Kugel’s work on antifolates piqued a greater interest in cancer metabolism, which in turn inspired a deeper investigation into DNA packaging and its potential role in cancer.
We have nearly six and a half feet of DNA in each of our cells; to fit, it must be neatly bundled and compressed, or packaged. Cells also use DNA packaging to help control when genes are turned on and off: Denser bundling keeps genes turned off, and looser DNA helps turn them on. Specific metabolites can be attached to or removed from proteins that help package the DNA, and these changes can relax or tighten the DNA bundling.
Colleagues close to Kugel inspired her to turn her attention to pancreatic cancer, a disease known to be fatal in nearly all cases. She discovered that the proteins that work to keep DNA tightly bundled are more likely to be lost in a particularly aggressive subtype of pancreatic cancer. The looser DNA allows specific genes, usually only turned on early in our development, to get reawakened in these pancreatic cancer cells. Unfortunately, genes that are useful in early development — to rapidly create more cells or to keep cells from adopting specialized functions too soon — can wreak havoc in cells that should be specialized and not dividing rapidly, like pancreatic cells.
“I have been the family member sitting in the hospital, hoping that someone will come up with a new drug.”
When Kugel first established her laboratory at Fred Hutch, she focused on how alterations in DNA packaging can give cancer cells a leg up when it comes to survival, helping cancer cells multiply themselves and resist drugs. But life inspired a new direction and a new approach.
Kugel initially set up her lab next to her collaborator and husband, Dr. Supriya “Shoop” Saha, whom she met when they worked in neighboring labs during their postdoctoral studies at Harvard University. Saha studied intrahepatic cholangiocarcinoma, a cancer of the bile ducts. Like pancreatic cancer, ICC is aggressive: Only about 10% of patients with ICC or pancreatic cancer will survive five years past diagnosis.
But then Saha was diagnosed with myelofibrosis, a blood disorder, and died at just 40 years old.
Kugel’s second traumatic loss to cancer brought a new sense of urgency to her work: “I have been the family member sitting in the hospital, hoping that someone will come up with a new drug,” she said.
Her commitment to researching the questions most likely to help others intensified. Now she and her team study both pancreatic cancer and ICC. Kugel seeks to understand the vulnerabilities specific to subtypes of these tumors that researchers use to develop new, tailored treatments that benefit patients. And as a principal investigator leading a research team, she relishes the chance to mentor young scientists and pay forward her valuable mentorship experiences while continuing to delve into cancer biology.
Her human-focused approach shapes not only the biological questions Kugel asks but also the scientific approach she takes. Rather than focusing on a specific biological process and seeing how it may play out in different tumor types, she works to understand the biological processes specific to pancreatic cancer and ICC that could make these tumors vulnerable to new treatment strategies. To support these studies, Kugel creates cutting-edge preclinical tumor models that mimic patients’ tumor biology as closely as possible.
“Focusing on the disease allows a certain depth to our studies,” Kugel said. “We’ve created a wide variety of model systems and developed close collaborations with surgeons and oncologists treating patients with these cancers, so all the questions we ask can be very disease-relevant.”
Though much of her work still focuses on changes in DNA packaging in these tumors, Kugel’s explorations have led her to other cellular processes, including how cells respond to stress and create proteins. Her work now encompasses many regions of the cell, from the nucleus where DNA is stored to the nucleolus, where the molecular machines that synthesize proteins are created.
“Cancer cells have plasticity and ability to evolve on a cellular level and survive all of the different insults in the tumor microenvironment, in addition to the things we throw at them. Spending my career studying that is pretty fascinating,” said Kugel.
But fascinating biology is secondary to her ultimate goal: to find new vulnerabilities lurking within cancer cells and new therapies that can exploit them and save lives.
“Being able to make a meaningful impact on cancer as a disease — I think that is an amazing thing to be able to focus on each day,” Kugel said.
— By Sabrina Richards, July 26, 2022