Making Strides in the Management of Pancreatic Cancer

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The Special Conference on Pancreatic Cancer, sponsored by the American Association for Cancer Research (AACR) and held virtually this year, showcased cutting-edge discoveries and promising advances in the understanding and treatment of pancreatic cancer, reported by some of the world’s foremost scientists in this malignancy. The ASCO Post editorial advisory board member and Conference Co-Chair, Elizabeth M. Jaffee, MD, talked to us about the importance of this meeting and some of its takeaways. Dr. Jaffee is the Dana and Albert “Cubby” Broccoli Professor of Oncology and Co-Director of the Gastrointestinal Cancers Program at Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore.

Elizabeth M. Jaffee, MD

Elizabeth M. Jaffee, MD

Conference Numbers Continue to Increase

The 2019 in-person conference was the most successful special conference recently sponsored by the AACR, according to Dr. Jaffee, who noted the rapid growth of the annual meeting. “For the first national pancreatic cancer meeting more than 15 years ago, we couldn’t find 50 people who were doing research in pancreatic cancer. This past year, about 500 individuals attended in person,” she said. This created the kind of “momentum” the organizers sought to maintain.

“That’s why we decided to go virtual and not stop the momentum,” Dr. Jaffee continued. “We had great involvement from attendees all over the country and even the world.” This year’s numbers have not yet been calculated, she added, “but the enthusiasm and the energy were wonderful.”

For this, she credited the valuable contribution of young investigators, both as attendees and presenters. “One of our primary goals was to ensure we had as many young scientists on the podium as we could. All their presentations were fabulous. In fact, in some of the sessions, the audience was so interactive we could not get to all the questions…. A lot of these young researchers wanted to present, and they got to do so in two special sessions, in addition to a few being invited to present in plenary sessions.”

Of note, many of the concepts and research findings were novel. “The pancreatic community is so involved in trying to make a difference to patients that scientists are willing to present their unpublished data for the first time,” she said.

“We now have many new technologies that have allowed us to interrogate tumors and learn a lot about the biology of this cancer.”
— Elizabeth M. Jaffee, MD

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Growing Interest in Pancreatic Cancer

Research interests in pancreatic cancer are high and have been steadily growing over the past decade. One reason is the availability of the genetically engineered mouse model created by David Tuveson, MD, PhD, Director of the Cold Spring Harbor Laboratory. Dr. Tuveson delivered a keynote address titled, “Overcoming the Seven Deadly Hallmarks of Pancreatic Cancer.”

“Another reason for this high interest,” Dr. Jaffee noted, “is we now have many new technologies that have allowed us to interrogate tumors and learn a lot about the biology of this cancer.”

One important advance has been the genetic profiling of pancreatic tumors. Unlike many other malignancies, pancreatic cancer is not heavily molecularly driven but is initiated most often by one oncogene—mutated KRAS—which currently remains undruggable. Although researchers are trying to understand why KRAS is so critical in this malignancy, a strong push is also being made to elucidate the 10% or so of cases in which tumors are not associated with KRAS and to effectively treat those patients. By becoming able to subtype pancreatic cancer, clinicians can “separate out what is genetically driven and can be targeted,” Dr. Jaffee said.

A subset of this 10% harbors a mutation in BRCA, making these patients candidates for inhibitors of poly (ADP-ribose) polymerase; another smaller subset includes tumors marked by microsatellite instability, which may respond to immunotherapy. The hope is that other such subsets can be identified and eventually targeted.

Heterogeneity and Plasticity

Tumor heterogeneity and plasticity are other active research arenas, as reflected by a number of abstracts and lectures on these topics at the conference. Heterogeneity observed among patients regarding symptoms, clinical evolution, predisposition to early metastasis, and sensitivity to treatments is one of the major problems in treating pancreatic cancer. Heterogeneity can start with the first genetic mutations that give rise to the tumor and persist in various ways across disease stages. It is now appreciated that heterogeneity in this disease is not fully explained by genetic profiles, and researchers are shifting their focus to its other mechanisms.

“With new technologies, we have been able to interrogate tumors at the level of a single cell. This includes not only all of the cells within a pancreatic tumor, but also stroma, fibroblasts, inflammatory cells, and other cells that the tumor co-opts to help it grow and metastasize,” Dr. Jaffee said. “It’s not as if these cells are permanently programmed to be ‘protumor.’ You can actually reprogram them to be ‘anticancer.’”

“The Mix of Seed and Soil” was the title given by David Ting, MD, of Massachusetts General Hospital Cancer Center, to his discussion of the heterogeneity and plasticity of this tumor. Dr. Ting reviewed what information can be gained through the interrogation of single cells and how single cells, exerting different functions, are related spatially.

In other words, he and others in his field have gone beyond enumerating fibroblasts and genes into discovering which subtypes of cells are actually located next to the tumor and signaling to it. Better understanding of these spatial relationships can allow for manipulations—perhaps therapeutically—that might disrupt these signals and stop tumor growth, Dr. Jaffee explained.

In a related area, Samantha Tinsley, a doctoral candidate at Purdue University Center for Cancer Research, presented a paper on the role of PP2A-B56α in acinar-to-ductal metaplasia. This also is involved in the initiation of pancreatic cancer through a pathway that might be regulatable.

Dr. Jaffee also highlighted the Rising Star Keynote, “Role of the Gut-Tumor Microbial Axis in Pancreatic Ductal Adenocarcinoma” by Florencia McAllister, MD, of The University of Texas MD Anderson Cancer Center. Dr. McAllister discussed the ways the gut microbiome may influence the development of pancreatic cancer and how it responds to treatments. For instance, her team and others have shown that bacteria can live in the pancreas, which may have functional relevance in tumor initiation and in resistance to standard treatments.

The many exciting findings shared at the AACR Pancreatic Conference have shown the oncology field that we are making progress, Dr. Jaffee said. “We are chopping off little pieces of this disease…. The biology is ‘there,’ and we are harnessing it for new treatments.”

Watch for other presentations from this meeting and an interview with Dr. Tuveson in this and future issues of The ASCO Post.

DISCLOSURE: Dr. Jaffee holds stock or other ownership interests in ABMETA Therapeutics; has served as a consultant or advisor to Achilles Therapeutics, Adaptive Biotechnologies, Avidea Technologies, CStone Pharmaceuticals, Dragonfly Therapeutics, Genocea Biosciences, Incyte, and Medically Home Inc.; has received research funding from Aduro Biotech, Amgen, Avidea Technologies, Bristol Myers Squibb, Corvus Pharmaceuticals, and Roche Holding AG; holds intellectual property in GVAX; and has been reimbursed for travel, accommodations, or other expenses by Bristol Myers Squibb, Genocea Biosciences, Medically Home Inc, and MedImmune.