Research Insights From the AACR Special Conference on Pancreatic Cancer


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David Tuveson, MD, PhD

Christine Iacobuzio-Donahue, MD, PhD

The significance of these and other findings are yet to be determined, but they are examples of steps we are taking to understanding the complexity of [pancreatic ductal adenocarcinoma] and make inroads.

—Christine Iacobuzio-Donahue, MD, PhD

Pancreatic cancer still kills 40,000 Americans a year out of approximately 44,000 diagnosed. While advances in diagnosis and treatment are extending the lives of patients with other cancers, pancreatic ductal adenocarcinoma remains the second most lethal tumor (behind lung cancer).

While a magic bullet is not on the horizon, a very positive energy was felt at the American Association for Cancer Research (AACR) special conference, Pancreatic Cancer: Innovations in Research and Treatment. Close to 500 pancreatic cancer researchers from around the world gathered at the 3-day meeting in New Orleans to exchange insights, the highlights of which were described by three Conference leaders.

Novel Diagnostics

David Tuveson, MD, PhD, Director of Research for The Lustgarten Foundation, and the Roy J. Zuckerberg Professor of Cancer Research and Deputy Director of the Cancer Center at Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, focused on ways to diagnose and monitor pancreatic ductal adenocarcinoma.

Only about 10% of pancreatic cancers are diagnosed while the disease is still localized, leading to a dismal 1-year survival rate of less than 20%. The potential for early diagnosis via blood-based biomarkers now seems possible, Dr. Tuveson said.

One method has identified circulating tumor DNA in about 75% of patient with various solid tumors, including pancreatic ductal adenocarcinoma. In the case of tumors with KRAS mutations, which are common in pancreatic ductal adenocarcinoma, the sensitivity of circulating tumor DNA approached 90% and specificity exceeded 99%.1 Researchers at The University of Texas MD Anderson Cancer Center, Houston, are also working on a cancer-specific marker on cell fragments called exosomes that are present in the blood of pancreatic ductal adenocarcinoma patients.2 This also holds promise for the early, blood-based detection of cancer, according to Dr. Tuveson.

A third blood test combines the known pancreatic cancer biomarker CA19-9 with three other putative pancreatic cancer biomarkers.3 Approximately 90% of the time, the biomarker panel accurately distinguished individuals with pancreatic ductal adenocarcinoma from healthy controls, or persons with chronic pancreatitis or pancreatic cysts. Its negative predictive value was 98%.

Other researchers found a way to improve upon the current unsatisfactory use of positron-emission tomography (PET) in differentiating and staging pancreatic cancer by incorporating the CA19-9 antigen, which is elevated in the disease.4 The recombinant monoclonal antibody 5B1 potently binds an extracellular epitope on the CA19-9 protein, providing a platform for developing an immuno-PET agent for imaging of pancreatic ductal adenocarcinoma. The result has been exceptional PET images, Dr. Tuveson noted.

“The CA19-9 antibody test has not yet been tested in patients, but we are excited about that possibility,” he commented.

Dr. Tuveson also highlighted research regarding the alterations in systemic metabolism that are a defining feature of pancreatic ductal adenocarcinoma. This is an important area of investigation because the risk for pancreatic ductal adenocarcinoma is known to be increased among persons with chronic obesity, hyperglycemia, and hyperinsulinemia; weight loss and new-onset diabetes frequently develop in the 2 years prior to diagnosis; and cachexia and sarcopenia are often observed in these patients.

Researchers from Dana-Farber Cancer Institute, Boston, profiled circulating metabolites in prediagnostic plasma from approximately 1,500 pancreatic patients and matched controls. They found that 5 to 6 years before developing cancer, individuals ultimately diagnosed with pancreatic ductal adenocarcinoma had elevations in three particular branch chain amino acids.5 “This may give us an early warning sign for [pancreatic ductal adenocarcinoma],” Dr. Tuveson indicated.

Inflammation and Immunity

Alec Kimmelman, MD, PhD, Assistant Professor of Radiation Oncology at Harvard Medical School and the Dana-Farber Cancer Institute, Boston, highlighted inflammation and immunity as being of high interest at the meeting.

Researchers developed a state-of-the-art mouse model of diet-induced obesity and pancreatic cancer that resembles important clinical features of human obesity.6 Compared to control animals, the high-fat diet–fed animals showed signs of marked inflammation in and around the pancreas, with increased numbers of infiltrating inflammatory cells, infiltrating natural killer cells, myeloid-derived suppressor cells, regulatory T cells and tumor-infiltrating macrophages, along with a significant change in the pancreatic cytokine profile. Most importantly, the high-fat diet led to accelerated development of the cancer precursor, pancreatic intraepithelial neoplasia, he noted.

“This research is about the development of a system that allows us to understand whole-body metabolism, and the importance of obesity on the inflammatory response,” he said.

Dr. Kimmelman also emphasized the importance of the dense stromal tissue surrounding and infiltrating many pancreatic tumors, which impedes both imaging and drug delivery. Stellate cells are a component of the stroma, and they secrete factors that can reprogram tumor cells to express key genes that are important for tumor growth. These stellate cells express the vitamin D receptor, which acts as a master transcriptional regulator of the stellate cell. In vivo, a synthetic vitamin D receptor agonist induced remodeling of the tumor stroma, and this enhanced the antitumor effects of gemcitabine by increasing its concentration within the tumor, researchers reported here.7

Researchers from the United Kingdom have been attempting to decipher why pancreatic ductal adenocarcinoma does not respond to the T-cell checkpoint antagonists—anti–CTLA-4 and anti–PD-L1—and they have been able to attribute this largely to the chemokine CXCL12, which is secreted by a type of fibroblast in the tumor, as the mediator of immune suppression. They reported that CXCL12 protein selectively coats the cancer cells, and T cells are excluded from cells in the region where this occurs.8 Treatment of pancreatic ductal adenocarcinoma–bearing mice with the small-molecule CXCL12 receptor antagonist plerixafor (Mozobil), alone or together with anti–PD-L1, suppressed tumor growth, reduced tumor volume, and was associated with the presence of numerous T cells within the tumors.

“The tumor can elicit an immune response from the body, but there is a barrier for the T cell to get into the tumor because of this coating from CXCL12. Plerixafor can block the interaction of this secreted factor with the receptor, and in preclinical models can eradicate the tumor,” Dr. Kimmelman noted.

Disease Complexity

Christine Iacobuzio-Donahue, MD, PhD, Associate Director of Translational Research at the David M. Rubenstein Center for Pancreatic Research at Memorial Sloan Kettering Cancer Center, New York, was struck by new findings concerning the complexity and heterogeneity of pancreatic ductal adenocarcinoma.

“We learned at this meeting that pancreatic cancer is complex at a level that has not been appreciated before,” she said.

“We heard some very exciting but preliminary data about heterogeneity, specifically, that there are RNA and DNA differences within the same cell that can potentially impact on signaling and therapeutic pathways.9 We also heard about heterogeneity in terms of the types of cells in [pancreatic ductal adenocarcinoma],” Dr. Iacobuzio-Donahue said.

An emerging part of this story involves acinar cell transdifferentiation, which sets the stage for early tumor heterogeneity. This process involves tuft cells, which have stem cell–like properties and which were recently identified as being potential initiators of pancreatic intraepithelial neoplasia.10

At the conference, Dr. Iacobuzio-­Donahue discussed the genetic evolution of pancreatic ductal adenocarcinoma from the time of its inception to its dissemination to distant sites, including evidence for the role of the microenvironment as a selective force in clonal evolution.11 She alluded to new insights regarding pancreatic intraepithelial neoplasia—in particular, the timing and order of the known founder genetic alterations that drive progression.

She also cited evidence in support of distinct biologic subsets of pancreatic ductal adenocarcinoma and drew from whole-genome sequencing data to describe “the first estimation of the extent of heterogeneity among different metastases in the same distant organ.”

“The significance of these and other findings are yet to be determined, but they are examples of steps we are taking to understanding the complexity of [pancreatic ductal adenocarcinoma] and make inroads,” she added. ■

Disclosure: Dr. Tuveson is a consultant for Bethyl Laboratory, Pfizer, Millennium, and Celgene, and he has received licensing royalties from Novartis. Dr. Kimmelman is a consultant for Forma Therapeutics. Dr. Iacobuzio-Donahue reported no potential conflicts of interest.

References

1. Diaz LA: Circulating tumor DNA. AACR Special Conference on Pancreatic Cancer. Abstract IA12. Presented May 20, 2014.

2. Kalluri R: Diagnosis and treatment of pancreas cancer. Lecture. AACR Special Conference on Pancreatic Cancer. Presented May 20, 2014.

3. Taguchi A, Capello M, Zhao Y, et al: Development and validation of diagnostic biomarker model for detection of early stage pancreatic cancer. AACR Special Conference on Pancreatic Cancer. Abstract B20. Presented May 20, 2014.

4. Lewis JS: New methods of PET imaging pancreas cancer. AACR Special Conference on Pancreatic Cancer. Abstract IA16. Presented May 20, 2014. 

5. Wolpin BM: Pancreatic adenocarcinoma and altered whole-body metabolism. AACR Special Conference on Pancreatic Cancer. Abstract IA26. Presented May 21, 2014.

6. Eibl G: Obesity, inflammation, and pancreatic cancer. AACR Special Conference on Pancreatic Cancer. Abstract IA18. Presented May 20, 2014. 

7. Sherman MH, Ding N, Collisson EA, et al: Vitamin D: Shining light on pancreatic cancer. Abstract IA9. Presented May 19, 2014. 

8. Fearon DT: The basis of immune suppression in murine pancreatic ductal adenocarcinoma. AACR Special Conference on Pancreatic Cancer. Abstract IA21. Presented May 21, 2014.

9. Rhim A: Generation of intratumoral heterogeneity via RNA-DNA differences in pancreatic cancer. Lecture. AACR Special Conference on Pancreatic Cancer. Presented May 19, 2014.

10. Takeuchi KK, Delgiorno KE, Halbrook CJ, et al: Acinar cell transdifferentiation sets the stage for early tumor heterogeneity. AACR Special Conference on Pancreatic Cancer. Abstract IA13. Presented May 19, 2014. 

11. Iacobuzio-Donahue CA: Dynamics and evolution of pancreatic cancer from inception to invasive. AACR Special Conference on Pancreatic Cancer. Abstract IA1. Presented May 18, 2014.

 



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