By Kirsten Weir
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, MD, DPhil, director of the University of Pennsylvania’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. The concept isn’t unheard of. During colonoscopy, for instance, a gastroenterologist looks for adenomatous polyps that could go on to become colorectal tumors — and snips them out before they can go rogue. That form of mechanical interception saves lives. Now, genetic and molecular tools are opening the door to new methods of interception, for a range of cancer types.
“Interception is not prevention per se, and it’s not therapy. It’s truly taking the football out of the quarterback’s hands,” Vonderheide explains. “If we can do this successfully, it will be a whole new space to impact the burden of cancer.”
A New Cancer Interception Institute for BRCA
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. “There’s a whole host of technology that is allowing us to find these needles in the haystack,” he says.
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, MD, 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.”
The Basser Center for BRCA and Its New Focus to Intercept Cancer
The Basser Center was established in 2012 with support from Penn alumni Mindy and Jon Gray in honor of Mindy’s sister Faith Basser, who died of BRCA-related ovarian cancer at age 44. The center has been a world leader in BRCA research. Now, Domchek and her colleagues are taking aim at interception. In late 2022, the Grays announced a $55 million gift to launch the new Cancer Interception Institute at the Basser Center. The Grays’ total commitment to Penn over the last decade has now surpassed $125 million, including their transformative $25 million gift that established the Basser Center in 2012.
Domchek and her colleagues are launching many initiatives for the new Institute. For example, she is leading 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. If the approach is successful, it could open the door for intercepting the various cancers associated with BRCA mutations.
Other Basser Center scientists have set their sights on basic research questions that could lead to new avenues to intercept cancer. “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.”
One scientist working toward that goal is Katherine Nathanson, MD, the Pearl Basser Professor for BRCA-Related Research and deputy director of the Abramson Cancer Center. With support from the Gray Foundation, Nathanson 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.
In an initial collaborative study, they’ve discovered a subset of cells, known as basal-luminal cells, that accumulate with age and appear to display early genetic changes that may be associated with some cancers. Now they’re expanding on that work to further determine how factors such as menopausal status or the presence of BRCA mutations might influence those changes. “These are targets for future research,” Nathanson says. “We’re focusing on high-risk individuals to understand what’s happening that may be helpful for preventing disease.”
The Role of Early Cancer Detection in Cancer Interception
Realizing the full potential of cancer interception will also rely on advancing the science of early cancer detection — and then continuing to look farther to the left on the metaphorical line on the chalkboard.
That’s the goal of an ongoing study by Penn Medicine researchers Erica Carpenter, MBA, PhD, director of the Liquid Biopsy Laboratory at the Abramson Cancer Center, and Bryson Katona, MD, PhD, director of the Gastrointestinal Cancer Genetics and Gastrointestinal Cancer Risk Evaluation Programs. They are collaborating 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.
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.”
Halting Cancer In Its Tracks: Interception in Action at Penn
Elsewhere at Penn, interception efforts are already reaching patients. Nathanson, who is developing the pre-cancer atlas for BRCA mutations, has also helped to develop an approach to intercept cancer in patients with von Hippel-Lindau (vHL) disease. The inherited disorder causes tumors and cysts throughout the body. Penn patients participated in a trial, led by Vivek Narayan, MD, MSCE, an assistant professor of Hematology-Oncology, that led to FDA approval of belzutifan, which inhibits the development of several VHL-associated tumors including renal cell carcinomas and pancreatic neuroendocrine tumors.
Previously, surgery was the only way to treat patients with vHL. Now, they have a new tool to keep tumors at bay. “I have a patient whose mother died from this disease. Now I can treat him in a way we were never able to treat his mother,” says Nathanson, who leads the vHL Comprehensive Care Center. “It’s a game changer for many of these patients.”
Meanwhile, Katona is teaming up with Maayan Levy, PhD, an assistant professor of Microbiology, to study interception in patients with Lynch syndrome. The inherited disorder increases the risk of many cancer types, especially colorectal cancers. Yet even when people have this genetic predisposition, the age of onset and rate of cancer progression varies widely, Levy says. “We now understand that there’s a strong environmental contribution to developing colorectal cancer,” she adds. “There’s an urgent need to understand how we can modify those [environmental] factors to reduce disease.”
In a study published in Nature in 2022, Levy and her team compared different diets in mouse models of colorectal cancer. They found mice who ate a ketogenic diet, rich in fat but low in carbohydrates, were strikingly resistant to developing colorectal tumors. Investigating further, they zeroed in on beta-hydroxybutyrate (BHB), a molecule produced in the liver in response to ketogenic diets. BHB, they found, suppressed tumors by slowing the proliferation of epithelial cells in the colon. When Levy administered BHB to mice, they developed fewer colorectal tumors — even without the keto diet. What’s more, any preexisting tumors appeared to stop growing.
It was an exciting finding, not only because BHB appeared to intercept colorectal cancer so well, but also because the compound is widely available as a diet supplement. Just a few short months after the mouse study was published, Levy and Katona launched a trial supported by the Abramson Cancer Center, still ongoing, to test BHB in people with Lynch syndrome. Participants drink the supplement over four weeks. During routine colonoscopies before and after the intervention, the researchers are collecting intestinal biopsies to see whether the treatment reduces cellular proliferation in the colon.
The four-week course of treatment highlights a unique and important feature of interception: These therapies may not need to be taken long term. Colonoscopy intercepts colon cancer by removing pre-cancerous polyps, effectively resetting the cancer clock. Pharmaceutical interception may work the same way. Vonderheide envisions drugs or vaccines that could be given for a few weeks or months to pick off precancerous cells. Because it takes time for the lesions to regrow, a person might not need a booster dose again for several years. “That decreases drug exposure and minimizes toxicity,” he says. “You may be scot-free until it’s time to intercept again.”
Translational Science at Penn Medicine
Plenty of scientific puzzles remain to be solved before cancer interception becomes the norm. But as the field comes into its own, Penn Medicine is doing its part to answer those questions. The institution has all the pieces to push the field forward, says Levy, who moved her work on intercepting colorectal cancer from mouse models to human participants in a matter of months.
“I think if I worked at a different university, this might have stayed a basic research observation,” she says. Fortunately, Katona and his colleagues already had established relationships with Lynch syndrome patients, who come to Penn for regular cancer screenings. “The infrastructure we have here allowed us to move so quickly,” Levy adds.
Similar possibilities exist for other hereditary disorders, including patients with BRCA1 and BRCA2 mutations. “We have a strong hereditary disease program at Penn, and our ability to link [new therapies] into that program is almost unparalleled. We’re amazing at translation,” Nathanson says.
At the new Basser Cancer Interception Institute, and across Penn’s labs and clinical spaces, researchers are beginning to realize the potential of interception. “Cancer interception is really a new pillar of cancer treatment,” Levy says. “This is not impossible. We have the tools to do it, and we need to be putting in all the effort to make it work.”
This story will be published in the Spring 2023 issue of Penn Medicine magazine and is available early online.