According to the American Association for Cancer Research, it is estimated that there will be 64,050 individuals diagnosed with pancreatic cancer in the United States and 50,550 deaths from these cancers this year. There are two categories of pancreatic cancer – exocrine pancreatic cancer and neuroendocrine pancreatic cancer – each comprising several cancer types that could vary in symptoms and prognosis.

“Unfortunately, pancreatic cancer is still the major cancer with the lowest five-year survival rate of 12%,” said Andrew Waters, PhD, a basic scientist at the University of Cincinnati Cancer Center and assistant professor within the Division of Surgical Oncology and the Department of Cancer Biology at UC. “Pancreatic cancer is the third leading cause of cancer deaths in the United States, and it is projected to become the second leading cause by 2030.”

Reflecting on the journey that the treatment of pancreatic cancer has taken, Dr. Waters explained that it has largely remained the same over the past five years. However, the use of neoadjuvant therapy has increased, and the five-year survival rate has increased since then as well. The increase in survival rate can largely be attributed to the improvements in early detection and management.

Unfortunately, the incidence of pancreatic cancer is increasing, and the increase in incidence is outpacing the improvements that have been made in the five-year survival rates. In 2018, there were only 55,440 estimated cases of pancreatic cancer in the United States, and Dr. Waters anticipates that this number will continue to rise, primarily because we do not fully understand the increase in incidence.

“I do think we might be at the precipice of a treatment paradigm shift, where targeted KRAS inhibitor therapy might take over the standard-of-care from traditional chemotherapies for pancreatic cancer,” he said. “In my opinion, targeted KRAS inhibitor therapies offer hope to all pancreatic cancer patients. I think they have a strong potential to help pancreatic cancer patients with distant disease – a patient population that researchers and clinicians have struggled with for decades.”

Dr. Waters is the leader of the Waters Lab – comprised of Grace Goodhart; Szu-Aun Lim, MD; Amber Amparo; Cleo Steward; Emaan Asghar – which focuses on utilizing first-in-class KRAS inhibitors relevant to all pancreatic cancer patients with the goal of understanding the molecular consequences and resistance mechanisms to KRAS inhibitors in pancreatic cancer. The lab utilizes a panel of pancreatic cancer cell lines, patient-derived pancreatic organoids, and multiple mouse models to accomplish these goals.

“Understanding how pancreatic cancer cells adapt to be able to persist, even in the presence of KRAS inhibition, is a major focus of my lab, as well as many other labs across the world,” said Dr. Waters. “It is no secret that combination therapies will be needed to extend the efficacy of KRAS inhibitors in the clinic. Although, because the clinical trials relevant for pancreatic cancer patients have just started, we have no idea how pancreatic cancer cells adapt to KRAS inhibitor treatment. Our goal is to identify these resistance mechanisms, discover therapeutic vulnerabilities, and then apply combination therapies that will help mitigate resistance. Our lab has recently received an NCI funding award (K22). We are co-authors on a manuscript under revision at a high-profile journal that really has an opportunity to shape the field.”

According to the Pancreatic Cancer Action Network, small changes to healthy cells can sometimes lead to cancer. In almost every case of pancreatic cancer, one of those changes is a mutation in the gene KRAS. The mutated KRAS protein causes the cells to behave like cancer.

“Nearly 90% of pancreatic cancer patients have mutations in the KRAS gene, and the cancer cells rely on mutant KRAS for survival. We have been aware of this KRAS dependency for a long time, but despite intense research efforts, KRAS has been deemed ‘undruggable’ for decades,” said Dr. Waters. “Since KRAS is the most mutated gene in human cancers, it has been called the ‘beating heart of cancer’ and targeting KRAS pharmacologically has been the holy grail of cancer research. However, due to milestone advancements in the field over the last few years, there are now at least two KRAS inhibitor clinical trials that are relevant for KRAS-mutant pancreatic cancer patients.”

At the Cancer Center, community outreach is of the utmost importance as these practices work to establish and strengthen community partnerships throughout the region by connecting members of the community as well as community organizations directly to researchers and clinicians. By leveraging these partnerships, we hope to better address the cancer-related challenges in our region, and over time, reduce the overall burden of cancer.

“One thing that I think I struggle with as a scientist sometimes is communicating the implications of our discoveries to the people who are most impacted by what we do in the lab. Therefore, I have been trying to make a conscious effort to engage the community in our research,” Dr. Waters shared. “I volunteer for the PanCAN Cincinnati affiliate and update the group on research findings. Our lab, as well as others within the Cancer Center, engage in pancreatic cancer fundraising and advocacy opportunities. Recently, we engaged pancreatic cancer advocates, survivors, and volunteers at PanCAN by opening up our lab and providing a lab tour.”

Upon reflection, Dr. Waters shared that the accomplishment he is most proud of is receiving his first grant, which was from the American Cancer Society. After years of donating to the organization in honor and memory of his family and friends who have been diagnosed with cancer, he was extremely grateful to have an organization that he invested in invest in his scientific ideas. Since joining the University of Cincinnati and the Cancer Center, Dr. Waters has found the collaborative environment extremely beneficial in his work.

“The pancreatic cancer research environment within the University of Cincinnati Cancer Center is very strong. I think one thing the Cancer Center does really well is integrating the various groups of pancreatic cancer researchers across the University of Cincinnati, UC Health, and Cincinnati Children’s,” explained Dr. Waters. “We have clinicians, physician scientists, and basic researchers all working together to achieve a common goal. We engage in several collaborative meetings each month, which really allows us to take a bench to bedside to bench approach and make rapid progress against this deadly disease. The integration of these groups and collaborative projects have really allowed me to hit the ground running since I started at the University of Cincinnati in October of 2022.”