One of my favourite journals, Cancer Research, has a new paper available via open access (i.e. free to the public, thank you AACR), which you can obtain from the link in the Reference section below.
It caught my attention because there was a fascinating symposium on angiogenesis at ESMO this summer with some heavyweight debates from Robert Kerbel (accelerated metastasis) and Lee Ellis (normalisation of tumour vessels) taking different viewpoints on the pros and cons of VEGF inhibition. I took a few photos of the slides for private study and reflection, as they were going too fast for me to keep up with the key points with unreadable chicken scratch notes, but sadly my iPhone went missing in the exhibit hall less than an hour afterwards before I could download the photos :(. That said, both sides argued with very compelling data for their perspective that I’m not sure which way I roll on the issue.
In this latest paper, di Tomaso et al., from Boston discuss the concept of recurrent glioblastomas and the tendency to relapse after VEGF therapy. They noted that there are two current theories for how this might happen:
- Switch to VEGF-independent angiogenic pathways
- Vessel co-option
They therefore decided to investigate these mechanisms in patients with relapsed glioblastoma using a pan VEGF inhibitor, cediranib. Now, it should be noted that cediranib (Recentin) is not yet approved and is a small molecule inhibitor, whereas another VEGF inhibitor, bevacizumab (Avastin), is a monoclonal antibody approved for relapsed GBM, so I’m sure why they didn’t use that instead. It does make extrapolation of the findings a little more tricky though, as you cannot always assume a class effect.
Here are the key findings:
- Endothelial proliferation and glomeruloid vessels were decreased
- Vessel diameters and perimeters were reduced to levels comparable to the unaffected contralateral brain hemisphere
- Tumour endothelial cells expressed molecular markers specific to the blood–brain barrier, indicative of a lack of revascularization despite the discontinuation of therapy
- Cellular density in the central area of the tumour was lower than in control cases and gradually decreased toward the infiltrating edge, indicative of a change in growth pattern of relapsed GBM after cediranib treatment
- Cediranib-treated GBMs showed high levels of PDGF-C (platelet-derived growth factor C) and c-Met expression and infiltration by myeloid cells, which may potentially contribute to resistance to anti-VEGF therapy
The authors therefore concluded that:
“rGBMs switch their growth pattern after anti-VEGF therapy—characterized by lower tumor cellularity in the central area, decreased pseudopalisading necrosis, and blood vessels with normal molecular expression and morphology—without a second wave of angiogenesis.”
What intrigued me in particular was not the lack of rebound vascularisation effect but the myeloid component. Many of you will remember the AACR meeting last September on Molecular Diagnostics in Cancer Therapeutics, where AVEO presented data on their VEGF inhibitor in development and found that the myeloid component acted as a useful biomarker of response for tivozanib in renal cell cancer. You can read more about that here if you missed it.
This raises several interesting questions for me:
- Is the myeloid marker that AVEO found with tivozanib actually more useful and applicable to VEGF therapies in general?
- Does the myeloid component indicate acute inflammation, as we have seen with respiratory and other diseases?
- If PDGF and MET expression rise as resistance sets in, does that suggest logical combination therapies for the treatment of GBM?
- How can we better overcome the blood brain barrier, which is a physical impediment to improving outcomes.
Time will tell but clearly the research in relapsed GBM has a-ways to go before we figure out how best to approach it yet.
di Tomaso, E., Snuderl, M., Kamoun, W., Duda, D., Auluck, P., Fazlollahi, L., Andronesi, O., Frosch, M., Wen, P., Plotkin, S., Hedley-Whyte, E., Sorensen, A., Batchelor, T., & Jain, R. (2011). Glioblastoma Recurrence after Cediranib Therapy in Patients: Lack of “Rebound” Revascularization as Mode of Escape Cancer Research, 71 (1), 19-28 DOI: 10.1158/0008-5472.CAN-10-2602