Resistance mechanism of colorectal cancer to bevacizumab detailed
When colorectal cancer is targeted by the drug bevacizumab (Avastin), tumors may switch dependence from VEGF-A, which is targeted by the drug, to related growth factors that include VEGF-C, VEGF-D, and placental growth factor. This change to dependence on new growth factors may allow colorectal cancer to push past bevacizumab's blockage of VEGF-A and continue to drive tumor growth.
"Think of it like damming a river. Bevacizumab can block the main flow, but then once a tumor's need builds up behind this dam, water starts to flow around the blockage in the form of streams and tributaries. That's like these other growth factors—eventually a tumor becomes able to use these tributaries of VEGF-C, VEGF-D, and placental growth factor to supply itself with the 'water' it needs," said lead author Christopher Lieu, MD, who is an investigator at the CU Cancer Center and assistant professor of Medical Oncology at the University of Colorado School of Medicine in Denver.
The analogy of liquid is an apt one—bevacizumab slows cancer's growth by limiting a tumor's ability to grow the new blood vessels it needs to supply itself with nutrients. Especially in combination with chemotherapy, bevacizumab has proved an effective treatment for colorectal cancer. But then there frequently comes a point at which bevacizumab stops working and the tumor restarts its growth. This study, published in PLOS One (2013; doi:10.1371/journal.pone.0077117), asked why.
Specifically, Lieu and colleagues serially tested the levels of other VEGF-related growth factors in 42 patients treated with bevacizumab and chemotherapy. These tests occurred at many points during the course of their treatment.
"What we saw is that levels of VEGF-C and placental growth factor went up just before tumors progressed and then stayed high during the periods of tumor growth. Interestingly, VEGF-D was only elevated during progression. But it seems that tumors may be using these growth factors as ways to create blood vessel growth in the absence of VEGF-A, blocked by bevacizumab," Lieu said.
Then the researchers also took a snapshot of levels in 403 colorectal cancer patients, at one time during treatment. Because this group included patients who were and were not being treated with chemotherapy along with bevacizumab, they could show that the rise in VEGF levels was, in fact, due to bevacizumab and not to some interaction with the chemotherapy.
"It's too early to say with certainty that VEGF-C, VEGF-D, and placental growth factor are the cause of colorectal cancer resistance to bevacizumab, but the correlation we saw in this study is compelling," Lieu said.
Current studies are exploring the use of drugs that block more blood-vessel-growth-promoting factors than VEGF-A. For example, Lieu points to the example of aflibercept (Zaltrap), which was given FDA approval in August 2013 for the treatment of metastatic colorectal cancer, along with the chemotherapy regimen known as FOLFIRI. The drug inhibits placental growth factor along with VEGF-A.