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Biological Breakthroughs in Pancreas Cancer

Panelists: Johanna C. Bendell, MD, Sarah Cannon Research Institute; Winson Y. Cheung, MD, MPH, University of Calgary and CancerControl Alberta; Manuel Hidalgo, MD, PhD, Harvard Medical School and Beth Israel Deaconess Medical Center; Ramesh K. Ramanathan, MD, Mayo Clinic; Tanios Bekaii-Saab, MD, FACP, Mayo Clinic; Thomas Seufferlein, MD, University of Ulm
Published: Tuesday, Oct 10, 2017



Transcript: 

Johanna C. Bendell, MD: Hello. Thank you for joining this OncLive® Peer Exchange® titled “Viewpoints on Pancreatic Ductal Adenocarcinoma.”

Outcomes for patients with advanced pancreatic adenocarcinoma have recently begun to improve, owing to the refinement in the use of combination chemotherapy and new sequencing strategies for therapies. We are now entering an era where we are learning more about molecular differences and driving mechanisms among pancreatic cancers, with the hope of identifying personalized therapies for patient subsets. In this Peer Exchange® discussion, I am joined by a panel of international experts in the field of gastrointestinal oncology. Together, we will provide you with our perspective on recent advances and what they mean to the future of patient care.

I am Dr. Johanna Bendell, director of the GI Cancer Research Program and associate director of the Drug Development Program at the Sarah Cannon Research Institute in Nashville, Tennessee.

Participating, today, on our distinguished panel are Dr. Winson Cheung, a medical oncologist at the University of Calgary, associate professor of medicine in the Department of Oncology, and chair and provincial director of health services research for CancerControl Alberta; Dr. Manuel Hidalgo, professor of medicine at Harvard Medical School and chief of hematology/oncology at Beth Israel Deaconess Medical Center in Boston, Massachusetts; Dr. Ramesh Ramanathan, professor of medicine and director of the GI Medical Oncology Program, Division of Hematology/Oncology, at the Mayo Clinic in Phoenix, Arizona; Dr. Tanios Bekaii-Saab, professor of medicine and science, program leader of the GI Oncology Cancer Program, and senior associate consultant, at Mayo Clinic, Arizona; and Dr. Thomas Seufferlein, professor of medicine and chair of the Department of Internal Medicine, and member of the AIO executive board, as well as the AIO steering committee, for pancreatic cancer.

Thank you so much, everybody, for joining us. Let’s begin. We’re here in beautiful Madrid, at The European Society for Medical Oncology (ESMO) 2017 Congress. There are a lot of new data with a lot of promising things to come for patients with pancreas cancer. We’re looking so much, now, across cancers to the biology of disease and what drives these cancers to not only grow but sometimes be resistant to the therapies that we’re giving. Dr. Hidalgo [Manuel], you have done extensive research on the biology of pancreas cancer. Can you tell us a little bit more about pancreas cancer and this theory of the microenvironment being so important in the treatment of this disease?

Manuel Hidalgo, MD, PhD: Thank you, and good morning. It’s really a pleasure to be here this morning. The microenvironment has been noted, for many years, to be an important component in pancreas cancer. When we look at these tumors under the microscope, you see more stroma. The role of the stroma has been, and continues to be, elucidated over the past few years. I think we have transitioned through different phases. In one phase, we thought that the stroma was bad and was restraining the diffusion of chemotherapy to the tumor. There are strategies, that we’ll probably discuss later on, to eliminate the stroma to facilitate diffusion of chemotherapy.

Then, some of the papers have shown that the stroma may also have a protective effect in the sense that it is, to some extent, restraining or compromising the ability of the cancer to metastasize. So, if you eliminate it completely or too abruptly, those tumors, at the end, become even more aggressive. This may be the reason why some of the drugs that have been tested in that environment have failed.

What I think is new and is very interesting is, really, the interaction between the stroma and the epithelial component—at the oncogene signaling level—and how they crosstalk and, perhaps, more recently, at the metabolic and feeding effect, in the sense that the cancer is taking advantage of the stroma to secure nutrition (mainly proteins and other nutrients) to be able to grow. It’s really a fascinating biological aspect of the disease that I think would provide therapeutic targets for intervention.

Johanna C. Bendell, MD: It’s so interesting. When we are taught (in medical school) about treating cancers, you’re thinking about attacking the cancer cell. But we have to realize that we’re not only treating and attacking the cancer cell, but the surrounding stroma, the microenvironment, as well.

Ramesh, there have been some very interesting data that are starting to come out looking at KRAS mutations and how they might even affect signaling and stromal interaction. Can you tell us a little bit more about that?

Ramesh K. Ramanathan, MD: That’s correct. We know that pancreatic cancer depends on KRAS signaling. About 95% to 98% of pancreatic cancers have a KRAS mutation. And a recent paper, published in 2016, showed that pancreatic cancer cells can also interact with the stroma. These cells recruit fibroblasts in the stroma, which is activated and, in turn, can regulate the pancreatic cancer cell growth and apoptosis. So, it’s not just the tumor cell, but importantly, the stroma plays an active part in cancer cell growth.

Johanna C. Bendell, MD: It’s just more evidence that the interaction and the crosstalk is helping the cancer and protecting the cancer and letting it continue to be bad—more crosstalk, not only with the RAS mutation, but looking at other crosstalk that we’re seeing. Thomas, we’ve also seen recent data looking at alanine crosstalk?

Thomas Seufferlein, MD: Yes. This is, actually, fascinating. This is work dating back to when the late Dr. Max Bachem, from Ulm, suggested the discovery of pancreatic stellate cells. It’s a specialized form of myofibroblasts in the pancreas. There was, early on, a very interesting interaction between the stellate cells and the tumor, and there was a lot of work done suggesting that they stimulate the growth of each other—they secrete factors that actually produce stroma. But now (this is very interesting), there is a notion that stellate cells actually feed the tumor cells and provide, by secreting, actively secreting alanine to the tumor cells, which, otherwise, is maybe not available due to tumor hypoxia. So, it’s a symbiosis between the tumor cells and the stellate cells, and alanine seems to be a critical amino acid provided from one cell to the other to support tumor growth.

Transcript Edited for Clarity 

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Transcript: 

Johanna C. Bendell, MD: Hello. Thank you for joining this OncLive® Peer Exchange® titled “Viewpoints on Pancreatic Ductal Adenocarcinoma.”

Outcomes for patients with advanced pancreatic adenocarcinoma have recently begun to improve, owing to the refinement in the use of combination chemotherapy and new sequencing strategies for therapies. We are now entering an era where we are learning more about molecular differences and driving mechanisms among pancreatic cancers, with the hope of identifying personalized therapies for patient subsets. In this Peer Exchange® discussion, I am joined by a panel of international experts in the field of gastrointestinal oncology. Together, we will provide you with our perspective on recent advances and what they mean to the future of patient care.

I am Dr. Johanna Bendell, director of the GI Cancer Research Program and associate director of the Drug Development Program at the Sarah Cannon Research Institute in Nashville, Tennessee.

Participating, today, on our distinguished panel are Dr. Winson Cheung, a medical oncologist at the University of Calgary, associate professor of medicine in the Department of Oncology, and chair and provincial director of health services research for CancerControl Alberta; Dr. Manuel Hidalgo, professor of medicine at Harvard Medical School and chief of hematology/oncology at Beth Israel Deaconess Medical Center in Boston, Massachusetts; Dr. Ramesh Ramanathan, professor of medicine and director of the GI Medical Oncology Program, Division of Hematology/Oncology, at the Mayo Clinic in Phoenix, Arizona; Dr. Tanios Bekaii-Saab, professor of medicine and science, program leader of the GI Oncology Cancer Program, and senior associate consultant, at Mayo Clinic, Arizona; and Dr. Thomas Seufferlein, professor of medicine and chair of the Department of Internal Medicine, and member of the AIO executive board, as well as the AIO steering committee, for pancreatic cancer.

Thank you so much, everybody, for joining us. Let’s begin. We’re here in beautiful Madrid, at The European Society for Medical Oncology (ESMO) 2017 Congress. There are a lot of new data with a lot of promising things to come for patients with pancreas cancer. We’re looking so much, now, across cancers to the biology of disease and what drives these cancers to not only grow but sometimes be resistant to the therapies that we’re giving. Dr. Hidalgo [Manuel], you have done extensive research on the biology of pancreas cancer. Can you tell us a little bit more about pancreas cancer and this theory of the microenvironment being so important in the treatment of this disease?

Manuel Hidalgo, MD, PhD: Thank you, and good morning. It’s really a pleasure to be here this morning. The microenvironment has been noted, for many years, to be an important component in pancreas cancer. When we look at these tumors under the microscope, you see more stroma. The role of the stroma has been, and continues to be, elucidated over the past few years. I think we have transitioned through different phases. In one phase, we thought that the stroma was bad and was restraining the diffusion of chemotherapy to the tumor. There are strategies, that we’ll probably discuss later on, to eliminate the stroma to facilitate diffusion of chemotherapy.

Then, some of the papers have shown that the stroma may also have a protective effect in the sense that it is, to some extent, restraining or compromising the ability of the cancer to metastasize. So, if you eliminate it completely or too abruptly, those tumors, at the end, become even more aggressive. This may be the reason why some of the drugs that have been tested in that environment have failed.

What I think is new and is very interesting is, really, the interaction between the stroma and the epithelial component—at the oncogene signaling level—and how they crosstalk and, perhaps, more recently, at the metabolic and feeding effect, in the sense that the cancer is taking advantage of the stroma to secure nutrition (mainly proteins and other nutrients) to be able to grow. It’s really a fascinating biological aspect of the disease that I think would provide therapeutic targets for intervention.

Johanna C. Bendell, MD: It’s so interesting. When we are taught (in medical school) about treating cancers, you’re thinking about attacking the cancer cell. But we have to realize that we’re not only treating and attacking the cancer cell, but the surrounding stroma, the microenvironment, as well.

Ramesh, there have been some very interesting data that are starting to come out looking at KRAS mutations and how they might even affect signaling and stromal interaction. Can you tell us a little bit more about that?

Ramesh K. Ramanathan, MD: That’s correct. We know that pancreatic cancer depends on KRAS signaling. About 95% to 98% of pancreatic cancers have a KRAS mutation. And a recent paper, published in 2016, showed that pancreatic cancer cells can also interact with the stroma. These cells recruit fibroblasts in the stroma, which is activated and, in turn, can regulate the pancreatic cancer cell growth and apoptosis. So, it’s not just the tumor cell, but importantly, the stroma plays an active part in cancer cell growth.

Johanna C. Bendell, MD: It’s just more evidence that the interaction and the crosstalk is helping the cancer and protecting the cancer and letting it continue to be bad—more crosstalk, not only with the RAS mutation, but looking at other crosstalk that we’re seeing. Thomas, we’ve also seen recent data looking at alanine crosstalk?

Thomas Seufferlein, MD: Yes. This is, actually, fascinating. This is work dating back to when the late Dr. Max Bachem, from Ulm, suggested the discovery of pancreatic stellate cells. It’s a specialized form of myofibroblasts in the pancreas. There was, early on, a very interesting interaction between the stellate cells and the tumor, and there was a lot of work done suggesting that they stimulate the growth of each other—they secrete factors that actually produce stroma. But now (this is very interesting), there is a notion that stellate cells actually feed the tumor cells and provide, by secreting, actively secreting alanine to the tumor cells, which, otherwise, is maybe not available due to tumor hypoxia. So, it’s a symbiosis between the tumor cells and the stellate cells, and alanine seems to be a critical amino acid provided from one cell to the other to support tumor growth.

Transcript Edited for Clarity 
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