'undruggable’ for several reasons, including its central role in controlling the proliferation and survival of normal cells. In fact, the pharmaceutical industry had tried for decades to develop RAS inhibitors that have either failed or, more recently, have resulted in new drugs that are FDA approved but have only modest efficacy and limited use.”
A unique approach to inhibiting RAS
It is no secret that selectively targeting cancer cells is a major challenge. Many cancer treatments affect every cell they come into contact with, normal and cancerous, and can cause many of the side effects most people associate with cancer treatment.
“In many ways, cancer cells are just like normal cells, especially those cells in tissues where there is rapid cell division, for example, in the gut,” said Piazza. “The difficulty in cancer drug development has always been the ability for find target-directed small molecules that can selectively kill cancer cells without harming normal cells.”
Piazza is optimistic that their lead compound, ADT-1004, is an attractive drug candidate inching closer and closer to clinical trials. Although more research is needed, Piazza is encouraged by the promising anticancer activity that ADT-1004 has shown in mouse models of pancreatic cancer and our detailed understanding of how the drug can selectively kill cancer cells.
“Finding a drug target that is specific to cancer cells is the holy grail of cancer research and the group of compounds we are studying have a unique property of interacting with RAS to selectively induce apoptosis of cancer cells harboring RAS mutations but without affecting normal cells,” said Piazza. “This selectivity is very interesting and unique to our RAS inhibitors as it takes advantage of a natural physiological process by which normal cells contain enzymes that can metabolize and detoxify certain drugs.”
Efficacy in preclinical models is the gatekeeper for advancing any experimental anticancer drug to the clinic, but extensive safety testing will also be needed that, unfortunately is expensive, and is not funded by grants available to academic scientists.
Drug development is typically done by pharmaceutical companies with deep pockets and interests in commercializing drugs. Looking for a solution to this obstacle, Piazza and his colleagues, Drs. Chen and Keeton, formed a company, ADT Pharmaceuticals LLC., and filed patent applications to protect their innovative discovery. Along with UAB collaborators, Piazza’s team in the Cancer Research Center at Auburn recently submitted a grant application to the NIH/NCI to conduct safety studies needed for the FDA to allow clinical trials in patients with advanced stage pancreatic cancer.
Potential at Auburn
Having already distinguished himself in his career, Piazza was intrigued by the potential of joining Auburn when he interviewed for the department head position in 2021. Having spent most of his career in Alabama and married to a native Alabamian, Nancy, whose father was a loyal Auburn fan, Piazza knew much about Auburn and even experienced the university as a parent as his son, Tyler, is a 2016 Auburn graduate.
“Most of my career prior to joining Auburn was in the pharmaceutical industry where I learned the value of collaboration and in cancer centers, I saw sick patients everyday coming in for chemotherapy, which made me more determined to not be satisfied with only conducting basic research,” said Piazza. “When I was looking into the open department head position here at Auburn at a college of pharmacy, I recognized the diverse expertise within the college, which I believed could help solve some of the major hurdles we encountered to advance our experimental anticancer drugs to the clinic.”
HCOP’s Department of Drug Discovery and Development has a broad and applied approach with faculty conducting research in multiple disease areas or in various aspects of pharmaceutical sciences. Investigators can discover compounds that can target various molecular entities to treat disease, but a major challenge always presents itself in putting an experimental drug into a pill or an injectable formulation that a human can safely take and ensure that it reaches the target.
“I saw that the department, as well as the college of engineering, had strengths in drug delivery, which along with expertise in pharmacokinetics and pharmacogenomics, and other fields where the is strong potential for synergy needed to develop a drug,” said Piazza.
Piazza is excited about what can be accomplished on The Plains to be a beacon of hope in the battle to fight cancer.
“Medicinal chemistry is another unique strength within the department where I believe there are opportunities to collaborate with investigators at universities with academic medical centers that do not have such expertise and resources,” said Piazza. “These are the disciplines that are essential to advance a drug from the bench into the clinic.”
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Auburn University’s Harrison College of Pharmacy is ranked among the top 25 percent of all pharmacy programs in the United States, according to U.S. News & World Report. Fully accredited by the Accreditation Council for Pharmacy Education (ACPE), the College offers doctoral degrees in pharmacy (Pharm.D.) and pharmaceutical sciences (Ph.D.) while also offering a master’s in pharmaceutical sciences. The College's commitment to world-class scholarship and interdisciplinary research speaks to Auburn's overarching Carnegie R1 designation that places Auburn among the top 100 doctoral research universities in the nation. For more information about the College, please call 334.844.8348 or visit http://pharmacy.auburn.edu.