Developing New Tools to Fight Cancer

For decades, medical cancer treatment has generally meant chemotherapy, radiation, or surgery, alone or in combination. But things are changing rapidly. Today, new approaches such as immunotherapies and targeted therapies are becoming available, with many more in research and development. In many cases, the new treatments are more effective, with fewer side effects.

"It's an exciting time to be in cancer research and cancer discovery," said Colin Duckett, PhD, professor of pathology, interim chair of the Department of Pharmacology and Cancer Biology, and vice dean for basic science."

"We’re moving into this era where we have a new set of tools we can use to treat cancer."-Colin Duckett, PhD

Researchers in the Duke Cancer Institute (DCI) and across the School of Medicine are helping to create these new tools, fueled by the knowledge and experience of experts from a wide range of disciplines.

Indeed, cancer research has always been a team-based endeavor at DCI.

"DCI was specifically created a decade ago to break down barriers between disciplines to stimulate collaborative research and multidisciplinary interaction," said DCI Executive Director Michael Kastan, MD, PhD, the William and Jane Shingleton Distinguished Professor of Pharmacology and Cancer Biology.

Adding fuel to the fire is the Duke Science and Technology (DST) initiative, which aims to catalyze and support collaborative research in service of solving some of the world's most pressing problems, including cancer.

The new tools, though varied, all represent advances in personalized cancer medicine. Targeted treatments are chosen based on the genetic signature of a patient's tumor. Some immunotherapies take personalization even further, by manipulating a patient's own immune cells to create a treatment for that individual alone.

To match treatments to patients, the multidisciplinary Duke Molecular Tumor Board, led by John Strickler, MD, HS’11, and Matthew McKinney, MD’06, HS’06-’09, HS’10-’13, helps providers identify best practices, newly approved treatments, or clinical trials for advanced cancer patients based on genetic sequencing of their tumors.

"In precision cancer medicine — the right therapy for the right patient at the right time — all these things come together, the targeted therapies, the immunotherapy, even standard chemotherapy, all of that is part of precision cancer medicine."-Michael Kastan, MD, PhD

Immunotherapy aims to harness the power of the immune system to fight cancer. That can mean activating the immune system, energizing exhausted immune cells, or helping immune cells find cancer cells by guiding them there or by removing cancer's "good guy" disguises.

Duke's Center for Cancer Immunotherapy supports these efforts by identifying promising basic science discoveries and building teams to translate those ideas into treatments.

"There are so many world-class basic research scientists here making discoveries..."-Scott Antonia, MD, PhD

"...discoveries that are potentially translatable as immunotherapeutic strategies," said Scott Antonia, MD, PhD, professor of medicine and the center's founding director. "That's what motivated me to come to Duke, because of the great opportunity to interact with basic scientists to develop new immunotherapeutics and get them into the clinic."

Antonia believes immunotherapy has the potential to revolutionize cancer treatment, but more work remains to be done to realize its promise. "The proof of principle is there," he said, "but still only a relatively small fraction of people enjoy long-term survival. If we can hone immunotherapeutic approaches, that's our best opportunity."

Among the most exciting immunotherapy work being facilitated by the center involves removing a patient's own T cells (a type of lymphocyte), manipulating them in the lab to make them more effective against tumors, then injecting them back into the patient.

T cells can be manipulated in the lab in a number of different ways. In one approach, called CAR T-cell therapy, the T cells are engineered with an addition of synthetic antibody fragments that bind to the patient's tumor, effectively directing the T cells directly to the tumor cells.

In another approach, called tumor-infiltrating lymphocyte (TIL) adoptive cell therapy, the subset of a patient's T cells that have already managed to find their way into the tumor are extracted and then grown to large numbers before being returned to the patient. Antonia and his colleagues recently published a paper demonstrating the effectiveness of TIL expansion in lung cancer. "We’re now doing the preparative work to develop clinical trials using this approach in brain tumors, and our intention is to expand into many other cancers as well," he said.

Antonia points out that innovations in CAR T-cell therapy and TIL therapy happening at Duke are possible because of collaborations with scientists in an array of disciplines, including antibody experts like Barton Haynes, MD, HS’73-’75, the Frederic M. Hanes Professor of Medicine, and Wilton Williams, PhD, associate professor of medicine and surgery, at the Duke Human Vaccine Institute, and biomedical engineers like Charles Gersbach, PhD, the John W. Strohbehn Distinguished Professor of Biomedical Engineering at the Pratt School of Engineering.

Furthermore, clinical trials for these kinds of cellular therapies require special facilities to engineer or expand the cells, which are provided by Duke's Marcus Center for Cellular Cures, led by Joanne Kurtzberg, MD, the Jerome S. Harris Distinguished Professor of Pediatrics, and Beth Shaz, MD, MBA, professor of pathology." It's been a very productive collaboration highlighting how Duke is uniquely positioned to develop immunotherapeutic strategies," Antonia said.

Targeted therapies exploit a tumor's weak spot: a genetic mutation, for example. The benefit is that the treatment kills only cancer cells and not healthy cells. The prerequisite is knowing the genetics and biology of the specific tumor, no simple task.

Trudy Oliver, PhD’05, who joined the Department of Pharmacology and Cancer Biology faculty as a Duke Science and Technology Scholar, studies cancer development and the biology of tumor subtypes, particularly squamous cell lung cancer and small cell lung cancer.

"Even within small cell lung cancer, there are subsets that behave differently from each other," she said. Some of the treatments she's identified are in clinical trials

"Our work suggests that when you tailor therapy to those subsets, you can make a difference in outcome."-Trudy Oliver, PhD'05

Some of the treatments she's identified are in clinical trials.

Sandeep Dave, MD, Wellcome Distinguished Professor of Medicine, is leading an ambitious project to analyze the genomics of the more than 100 different types of blood cancer. His project will streamline the diagnosis of blood cancer and uncover potential therapy targets.

"All cancers arise from genetic alterations that allow cancer to survive and thrive at the expense of the host," he said. "These genetic alterations are a double-edged sword —they allow these cancer cells to grow, but on the other hand they do confer specific vulnerabilities that we can potentially exploit."

Dave said his background in computer science, genetics, and oncology helped him as he designed the project, which uses huge datasets.

"We’ve done the heavy lifting in terms of tool development and methodology, which is ripe to be applied to every other type of cancer."-Sandeep Dave, MD

Cancer disparities are caused by a complex interplay of elements, including access to health care and other resources, institutional barriers, structural racism, and biology, such as ancestry-related genetics. For example, some genetic biological factors and social elements contribute to disparities in many types of cancer.

"Cancer treatment is approaching this personalized space where patients are no longer treated with a one-size-fits-all paradigm."-Tammara Watts, MD, PhD

"It's becoming increasingly apparent that there are differences in outcome with respect to race and ethnicity," said Tammara Watts, MD, PhD, associate professor of head and neck surgery & communication sciences, and associate director of equity, diversity, and inclusion at DCI. "The very broad hypothesis is that there are genetic ancestry-related changes that may play a critical role in the disparate clinical outcomes we see every day in our cancer patients."

For example, self-identified white patients with throat cancer associated with the human papilloma virus (HPV) have better outcomes compared to self-identified Black patients, even when controlling for elements such as health care access, education, and socioeconomic status.

Watts is collaborating with bioinformatics experts at DCI to try to identify significant differences in gene expression among the two groups.

"I’m trying to tease out differences that may be impactful for disadvantaged patients based on race and ethnicity," she said. "But there could be differences that emerge that could be useful for designing targeted treatments for a broad group of patients."

That's because a targeted treatment for a particular genetic expression that might occur more commonly in Black people would help all patients with that expression, regardless of race or ethnicity.

Watts is far from alone in doing cancer disparity research at DCI. Tomi Akinyemiju, PhD, associate professor in population health sciences, uses epidemiology to study both biological factors and social elements that contribute to disparities in many types of cancer.

Jennifer Freedman, PhD, associate professor of medicine, Daniel George, MD’92, professor of medicine, and Steven Patierno, PhD, professor of medicine and deputy director of DCI, are studying the molecular basis for why prostate, breast, and lung cancer tend to be more aggressive and lethal in patients who self-identify as Black. Patierno, who has been a national leader in cancer disparities research for more than 20 years, leads the Duke Cancer Disparities SPORE (Specialized Program of Research Excellence), funded by the National Cancer Institute. The SPORE grant supports these researchers as well as other DCI teams working on cancers of the breast, lung, stomach, and head and neck.

"One of the things that impresses me is that [cancer disparities research] is a high priority within DCI," said Watts, who joined the faculty in 2019. "These groups are actively engaged and collaborating and asking the questions that will drive change for patients who have worse outcomes that are related to ancestry."

Even better than a cancer cure is avoiding cancer altogether.

At DCI, Meira Epplein, PhD, associate professor in population health sciences, and Katherine Garman, MD’02, MHS’02, HS’02-’06, HS’09, associate professor of medicine, are looking to decrease the incidence of stomach cancer by improving detection and treatment of the bacteria Helicobacter pylori, which can set off a cascade leading to stomach cancer. Epplein and Garman, also funded by the Duke Cancer Disparities SPORE grant, hope their work will reduce disparities because H. pylori infections and stomach cancer are both more prevalent among African Americans than whites.

When preventing cancer isn't successful, the next best thing is to detect and treat early. A relatively new concept in cancer care is "interception," which means catching cancer just as, or even just before, it begins.

"The point is to prevent it from progressing to full blown malignancy," said Patierno. "In other words, stop the cancer from getting over its own goal line."

Patierno envisions a future where patients with pre-cancerous conditions or early cancer could take a pill to halt cancer development without killing cells —in other words, a non-cytotoxic treatment, unlike standard chemotherapy.

"We know it's there, but we’re not going to poison it or burn it or cut it out because all of those have side effects. We’re going to find a non-cytotoxic way to prevent it from progressing. That's the goal."-Steven Patierno, PhD

Read About Alumni Making a Differencein Cancer Research and Care:

Changing the Status Quo: Lori Pierce MD'85

Treating the Whole Person: Arif Kamal, MD, HS’12, MHS’15

Targeting the Seeds of Cancer Growth: Eugenie S. Kleinerman, MD’75, HS’75

A Discovery That Comes Out of Nowhere: Bill Kaelin, BS’79, MD’82

Story originally published in DukeMed Alumni News, Fall 2022.

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