Tumor uptake of chemotherapy drugs is not the only factor that determines therapeutic efficacy, Cripe added. VEGF blockade appears to decrease the influx of innate inflammatory cells that contribute to a microenvironment favoring tumor growth, he noted. “By decreasing the influx of such cells, the antitumor effects of bevacizumab may be more profound than the loss of chemotherapy exposure,” he said. The effects of VEGF blockade plus chemotherapy may be “quite different among different tumor types,” such that the new study of non-small-cell lung tumor responses will not generalize to all cancers, Cripe added.

While tumor necrosis could impair docetaxel uptake late in the study period (eg, day 4), early impairment of tumors’ drug uptake was evident within hours of bevacizumab infusion, suggesting a more immediate mechanism is also at play, even if tumor necrosis occurs later.2 Van der Veldt and her colleagues suspect rapid vasoconstriction of tumor vasculature in response to bevacizumab administration is one likely explanation. If vasoconstriction is involved, administering cytotoxic drugs first and then administering bevacizumab could improve tumor retention of chemotherapy agents, they suggest.


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“Given previous clinical trials of bevacizumab and irinotecan in colorectal patients having some success, the results are counterintuitive,” said Michael Lewis, PhD, associate professor of Oncology for Tumor Biology at the University of Missouri. “An interesting possibility raised by these authors is to reverse the order of treatments: administer chemotherapy first, followed by antiangiogenic treatment. Based on their findings, a decrease in tumor perfusion caused by the antiangiogenic agent might increase retention of cytotoxic drugs in tumors.”

Indeed, that is just what Cripe and colleagues found in an animal study of how VEGF blockade affected the uptake of an oncolytic herpes virus, conducted at the Cincinnati Children’s Hospital Medical Center and published in 2010.9 That study showed that VEGF blockade hampered tumor uptake of an anticancer viral agent in mice when it preceded intravenous delivery of the oncolytic virus.9 But when VEGF blockade followed oncolytic virotherapy, the efficacy of virotherapy improved significantly.9

“In that case, the schedule did make a difference on the antitumor effect,” Cripe said. “Whether or not the mechanism inhibiting uptake [between bevacizumab and oncolytic virus] is similar, is unknown. In terms of the posited mechanism of vasoconstriction, it seems reasonable given the rapid timeframe that is really too early to allow for any major changes in gene or protein expression. Again, though, that effect may be transient and might be different at days 2 or 3.”

BLOCKING TUMOR CELL ESCAPE WITH C-MET

The sequence or timing of VEGF blockade is not the only hurdle to optimizing its efficacy as an anticancer therapy. Ironically, preclinical studies indicate that VEGF blockade can actually increase the risk of tumor spread and metastasis.10 Tumor cell hypoxia can activate the c-Met gene, for example, which upregulates production of the hepatocyte growth factor receptor proteins involved in tumor invasion and metastasis.10 c-Met activation increases cell proliferation and motility, potentially hastening tumor invasion and metastasis to distant organs.10

Tumor cell hypoxia has been shown to be associated with a higher risk of metastasis and poor prognosis.11 And in a recently published study of VEGF blockade and tumor spread in a mouse pancreas model, researchers at the University of California San Francisco reported that VEGF blockade-associated tumor cell hypoxia led to upregulated c-Met and greater tumor aggressiveness and more severe liver metastasis.10 The study confirmed that vascular pruning, hypoxia, and c-Met activation all play a role in VEGF blockade-associated tumor escape to new tissues.10 The study showed that an engineered antibody—cabozantinib—inhibits c-Met activation and reduces tumor aggressiveness, reflecting remarkable promise as a potential monotherapy for suppressing tumor angiogenesis, growth, invasion, and metastasis by simultaneously blocking both c-Met and VEGF-mediated angiogenesis.10 (Also see Oncology Nurse Advisor, In the News, August/September 2010, p. 8.) Whether other mechanisms also cause VEGF-blockade therapies to provoke metastatic processes leading to the regional lymph node or distant spread of tumors is not yet known.12

To counter the potential risk of tumor cell escape and spread during VEGF blockade, bevacizumab manufacturer Genentech is already conducting clinical trials of combined therapy with bevacizumab plus the c-MET receptor-blocking antibody onartuzumab in advanced NSCLC patients, and patients with advanced cases of triple-negative breast cancer and metastatic colorectal cancer.12 ONA


Bryant Furlow is a medical journalist based in Albuquerque, New Mexico.


REFERENCES

1. Montero AJ, Vogel C. Fighting fire with fire: rekindling the bevacizumab debate. N Engl J Med. 2012;366(4):374-375.

2. Van der Veldt AA, Lubberink M, Bahce I, et al. Rapid decrease in delivery of chemotherapy to tumors after anti-VEGF therapy: implications for scheduling of anti-angiogenic drugs. Cancer Cell. 2012;21(1):82-91. http://www.cell.com/cancer-cell/abstract/S1535-6108(11)00446-6. Accessed March 13, 2012.

3. Greenberg JI, Cheresh DA. VEGF as an inhibitor of tumor vessel maturation: implications for cancer therapy. Expert Opin Biol Ther. 2009;9(11):1347-1356.

4. Planchard D. Bevacizumab in non-small-cell lung cancer: a review. Expert Rev Anticancer Ther. 2011;11(8):1163-1179.

5. Potente M, Gerhardt H, Carmeliet P. Basic and therapeutic aspects of angiogenesis. Cell. 2011;146(6):873-887. http://www.cell.com/abstract/S0092-8674(11)01009-9. Accessed March 13, 2012.

6. FDA Commissioner announces Avastin decision: Drug not shown to be safe and effective in breast cancer patients. US Food and Drug Administration (FDA) Web site. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm280536.htm. Updated November 18, 2011. Accessed March 13, 2012.

7. Jain RK. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science. 2005;307(5706):58-62.

8. Goel S, Dude DG, Xu L, et al. Normalization of the vasculature for treatment of cancer and other diseases. Physiol Rev. 2011;91(3):1071-1121.

9. Eshun FK, Currier MA, Gillespie RA, et al. VEGF blockade decreases tumor uptake of systemic oncolytic herpes virus but enhances therapeutic efficacy when given after virotherapy. Gene Ther. 2010;17(7): 922-929.

10. Sennino B, Ishiguro-Oonuma T, Wei Y, et al. Suppression of tumor invasion and metastasis by concurrent inhibition of c-Met and VEGF signaling in pancreatic neuroendocrine tumors. Cancer Discovery. 2012; doi:10.1158/2159-8290.CD-11-0240.

11. Pouysségur J, Dayan F, Mazure NM. Hypoxia signalling in cancer and approaches to enforce tumour regression. Nature. 2006;441(7092):437-443.

12. Coghlan A. Multitasking drug keeps cancer at bay. New Sci. 2012; 2854:14-15.