Professor Makes Strides in Pancreatic Cancer Detection and Treatment

Earlier this year, the American Cancer Society released its annual cancer statistics, and the numbers for pancreatic cancer continue to be grim.

The average five-year survival ratefor pancreatic cancer is 10-13% - a rate that hasn't improved for the past three years. Pancreatic cancer has the lowest survival rate of all cancers. For the majority of patients, the cancer has metastasized by the time they are diagnosed, and their five-year survival rate is only 3%. And while cases in the U.S. are increasing, progress over the past few decades has remained stagnant.

Dr. Jill Smith is working to improve these statistics. Over the past decade, Smith, a gastroenterologist and professor of medicine in the School of Medicine, has made discoveries in the lab that she's working to translate to patients.

The physician-scientist developed a technology platform that holds the promise of detecting pre-cancerous lesions in the pancreas that are invisible on most imaging scans. She also discovered a treatment that penetrates the dense barrier surrounding pancreatic cancer cells, allowing treatment like chemotherapy to more effectively reach and attack the cancer.

Dr. Jill Smith, a gastroenterologist and professor, wears angel pins on her white coat collar that were gifts from her patients who passed away from pancreatic cancer.

Smith joined Georgetown in 2014 after working for the NIH's National Institute of Diabetes and Digestive and Kidney Diseases. Her discoveries have resulted in at least 12 patents, and in 2023, she was inductedinto the National Academy of Inventors.

Despite an uphill battle, Smith said her determination is fueled by her patientswho have passed away from this disease. She keeps their memory front and center, wearing angel pins on her white coat that were gifts from her cancer patients.

"The angels represent my patients who encourage me to persevere and not give up hope," she said.

Smith isn't giving up, even in the face of a cancer that is understudied, underfunded and unfurls its own unique set of challenges.

"I like challenges, and it has to be the most challenging cancer because it has the lowest survival of all solid tumors," she said. "When I've mentioned this to many of my patients I've had in studies over the years, it's very discouraging. They say, 'Don't give up, because we're making progress one patient at a time.'"

Why Pancreatic Cancer Is So Deadly

One of the major challenges with pancreatic cancer is that the disease is not caught early.

Of the five most lethal cancers, pancreatic cancer is the only one without a standard diagnostic test, according to the Pancreatic Cancer Action Network. Most pancreatic cancer patients are not diagnosed until Stage IV, the organization reports.

"People get colonoscopies to remove polyps in their colon so you can prevent colon cancer. People can get mammograms to pick up early breast cancer. But the pancreas is in a location behind the stomach and in front of the backbone, which you can't feel readily on an exam," Smith said. "Usually it's not until the cancer has gotten so large and has already spread that people get symptoms."

Like polyps and colon cancer, 85% of pancreatic cancers develop from precancerous lesions in the pancreas, Smith wrote in a 2021 paper. These microscopic lesions, called PanINs, are not detected with standard imaging or endoscopic procedures.

Smith knew if she could find a strategy to detect these lesions, there would be the potential to treat pancreatic cancer in the early stages when it is curable.

Her lab discovered a protein receptor, called CCK-BR, that is not found in a normal pancreas but is overexpressed in precancerous lesions and in pancreatic cancer. In 2020, Smith and her colleague, Stephan Stern from the National Cancer Institute, co-designed a fluorescent nanoparticle - one-billionth of a meter in size - that targets and binds to the receptor in the precancerous lesion. The fluorescent substance, once injected, is detected with imaging technologies.

In 2024, Smith was named Innovator of the Year by the Georgetown Office of Technology Commercialization for her pancreatic cancer research.

In mice with large pancreatic tumors, the nanoparticle slowed the cancer's spread and improved survival rates.

Georgetown's Office of Technology Commercialization recently licensed the technology to a company to develop it commercially. The nanoparticle was also accepted into the Assay Cascade evaluation in the Nanotechnology Characterization Laboratory of Frederick National Laboratory, which will evaluate its formulation properties and safety.

Why Pancreatic Cancer Is Difficult to Treat

A second reason pancreatic cancer is so deadly is that, in addition to its detection challenges, the cancer is hard to treat.

Pancreatic cancer creates a "fibrosis shield," Smith says, around its cancer cells. The fibrosis makes it difficult for immune cells, chemotherapy or immunotherapy drugs to effectively reach the cancer cells.

Smith discovered that a drug called proglumide, originally developed 30 years ago to treat peptic ulcers, can actually decrease the fibrosis and allow immune cells and chemotherapy to enter and attack the cancer.

Smith and her team have conducted three prior clinical trials with the drug in patients with fatty liver disease, cirrhosis and chronic pancreatitis.

Last year, with funding from Georgetown philanthropy and the Ruesch Center for the Cure of Gastrointestinal Cancers, they completed a phase I study in patients with pancreatic cancer that suggested the drug move to the next trial phase.

In 2020, the FDA designated proglumide as an orphan drugfor pancreatic cancer, which allows certain incentives for companies developing drugs for orphan diseases, or those that affect less than 200,000 Americans every year. A company has also licensed the technology and the intellectual property from Georgetown to commercialize proglumide.

"I think that there's great potential," Smith said of proglumide's efficacy. "We've shown that not only does it help get chemotherapy into the tumors because it decreases the fibrosis, but Dr. Lou Weinerand I showed that it also improves the efficacy of immune checkpoint inhibitors, compounds that typically don't work in pancreatic cancer. Combining treatments with proglumide could open the door for a lot of new treatments if we just had a chance."

Last year, Smith's grant submission to the National Institutes of Health (NIH) for the phase II trial was not funded due to budget cuts, and the review of her grant resubmission was delayed due to the government shutdown.

Still, despite funding and review difficulties, Smith persists. She remembers her patients, who urged her to keep fighting.

"I think of them often," she says.

Disclosures: Georgetown University has a patent on the referenced use of proglumide and Drs. Jill Smith and Louis Weiner are inventors with associated intellectual property rights and interests. Georgetown University has a patent for the referenced fluorescent nanoparticle, and Dr. Jill Smith is an inventor with associated intellectual property rights and interests.

Tagged

• School of Medicine