Imagine cancer as a line on a chalkboard. At the left is a healthy cell. Reading left to right, you can follow a cell’s journey as it begins to develop abnormalities, morphs to become a localized cancer, and finally metastasizes to an advanced cancer at the far side of the spectrum. “As a field, we’ve been spending a lot of time looking to the right. The opportunity now is to look to the left,” says Robert Vonderheide, director of Penn’s Abramson Cancer Center and the John H. Glick Abramson Cancer Center Professor in the Perelman School of Medicine. “Can we intercept those precursor lesions before they become cancer?”
That is the promise of the burgeoning field of cancer interception. The goal of interception is to catch, or intercept, cancer cells as they begin to develop into pre-cancers or very early cancers, and halt or reverse that process.
Researchers across Penn Medicine are coming at the study of interception from every angle, including basic science to understand the molecular changes that lead to cancer and to develop new methods for finding it. Much of this work takes advantage of emerging tools, Vonderheide says. New single-cell sequencing technologies, for instance, allow researchers to track changes at the level of an individual cell. Novel mouse models, many developed at Penn, are helping scientists to characterize the changes in pre-malignant tissues.
So far, scientists are largely focusing their efforts on people with a high risk of developing cancer, such as those with genetic variants like BRCA1 and BRCA2. BRCA mutations are well known for their association with hereditary breast and ovarian cancer, and are also associated with prostate and pancreatic cancers. People with inherited BRCA mutations are a natural choice for advancing the science of interception—both because their cancer risk is fairly well quantified, and because they are hungry for better options, says Susan Domchek, executive director of the Basser Center for BRCA at the Abramson Cancer Center and the Basser Professor in Oncology in the Perelman School of Medicine.
“Testing for a BRCA mutation has implications not only for the individual, but for their entire family. It’s very personal,” Domchek says. “Right now, we tell people they can reduce their risk of cancer by removing the breasts or the ovaries. But we want to offer better options than removing body parts.”
Domchek and her colleagues are launching many initiatives for the new Institute, including a pioneering study testing a new cancer vaccine in women with BRCA1 and BRCA2 mutations. In an initial trial, patients who were in remission after previously having cancer were vaccinated, with the goal of preventing recurrence. Now, she’s testing the vaccine in BRCA-positive participants who’ve never had cancer, in hopes that the vaccine response can intercept early lesions before tumors develop.
“Better understanding the molecular biology in which a normal cell becomes a cancer cell is key to understanding the best way to intercept it,” Domchek notes. “There’s a lot of basic science driving what we’re doing, and the purpose of the Institute is to figure out as many of these different possible directions as we can.”
Katherine Nathanson, the Pearl Basser Professor for BRCA-Related Research and deputy director of the Abramson Cancer Center is collaborating with researchers at Harvard University to develop a so-called “human breast atlas.” Looking at tissue samples from women with and without BRCA mutations, they are mapping the various types of cells present in breast tissue, as well as the molecular changes cells may undergo as they travel left to right along the route from healthy to malignant.
An ongoing study is looking to develop new blood-based biomarkers to identify pancreatic cancer at earlier stages. Pancreatic cancer is notorious for going undiagnosed until it is advanced and difficult to treat. The study is led by Penn Medicine researchers Erica Carpenter, director of the Liquid Biopsy Laboratory at the Abramson Cancer Center, and Bryson Katona, director of the Gastrointestinal Cancer Genetics and Gastrointestinal Cancer Risk Evaluation Programs.
Katona and Carpenter decided to combine multiple biomarkers linked to pancreatic cancer, including circulating tumor DNA, extracellular vesicles and a tumor marker known as CA-19-9. Using machine learning, they developed an algorithm to look for telltale patterns among those multiple markers. “We were able to come up with a blood-based signature of pancreatic cancer that was fairly sensitive and accurate,” Carpenter says. “But we felt we could do even better, so we’re continuing to refine the test before we test it in the clinic.”