Katrina Cooke and her sons, Logan and Camden, at her 140th infusion treatment.
Counting on a Cure
Published
From the Duke Cancer Institute archives. Content may be out of date.
After a diagnosis in 2011 of metastatic breast cancer—cancer that has spread beyond the breast and to distant organs—Katrina Cooke has already had many more years with her two sons—now 12 and 14—than she ever thought possible.
When she was diagnosed, the statistics she read told her that most people with her diagnosis live only an additional year or two. But a combination of treatments, including surgery, targeted treatments like herceptin, and anti-estrogen therapies, worked for her. In December 2012, she was declared to have “no evidence of disease.”
While experiencing many ups and downs since then, she has used that “extra time” to become a professional speaker, peer mentor, and advocate. She became a peer mentor with the American Cancer Society and in 2017 joined the Duke Cancer Institute Oncology Patient Advisory Council (OPAC), a volunteer program that gives Duke cancer patients and their caregivers an opportunity to provide their perspective on the patient experience and offer recommendations on how to enhance it. Since 2018, she’s served as community co-chair of the group.
In June of 2020, a spot was found on her rib. Bone can be tricky to biopsy, making bone metastasis difficult to confirm.
She is working with Duke interventional radiologist Alan Sag, MD, and medical oncologist Kelly Marcom, MD, on further diagnosis and treatment.
"
We have to do what it takes to save my life. My boys need their mom.
"
Katrina Cooke
/
Patient
“Research is the only thing that will keep me alive,” says Cooke. “Eventually, I will run out of options and that will be it. We have to do what it takes to save my life. My boys need their mom.”
This article appears in the Winter 2021 issue of Breakthroughs magazine, which is produced twice yearly by Duke Cancer Institute Office of Development.
A newly published study from Duke Cancer Institute researchers sheds light on a long‑standing mystery in cancer biology and reveals a potential new path toward more targeted treatments for pancreatic and other solid tumors.The work, led by Gerry Blobe, MD, PhD, leader of basic and translational science for the DCI Pancreatic Cancer Center, was recently published in Nature. The study uncovers how the loss of a protein called ALK4, present in a substantial percentage of pancreatic and breast cancers, drives tumor aggressiveness and metastasis. The research also identifies potential therapeutic strategies that may counteract this effect.For more than 20 years, scientists have known that some pancreatic cancers carry mutations in ALK4, a receptor involved in the transforming growth factor (TGF)‑beta signaling pathway. What remained unclear was how the loss of this receptor affects cancer behavior and whether it creates vulnerabilities that clinicians can target.Although ALK4 mutations occur in only about two percent of pancreatic cancers. Blobe and his team discovered that loss of ALK4 expression is far more common. Through mechanisms including loss of the gene itself, transcriptional downregulation, and epigenetic silencing, about 40 percent of pancreatic tumors lose ALK4 function. A similar pattern was found in breast cancer.This loss, Blobe explains, turns out to be far from harmless. Across multiple cell‑culture studies and animal models in pancreatic and breast cancer, the team observed the same striking pattern.“In animal studies, when ALK4 expression is lost, primary tumors do not grow faster, but they become significantly more metastatic, leading to worse outcomes,” Blobe said.Cells without ALK4 became more migratory and invasive. This change aligned with an increase in a biological process called epithelial‑to‑mesenchymal transition (EMT), a hallmark of cancer progression.Although ALK4 is part of the TGF‑beta family of receptors, losing ALK4 increased canonical TGF‑beta signaling, which is known to promote metastasis in advanced cancers.Through extensive molecular studies, the researchers discovered why:Loss of ALK4 increases glycosylation, a type of post‑translational modification that stabilizes other TGF‑beta receptors on the cell surface, essentially super‑charging the pathway. Receptors that remain become more abundant and more active, driving aggressive behavior.This same glycosylation‑based mechanism was also found to elevate other pro‑cancer signaling pathways, including VEGF and integrin pathways.When the team examined human tumor samples, findings from the lab held true:Patients whose tumors had lost ALK4 expression showed higher TGF‑beta signaling and poorer outcomes.Together, these discoveries point to several promising clinical applications.“This marker could help identify patients at higher risk of metastasis — particularly in pancreatic and breast cancers, where ALK4 loss is most common,” Blobe said. “Also, because TGF‑beta contributes to an immunosuppressive tumor microenvironment, patients with high TGF‑beta activity caused by ALK4 loss might benefit from combinations of TGF‑beta inhibitors and immunotherapy.”Blobe’s research continues through the postdoctoral fellow who led the study, now an independent investigator in China. Blobe remains involved as an advisor as she builds her program.As researchers continue to build on these findings, ALK4 may become an important marker for identifying aggressive tumors and for tailoring treatments that more precisely address the biological drivers of cancer progression.“This is one mechanism where the loss of one protein can reprogram cells and mediate wide‑scale changes in how cancer cells signal to become more aggressive and treatment‑resistant,” Blobe said.
A newly published study from Duke Cancer Institute researchers sheds light on a long‑standing mystery in cancer biology and reveals a potential new path toward more targeted treatments for pancreatic and other solid tumors.The work, led by Gerry Blobe, MD, PhD, leader of basic and translational science for the DCI Pancreatic Cancer Center, was recently published in Nature. The study uncovers how the loss of a protein called ALK4, present in a substantial percentage of pancreatic and breast cancers, drives tumor aggressiveness and metastasis. The research also identifies potential therapeutic strategies that may counteract this effect.For more than 20 years, scientists have known that some pancreatic cancers carry mutations in ALK4, a receptor involved in the transforming growth factor (TGF)‑beta signaling pathway. What remained unclear was how the loss of this receptor affects cancer behavior and whether it creates vulnerabilities that clinicians can target.Although ALK4 mutations occur in only about two percent of pancreatic cancers. Blobe and his team discovered that loss of ALK4 expression is far more common. Through mechanisms including loss of the gene itself, transcriptional downregulation, and epigenetic silencing, about 40 percent of pancreatic tumors lose ALK4 function. A similar pattern was found in breast cancer.This loss, Blobe explains, turns out to be far from harmless. Across multiple cell‑culture studies and animal models in pancreatic and breast cancer, the team observed the same striking pattern.“In animal studies, when ALK4 expression is lost, primary tumors do not grow faster, but they become significantly more metastatic, leading to worse outcomes,” Blobe said.Cells without ALK4 became more migratory and invasive. This change aligned with an increase in a biological process called epithelial‑to‑mesenchymal transition (EMT), a hallmark of cancer progression.Although ALK4 is part of the TGF‑beta family of receptors, losing ALK4 increased canonical TGF‑beta signaling, which is known to promote metastasis in advanced cancers.Through extensive molecular studies, the researchers discovered why:Loss of ALK4 increases glycosylation, a type of post‑translational modification that stabilizes other TGF‑beta receptors on the cell surface, essentially super‑charging the pathway. Receptors that remain become more abundant and more active, driving aggressive behavior.This same glycosylation‑based mechanism was also found to elevate other pro‑cancer signaling pathways, including VEGF and integrin pathways.When the team examined human tumor samples, findings from the lab held true:Patients whose tumors had lost ALK4 expression showed higher TGF‑beta signaling and poorer outcomes.Together, these discoveries point to several promising clinical applications.“This marker could help identify patients at higher risk of metastasis — particularly in pancreatic and breast cancers, where ALK4 loss is most common,” Blobe said. “Also, because TGF‑beta contributes to an immunosuppressive tumor microenvironment, patients with high TGF‑beta activity caused by ALK4 loss might benefit from combinations of TGF‑beta inhibitors and immunotherapy.”Blobe’s research continues through the postdoctoral fellow who led the study, now an independent investigator in China. Blobe remains involved as an advisor as she builds her program.As researchers continue to build on these findings, ALK4 may become an important marker for identifying aggressive tumors and for tailoring treatments that more precisely address the biological drivers of cancer progression.“This is one mechanism where the loss of one protein can reprogram cells and mediate wide‑scale changes in how cancer cells signal to become more aggressive and treatment‑resistant,” Blobe said.
