GRACE :: Lung Cancer

Fibroblast growth factor—the next molecular target in lung cancer?

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What is FGF?

FGF is a type of receptor tyrosine kinase. What, you might ask, is a receptor tyrosine kinase? Well, since you were so kind as to ask, and since I’m a bit of a nerd at heart, I’ll tell you. Receptor tyrosine kinases are a part of the machinery of a cell; they have a role in signaling to the rest of the cell what it should do.

rtks (click on image to enlarge)

You’ll notice on this family picture of receptor tyrosine kinases some familiar friends from our discussions here-EGFR most famously. We’re talking about FGF today because it is an up and coming target in lung cancer. While there’s a lot of work to be done before FGF-directed therapies are used in the clinic, there’s good reason to have some excitement based on the early work.

Before we move on to the in vitro (petri dish/lab) data, it’s worth defining what a fibroblast is. Fibroblasts are the cells that make the extracellular matrix and collagen. Extracellular matrix and collagen are the backbone structures that cells live in. Scientists believe that fibroblasts provide many important signals to cells, both cancerous and normal. Cancer research has recently expanded to target more than just the cancer cell-avastin works on tumor blood supply, zometa and denosumab work on bone, and anticoagulants prevent clots. Research on how the local environment surrounding a cancer affects its growth is one more important part of this kind of research.

FGF in Squamous Cell Carcinoma

Subtyping of adenocarcinoma into driving mutations has improved the care of many patients.

adenoca

We’ve talked about EGFR and EML4/ALK at length here and have spoken some as well about the others. This has left many patients with squamous cell lung cancer (SqCC) and small cell lung cancer (SCLC) (and those who care for them) asking the question, “What about us?”

Jonathan Weiss (no relation, although I do have a cousin by that name) and colleagues published a study last year that raised the possibility of a prominent role for FGFR in squamous cell lung cancer. First, they showed that the FGF receptor was commonly overexpressed in lung cancer, particularly in squamous cell lung cancer.

figure-1-fgf-weiss-jonathan-2 This first figure shows that FGF receptor amplification is particularly common in squamous cell lung cancer, a group that has long needed a molecular break. But does FGFR inhibition with a drug work against squamous cell carcinoma cells? The key point from Weiss’s 2010 paper from Lung Cancer is the upper left and lower right corners of the table in the next figure. The four cell lines with FGF receptor 1 (FGFR1) amplification are shown with red asterisk. The growth of three of these four lines was easily halted with low doses of an FGF receptor inhibitor, while 78 of 79 cell lines without FGF receptor amplification were unaffected by this same treatment.

fgfr1-and-sqcc-weiss

FGF in SCLC

Small cell lung cancer patients, like SqCC patients, also lack a molecular driven biologic therapy. This same drug was tried against SCLC lines, and it also worked.

pardo-figure-5

The black dots show the growth of placebo-treated cancer cells, while the white dots show the shrinkage of cells treated with an FGF inhibitor. The figure is from Olivier E. Pardo’s group from the UK in their 2009 Cancer Research paper.

FGF as EGFR-TKI resistance mechanism

We’ve talked a lot about EGFR mutation here on GRACE. While Tarceva (erlotinib) is a great drug for patients with EGFR mutation, I consider it a double, not a home run: progression-free survival, on average, is only a bit over a year for a patient with EGFR mutation. This has led to considerable research into mechanisms of resistance with the purpose of developing second line EGFR-directed therapies. While the data here is the least developed of all, indirect evidence indicates that FGF may be involves in resistance to EGFR directed agents, raising the hope that FGF inhibition could restore sensitivity.

ware

This figure above is from Kathyrn Ware and her group at the University of Colorado. In all experiments, the white has no FGF, grey has FGF2 (one subtype) and the black FGF7 (another subtype). On the far left is growth with no active drug. AG1478 inhibits EGF receptor, which, as you can see, inhibits lung cancer cell growth (as it does in human lung cancer with iressa and tarceva). RO is an FGF inhibitor, which does not inhibit the growth of the cells much when given alone. However, when you add on both the EGFR inhibitor and the FGF inhibitor, you get much more inhibition than with either alone (far right).

FGF inhibition in humans

Unfortunately, this is going to be a short section. That’s not because this isn’t a promising target. Rather, it’s because we’re reporting on FGF on GRACE at an early stage of the research. Some of these agents have a dose from phase I testing, and a phase II study is even being planned to open this year. These include:

AZD4547: Phase I in the EU and in Japan
AV369, AV370: No clinicaltrials.gov information regarding human trials
Brivanib: Phase II study being planned; note, drug is also VEGF inhibitor
FP1039- Phase I


6 Responses to Fibroblast growth factor—the next molecular target in lung cancer?

  • Dragonfruit says:

    Hi Dr. Weiss,

    Wow. This is welcome news. Is the hyperlink attached to the AZD4547 study supposed to read “EU” rather than “US”, though, or is the study also being conducted in the US somewhere? I couldn’t find any US sites for this study on my search. Given that my mom has squamous NSCLC, an exon 19 mutation, acquired EGFR resistance, and we’re running out of treatment options, these trials are very interesting to us (but appear to be so far away!). Is there such a thing as compassionate use programs for drugs still in dose-finding trials?

    Thank you, always.
    Anna

  • Dr. Weiss says:

    You are correct; it should read EU.

  • Dr West
    Dr West says:

    I made that correction. Thanks for pointing it out.

  • JoeSperrazza says:

    Dr. Weiss,

    Thank you for the terrific information.

    As an aside, I absolutely adore your writing!

    Cheers,

    Joe S

  • catdander forum moderator
    catdander says:

    Thanks Dr. Weiss,
    I agree with Joe, I love your writing:)
    I have a question about the last sentence of your post. One of the drugs under investigation is a VEGF inhibitor. An anti-angiogenic like avastin? Might there be a chance of bleeding in squamous patients with this like Avastin? Or do I have that comparison wrong?

  • Dr. Weiss says:

    In theory, it’s a concern, but there have been trials of other TKIs with VEGF inhibition in SqCC (for example, sutent). I think that it’s a bit of a leap to assume that just because avastin causes these problems that a pill TKI angiogenesis inhibitor will too. I do think that the experience with avastin is enough to give pause and lead to very careful monitoring for bleeding in the study of any related agents.

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