A generous contribution via the Gail V. Coleman-Kenneth M. Bruntel Charitable Grant Fund has enabled Jordan M. Winter, MD, FACS, Associate Professor of Surgery, and his team to initiate two innovative studies in pancreatic cancer. Here, Dr. Winter provides an overview of the purpose – and potential impact – of each project.
Studying Cancer Cell Metabolism
As Dr. Winter explains, metabolism is a fundamental biologic process for the viability of any cell – including cancer cells. “If you can find a way to impair that biology, you have an opportunity to treat cancer by killing those cells,” he says.
The challenge: Metabolism in cancer cells isn’t the same as in healthy cells. In pancreatic cancer cells, a protein called HuR appears to be an important regulator of metabolism – pancreatic cancer’s “secret weapon” in withstanding austere conditions.
“Even with very low levels of oxygen and other nutrients, such as glucose and glutamine, pancreatic cancer cells not only survive but thrive,” Dr. Winter says.
Prior work by Dr. Winter and Director of the Division of Surgical Research, Jonathan R. Brody, PhD, has focused on the role of HuR as a prosurvival protein. In other words, remove HuR and pancreatic cancer cells die.
Thanks to the Coleman-Bruntel contribution, Dr. Winter and his laboratory team will be conducting a sophisticated metabolic experiment to better understand the “how” and “why” of HuR. They will do so by mapping the flow of carbon through metabolic pathways in cells with and without HuR.
“Along with genetics and immunology, cancer cell metabolism is one of the hottest fields in cancer biology,” Dr. Winter notes. “This experiment is the first time anyone has examined how HuR affects metabolic pathways. It’s also the deepest exploration into how RNA biology plays a role in cancer cell metabolism.”
Understanding Chemotherapy Resistance
The Coleman-Bruntel gift has also enabled Dr. Winter and his team to take on a second, more translational study – in other words, work that will be more directly applicable in patient care. This one aims to enhance understanding of the mechanisms of chemotherapy resistance in pancreatic cancer.
“We’re studying patients with advanced pancreatic cancer who receive the most common treatment for stage 4 cancer, which is FOLFIRINOX and GEM/ABRAX,” explains Dr. Winter. “About half of these patients have some benefit, with the tumor remaining stable or shrinking. Eventually, though, the biology of every tumor adjusts to develop resistance.”
The team wants to understand how the tumor adapts at the genetic level.
For five to 10 patients, the team will first take a blood sample to obtain germline DNA to sequence (a laboratory process used to find mutations that may cause disease). Any mutations inherited from the germ cells (egg cell and sperm cell) of the patient’s parents will be found in this germline sequence. This will give the researchers a baseline for comparison.
Second, the team will take a tumor biopsy prior to starting chemotherapy. They will grow the cell line in the lab, extract DNA and sequence the genome of the cancer before treatment. Finally, they will take a second biopsy during treatment once the tumor stops responding to chemotherapy and begins progressing. In other words, they will re-sample the tumor only after the biology of the cancer has changed – likely as a function of new mutations.
“Analysis of the pre-treatment and post-progression biopsies will provide us with clues as to how the cancer evolves to gain resistance to the chemotherapy,” Dr. Winter explains. “A better understanding of which genes or pathways change may help in better targeting those pathways and, ultimately, in improving chemotherapy.”
Dr. Winter is quick to note that this is the first pilot of its kind and was made possible solely through the Coleman-Bruntel gift. It’s already serving as a springboard for further funding – and will likely be the first in a series of studies into chemotherapy resistance.