Ethan V. Abel, PhD, a 2021 Seed Grant recipient at Roswell Park Comprehensive Cancer Center, has provided an update on his research in deciphering the role of the HNF1A-SKP2 axis in therapeutic response in pancreatic ductal adenocarcinoma (PDAC). After receiving his award, Dr. Abel wrote that he hoped the grant would “allow [his] lab to explore how a poorly understood protein, called HNF1A, prevents drugs from working in pancreatic cancer, which is one of the largest challenges to treating this disease.”
Through funding from the Seed Grant, Dr. Abel has found that the pancreas transcription factor (a type of protein that controls gene expression) HNF1A directly upregulates SKP2. This known cancer-driving protein controls the process of cell proliferation. Dr. Abel has found that HNF1A can push up the levels of SKP2, even in the presence of drugs that normally decrease SKP2 levels and cause cancer cells to stop growing. It is through this interaction that HNF1A is able to drive resistance of pancreatic cancer cells to a number of drugs. In addition to SKP2, other cancer-driving proteins have been identified as potential targets of HNF1A, including c-MYC and EGFR, and the contributions of these proteins to HNF1A-mediated drug resistance is an ongoing effort in the lab. These findings are highly significant, if not surprising, as HNF1A has long been regarded as a tumor suppressor protein, leading to an underappreciation of HNF1A as a potential therapeutic target in pancreatic cancer.
In addition to these discoveries, funding from the Seed Grant has allowed the Abel lab to make additional exciting and unexpected discoveries, including the discovery that HNF1A may promote the metastatic spread of pancreatic cancer cells. As aggressive metastasis is a hallmark of pancreatic cancer and leads to the majority of patient deaths from the disease, understanding what drives metastasis and how to potentially stop cancer from spreading could sharply affect the mortality of the disease. Dr. Abel’s graduate student, Ms. Katherine Crawford, is conducting ongoing work exploring the role of HNF1A in metastasis.
These groundbreaking findings have already been shared with the scientific community. Ms. Crawford presented research posters at the 2022 AACR Pancreatic Cancer Special Conference, while Dr. Abel presented at the American Pancreatic Association’s 2022 annual meeting. A research manuscript summarizing this study is currently being prepared.
Dr. Abel wrote to us to say, “I would like to express my extreme gratitude to the Hirshberg Pancreatic Cancer Research Foundation, the scientific advisory board, the volunteers, and the donors for my Seed Grant Award. I am truly honored and excited! Research funding is scarce, especially in these trying times, and grants such as the Seed Grant Award are absolutely essential to foster young scientists like myself and enable us to establish research labs that will make impactful discoveries to help patients with pancreatic cancer. I am hopeful that the discoveries we make with support from this award will expand our understanding of drug resistance in pancreatic cancer and bring us a big step closer to finding ways to treat it better. Thank you again!”
Further underscoring the impact of this research, Dr. Abel leveraged data from his Seed Grant-funded study to secure an R01 grant from the National Cancer Institute/National Institutes of Health. This grant, entitled “Targeting HNF1A-mediated therapeutic resistance in pancreatic ductal adenocarcinoma,” will provide over $1.8 million in direct research funding over the next five years. This funding will support continued exploration of the role of HNF1A in both response and resistance to targeted therapies such as BET-inhibitors and KRAS-inhibitors.
By investing in early-stage research, the Hirshberg Foundation’s Seed Grant Program continues to accelerate discoveries that pave the way for new treatments. Dr. Abel’s work is a testament to the program’s impact in driving innovation in pancreatic cancer research and the importance of early-stage funding.
Update: In early 2023, Dr. Abel received an R01 research grant from the National Cancer Institute for his work targeting HNF1A-mediated therapeutic resistance in pancreatic ductal adenocarcinoma.
A few months later, his grant was selected to receive additional support through the prestigious Method to Extend Research in Time (MERIT) (R37) Award. The MERIT awards “provide long-term support to outstanding, experienced investigators.” R37 MERIT awards are very rare, and an individual only has one opportunity to receive one in their career. We congratulate Dr. Abel on his groundbreaking work and all he is doing to advance research towards a cure!
