read-more
Read more about Fred Hutch achievements and accolades.
Fred Hutchinson Cancer Center pancreatic cancer researcher Sita Kugel, PhD, has received an inaugural Translational Research Award from the V Foundation for Cancer Research. The $800,000, four-year grant will allow Kugel to pursue an innovative Phase 1b clinical trial to translate from the lab to the clinic breakthroughs her group has made in developing a tailored treatment for a subtype of pancreatic cancer.
“This trial would not be possible without V Foundation support,” Kugel said. “It fills a gap. It wouldn’t have been possible to do this investigator-initiated clinical trial any other way.”
Her work builds on findings her team published earlier this year in the journal Science Translational Medicine, showing that a specific subtype of pancreatic cancer is more vulnerable to certain inhibitors of cyclin-dependent kinases — a step forward in the development of targeted treatments for pancreatic cancer.
Kugel’s grant comes as part of the V Foundation’s A Grant of Her Own: The Women Scientists Innovation Award for Cancer Research program, developed by the foundation during the COVID-19 pandemic to help increase female-led innovation and representation of women in science. She expects the early-stage trial to open in late 2024.
A creative approach to testing a new treatment
Pancreatic cancer has remained a difficult cancer to treat. Only 20-30% of people diagnosed with pancreatic adenocarcinoma — the most common type of pancreatic cancer — live five years after diagnosis, even if their tumors can be surgically removed. Though 44% of people diagnosed with early-stage tumors live at least five years after diagnosis, that number drops to just 3% for people who are diagnosed with late-stage tumors that have already spread, according to the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) database. And because most tumors are diagnosed at later stages, the combined five-year survival rate for people with pancreatic adenocarcinoma is 12%.
Patients desperately need new treatment options, but finding promising targets has been difficult, Kugel said.
“The genetics of pancreas tumors are pretty homogeneous,” she said. By and large, pancreatic cancers share mutations, despite varying widely in aggressiveness and treatment responsiveness. Nothing in the tumors’ genetics explains what doctors see in the clinic, Kugel said.
Pancreatic researchers found reason to hope when they turned away from tumor gene sequences and looked at tumor gene expression, or the pattern of genes that are turned on and off in pancreatic tumors. Scientists saw two main patterns of gene expression that define two cancer subtypes, dubbed “basal” and “classical.”
“Basal pancreatic cancer is much more undifferentiated and has lost its (cellular) identity in a way that classical hasn’t,” Kugel said. “Classical pancreatic cancer is more glandular, closer in identity to normal pancreatic duct cells.”
Studies have shown that in general, basal-type tumors are more aggressive and patients with these tumors face grimmer prognoses.
But Kugel’s team discovered a potential vulnerability in basal pancreatic cancer. In the Science Translational Medicine paper, Nithya Kartha, PhD, then a postdoctoral fellow in Kugel’s lab, showed that basal-type pancreatic tumors are more sensitive to inhibitors of certain cyclin-dependent kinases, or CDKs, which are proteins that help regulate gene transcription and tumor growth.
Kugel and Kartha’s preclinical results are very promising, but the CDK inhibitors need to be tested in people. Testing new cancer treatments can be tricky: When lives are on the line, it can be difficult to justify giving people a new treatment when it’s unclear whether it works as well as standard therapy. Additionally, there are currently no clinical tests to determine whether a patient’s tumor is basal, classical, or a mixture of subtypes.
Supported by the V Foundation, Kugel has developed a creative strategy to test her tailored treatment while ensuring that patients receive the standard of care for pancreatic cancer. Currently, patients whose tumors have not metastasized receive a combination of therapy called FOLFIRINOX, or FFOX, which shrinks tumors so they are easier to remove via surgery. But research suggests that FFOX typically kills off classical-type tumor cells and then skews the tumor toward a basal subtype.
“We thought we’d use this for a small window-of-opportunity trial,” Kugel said. “We don’t need to subtype the patient up front — the standard-of-care treatment is actually creating the patient that is going to benefit.”
In the short window between FFOX treatment and surgery, patients will receive a CDK7 inhibitor. Tumor tissue and circulating tumor DNA from these patients will be monitored over time to see if Kugel and her team can identify biomarkers that predict whose tumors respond or develop resistance to the new therapy. In a second arm of the trial, Kugel and her team will look at whether a different standard-of-care treatment combination, gemcitabine and nab-paclitaxel, affects one tumor subtype more than the other, and whether a CDK7 inhibitor benefits patients.
At the same time, Kugel will be refining the approach using pancreatic tumor tissue taken from patients and grown in mice. These patient-derived xenograft, or PDX, models allow researchers to test new treatment strategies against tumors that are growing and evolving in an environment that’s closer to their original environment than any petri dish could be.
Kugel and her team have a collection of basal and classical pancreatic PDX models, which are allowing her to test different CDK7 inhibitors so that she can choose the best one to test in people. Patients who participate in the trial will also donate tumor tissue, before and after treatment, that Kugel and her team can use to create preclinical model systems that will allow them to learn more about how treatment resistance develops, and how to counteract it.
“That’s real-time experimentation you can do in a PDX model, that you can’t do in a patient,” Kugel noted. “It gives you the power of flexibility that you don’t have in a clinical trial.”
Fruition of V Foundation-fostered work
The new trial is the culmination of several years of V Foundation-funded work, Kugel said. In 2018, she received a V Scholar Grant, developed to support young tenure-track faculty, to help her pursue potential treatments that target different pancreatic cancer subtypes. The current trial grew from that foundation, she said.
“The V Foundation took me from the first Western blot (test) all the way to this clinical trial — they’ve been there at every step,” Kugel said.
And as the mother of two young kids who spent the pandemic balancing their care with running a laboratory and co-directing Fred Hutch’s Pancreatic Cancer Program, Kugel appreciates the goals of the V Foundation’s new grant program.
“It’s especially meaningful,” Kugel said. “Women scientists were disproportionately affected by the pandemic; it struck me as refreshing to have a funding body recognize that, validate it, and come up with a meaningful response. I’m very honored.”
Kugel’s work has been made possible through support from the V Foundation as well as other public and private funders, including Swim Across America.
