How Does Antiangiogenic Therapy Work?

Transcript:Mark A. Socinski, MD: Walk us through your understanding of how these agents work. You know we talk about vessel normalization; we talk about intratumoral pressures, and those sorts of things. Give us your understanding of how, what the mechanism of action is for these anti-angiogenic drugs.

Manish A. Shah, MD: Sure, and thank you for saying that this is my opinion, because I know exactly how it works. But I think that you mentioned some of them. Rakesh Jain’s theory on vessel normalization and then increasing the ability to deliver chemotherapy was very compelling. He had these very nice mouse models looking at the tumor growth within a year and showing how the interstitial pressures are messed up in a tumor. And then with an antiangiogenic therapy, you kind of get normalization and some larger blood vessels that then allow for better blood flow, of better delivery of potentially the chemotherapy.

Mark A. Socinski, MD: Or T-cells.

Manish A. Shah, MD: Or the T-cells, exactly. I think that that’s one mechanism. I think how it augments chemotherapy is probably the most likely way. These are mouse models for that, as well, where you actually can show in tissue biopsies that you have higher amounts of chemotherapy after antiangiogenic therapy. But I think that with the other mechanisms, in terms of you’re primarily blocking the new angiogenesis, there’s still lots to be learned about how that would work.

Mark A. Socinski, MD: Yes, I’ve always said sometimes our colleagues are very good at dissecting the pathway, understanding the way, and, therapeutically, sometimes it takes a while to target these sorts of things. We understood there were a number of ligands, there are three known receptors. And the strategy we’ve taken clinically is either the monoclonal antibody approach or the TKI approach. I wonder if you could walk us through these two different approaches.

Yelena Y. Janjigian, MD: Sure. So, as you alluded to, VEGF receptors—the transmembrane receptor—cross-span the cell wall. And there’s an outside portion, just like with many other receptor tyrosine kinases, and the inside portion. The monoclonal antibody was a form of different ways of trapping the VEGF receptor, such as VEGF-Trap, or monoclonal antibodies, such as bevacizumab and ramucirumab. It really helps for the folks out there. You know, when I talk to my non-oncology colleagues and friends, it focuses the discussion. So, for anyone googling monoclonal antibodies out there, this is for them, not for the experts.

Edward Garon, MD: It’s nice to be able to explain to people that it’s not magic.

Yelena Y. Janjigian, MD: Right. So, you’re looking at binding the receptor inhibiting the pathway outside of the cells for monoclonal antibodies.

Mark A. Socinski, MD: Right, but also ligand binding.

Yelena Y. Janjigian, MD: And the ligand binding, which is bevacizumab, which is VEGF-A. So, a ligand is a portion of the excretory molecule that activates the receptor, and you can sort of trap the ligand in the way that bevacizumab does. What tyrosine kinase inhibitors do—and as Johanna was mentioning it—there’s a lot more off-target effect, because they’re what we call dirty TKIs, tyrosine kinase inhibitors. So, they can inhibit, in addition to VEGF, other possibly important pathways such as PDGF (placental-derived growth factor), FGFR (fibroblast growth factor receptors), and so on. And then you get all the potential benefits of these pathways. Because you know they also play an important role in the growth of solid tumors, but also the off-target effects, such as LFT (liver function test) abnormalities and so on.

Mark A. Socinski, MD: Your opinion would be getting back to the antibodies in terms of, you know we have an antibody that targets the ligand and an antibody that targets the receptor. Is one better than the other?

Yelena Y. Janjigian, MD: Well, it’s interesting. In science and medicine, a lot of predictions can be made about which antibody, which receptor, will be more important. But the truth is, clinical data and the end speaks of itself. So, we can over-rationalize things, but a lot of the important discoveries are made actually in retrospect. You see the drug works and then you go back and try to identify why it works, similarly to erlotinib in EGFR mutations. I would say if you asked me 10 years ago, I would have not really been able to tell you which way is the better way to target VEGF, because it makes sense. Why not trap the ligand and prevent it from activating the receptor? This way, you get it before it even gets to the receptor, and maybe it’s a more complete and early point to inhibit the pathway. But now the data, at least in gastrics, adjusts the…There’s something different about targeting the receptor itself though, or the VEGF-R2. And ultimately, the clinical data is stronger for targeting the actual receptor as opposed to the ligand.

Mark A. Socinski, MD: Right. So, we know that although VEGF—and its various isoforms—are the major ligands, there are other proangiogenic ligands that can bind, which obviously bevacizumab would not necessarily inhibit.

Yelena Y. Janjigian, MD: Right.

Mark A. Socinski, MD: Yes. So, your point, it’s kind of bench to bedside, and then back from bedside to bench.

Yelena Y. Janjigian, MD: It has to cross-talk.

Transcript Edited for Clarity

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