Angiogenesis in Tumor Growth and Metastasis

Transcript:Mark A. Socinski, MD: Hello. Thank you for joining this OncLive Peer Exchange titled, “New Concepts Surrounding the Role of Anti-Angiogenic Therapy in Lung and Gastrointestinal Cancers.” As we are well aware, tumor growth and metastases are complex processes that involve not only transformed cells themselves, but also signaling from a dysfunctional microenvironment. Therapeutic targeting of abnormal cell proliferation and genetic instability is only part of the story. Today I am joined by a panel of experts in oncology, and we’ll be talking about one of the hallmarks of cancer, angiogenesis. We’ll discuss the success we’ve had to date in targeting vessel normalization with anti-angiogenic therapies, as well as an emerging understanding of the potential to perhaps enhance activity of the immune system using this strategy.

My name is Dr. Mark Socinski, and I am a professor of medicine and thoracic surgery and the director of the Lung Cancer Section, Division of Hematology/Oncology at the University of Pittsburgh. Participating today on our distinguished panel is Dr. Johanna Bendell, director of the GI Oncology Research Program and associate director of the Drug Development Unit at Sarah Cannon Research Institute, Dr. Edward Garon, an associate professor and director of Thoracic Oncology at the Jonsson Comprehensive Center at UCLA, Dr. Roy Herbst, an ensign professor of medicine and chief of medical oncology at Smilow Cancer Hospital of Yale Comprehensive Cancer Center, Yale School of Medicine, Dr. Yelena Janjigian, an assistant attending physician for the Gastrointestinal Oncology Service at Memorial Sloan Kettering Cancer Center, and lastly, Dr. Manish Shah, the director of the Gastrointestinal Oncology Program for the Weill Cornell Solid Tumor Oncology Practice Division of Hematology & Medical Oncology at Weill Cornell Medical College. Thank you for joining us, let’s begin.

So, I’m going to start just by getting kind of a global overview of the evidence for the role of inhibiting angiogenesis in a number of different tumor types. And I’ll start with Dr. Bendell, if you could give us your overview, and in colorectal cancer where anti-angiogenic therapy fits in.

Johanna Bendell, MD: Absolutely. So, we know when tumors are starting to grow— when they get larger than about 2 to 3 mm—they need to have their own blood supply, for oxygen delivery, nutrient delivery, and taking away waste products. And so what happens is that there’s an angiogenic switch, which is a very old concept, where those tumor cells start to trigger within their microenvironment the growth of tumor related blood vessels. And usually this is by increasing levels of VEGF, vascular endothelial growth factor, and when they start to do this—and there’s several other components to the angiogenic pathway—the blood vessels start to grow in. And when that happens and the tumor is able to continue to grow, the cells are able to multiply and actually form a standing solid tumor.

Mark A. Socinski, MD: So, is it fair to say that when you’re targeting anti-angiogenic pathways, you’re really targeting genetically normal cells and genetically stable cells?

Johanna Bendell, MD: Not necessarily. So, yes and no. You have abnormal endothelial cells that grow into the tumor that express VEGF, you have the tumor cells as well. And so you can target both normal and abnormal. When you’re targeting VEGF, yes, we are targeting part of the normal blood vasculature in the body itself. But, specifically, where those levels are really upregulated are in the tumor itself. So, it’s meant to go to the tumor and affect the tumor more than the regular body.

Mark A. Socinski, MD: And in gastric cancer there’s obviously a role for anti-angiogeneis. Your comments about where this fits in in the pathogenesis?

Yelena Y. Janjigian, MD: Sure. Well, to build on Johanna’s comments, which I absolutely agree with, I would add that inhibition of VEGF has both an on-target and off-target effect. Obviously, the most common and known on-target or off-target effect is hypertension. And trials have shown that, particularly, patients who develop high blood pressure while on these agents tend to benefit more from the treatment with these agents. And so we’re targeting the tumor microenvironment. Or the way that I explain it to my patients is that basically the blood supply and what is involved around the tumor is targeted. And particularly in solid tumor malignancies and in gastric cancer— which is my area of expertise and research—the data have been very strong. VEGF and with the growth of the blood vessels in the microenvironment are very important. Bevacizumab is one of the monoclonal antibodies that was studied. But really the drug that’s validated our findings—both in preclinical and clinical observations, that VEGF was an important target in gastric cancer—is ramucirumab. Although some of the data have always pointed toward importance of that pathway, ramucirumab in two large phase III studies really validated our suspicions and our observations.

Mark A. Socinski, MD: So, Eddie, from a lung cancer perspective, your thoughts.

Edward Garon, MD: Sure. So, anti-angiogenesis has been a validated approach in lung cancer now for several years. And this was originally shown as part of the E4599 study, in which standard chemotherapeutics—carboplatin and paclitaxel—were evaluated alone or with bevacizumab, and that led to an improvement in overall survival. And because of that, anti-angiogenesis with bevacizumab has been an established part of lung cancer care now for several years. And more recently, there are data indicating that in a previously treated population, ramucirumab is also associated with the prolongation in survival. That approval was based on a study that showed that when ramucirumab was added to docetaxel, the survival was improved over docetaxel alone. And so in lung cancer now, both in the front-line setting and in previously treated patients, there are FDA-approved options here in the United States for this mechanism.

Mark A. Socinski, MD: So, understanding the mechanism of angiogenesis really creates a common platform across many solid tumors. We talked about colorectal, gastric, and lung. But we know in GBM there’s a role for anti-angiogenic therapy, renal cancers, and other cancers. This is really a platform that should be common amongst all solid tumors.

Transcript Edited for Clarity