FGFR Inhibition: A Novel Therapeutic Strategy - Episode 1

Overview of Fibroblast Growth Factor

June 21, 2019

Richard Kim, MD:Welcome to thisTargetedOncologypresentation in precision medicine called “FGFR Inhibition: A Novel Therapeutic Strategy.” I am Dr Richard Kim, a medical oncologist at Moffitt Cancer Center in Tampa, Florida.

Targeted therapies have really come to the forefront of treatment of cancer. Today we are going to talk about an important emerging therapeutic class that has shown great promise among several advanced malignancies called FGFR [fibroblast growth factor receptor] inhibitors. These agents represent a paradigm-changing advance in precision oncology and drug development for FGFR mutation-driven cancers. I am here with my colleague Dr Rachna Shroff, a medical oncologist at the University of Arizona Cancer Center, Tucson, Arizona. Welcome Dr Shroff.

Rachna Shroff, MD, MS:Thank you.

Richard Kim, MD:Dr Shroff and I will be talking about cholangiocarcinoma. Later on, Dr Sumanta Pal will talk about FGFR inhibitors in bladder cancer. Let’s get started.

So before we delve into the role of FGF and FGFR in tumor or in cholangiocarcinoma, can you describe to us what role it plays in normal cell regulation?

Rachna Shroff, MD, MS:Absolutely. The fibroblast growth factor receptor pathway is a very complex signaling cascade that involves multiple downstream kinases to get activated through phosphorylation with attachment of the FGF ligand to the receptor. And what we know is that in normal functioning cells this plays an important role in cellular proliferation and differentiation. There’s actually a role in early stage embryonic differentiation, and then there’s a huge interplay between other angiogenic pathways. So FGFR interacts with the VEGF pathway, as well as a number of other angiogenic pathways to help with growth and promotion of angiogenesis.

Sumanta Pal, MD:Fibroblast growth factor receptor plays a pretty important role across a number of different disease types in oncology. I would say the principal role in bladder cancer is in the pathogenesis and progression of the disease. We actually see different levels of fibroblast growth factor across different stages, and there seems to be some downward migration in the rate of mutations and alterations as you go from localized to advanced bladder cancer.

So the fibroblast growth factor receptor actually works downstream through PI3K/Akt signaling, through the MAP kinase pathway, and a number of other elements to trigger cancer progression.

When it comes to bladder cancer, it seems as thoughFGFR3plays a particularly important role. We see a relatively high rate of mutations and fusions. I’ve done quite a bit of work with Foundation Medicine. And through my work with them, we actually published one of the largest series in advanced bladder cancer to date, around 300 patients. We identified that about 20% of patients have mutations inFGFR3. Mutations, fusions, both of these seem to trigger the same downstream cascades. One thing I will point out is upper tract bladder cancer, which is a particularly aggressive subtype, seems to harbor a much higher rate of alteration, something in the ballpark of 50% to 70%.

Richard Kim, MD:Currently there are 4 receptors that have been identified. So in your opinion, are they all equally important in terms of the treatment of the cancer?

Rachna Shroff, MD, MS:There’s been a number of studies looking at the role ofFGFR1,2,3, and4. And what’s interesting is that these different receptors are differentially important in various cancers. So when we talk about specific GI [gastrointestinal] malignancies,FGFR2seems to play an important role.FGFR3plays a role in urothelial malignancies. And so I think they all play an important role with disruption of that cascade leading to promotion of carcinogenesis, but I don’t necessarily think it’s the same receptor for every cancer.

Richard Kim, MD:So theFGFRaberration also differs depending on the types of tumor you have. The most commonFGFRaberrations that we see are probably amplification, mutation, and the third is probably fusion, or a translocation. Those are the most common. So in cholangiocarcinoma we know that the fusion occurs maybe 15% to about 20% of the time. Also in other tumors, can you tell us a little bit about the incidence of theFGFRaberrations that we see in types of tumors other than cholangiocarcinoma?

Rachna Shroff, MD, MS:Yes. The amplification, for instance, in things like gastric cancer or upper GI malignancies we seeFGFRamplification, as you mentioned. And those are actually more rare events. We see them anywhere from about 10% or so of gastric cancer. It’s a rare event in pancreatic cancer for instance. But the fusions,FGFRfusions in cholangiocarcinoma, we see them in, like I mentioned, urothelial cancer, those all seem to be around the range of 15% to 20%.

Richard Kim, MD:And the role ofFGFR4amplification, there’s some data, at least in ACC [adenoid cystic carcinoma], that overexpression ofFGFR4plays a role, but not much in cholangiocarcinoma.

Transcript edited for clarity.