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Obesity may promote resistance to antiangiogenic therapy for breast cancer

March 19, 2018, New York — Obesity, which is known to reduce survival in several types of cancer, may also explain the ineffectiveness of angiogenesis inhibitors in the treatment of breast cancer. A research team led by Ludwig Harvard investigator Rakesh Jain and his colleague Dai Fukumura at Massachusetts General Hospital (MGH) reports that obesity appears to induce resistance to antiangiogenic therapy, which inhibits the formation of blood vessels that feed tumors. Their paper, in the current issue of Science Translational Medicine, also details the specific factors underlying that resistance and proposes potential therapeutic strategies to overcome it.

Early studies led to accelerated FDA approval of the anti-vascular endothelial growth factor (VEGF) drug bevacizumab for treatment of metastatic breast cancer. But when several subsequent studies failed to show a long-term survival benefit with the therapy, that approval was withdrawn.

Analyzing data from a clinical trial of anti-VEGF therapy, the investigators found that participants with body mass index (BMI) measurements of 25 or more had tumors that were on average 33% larger upon diagnosis than those of their slimmer counterparts. Circulating levels of interleukin 6 (IL-6), which drives inflammation, and fibroblast growth factor 2 (FGF-2), which promotes blood vessel growth, were elevated in patients with higher BMIs, and these factors were expressed in fat cells and other types of cells within tumors.

Studies on mouse models expanded on these findings. The researchers show that the microenvironment of tumors from obese mice were rich in fat cells and low on oxygen and responded poorly to an anti-VEGF drug. In a model for estrogen receptor positive breast cancer, fat cells and certain immune cells within the tumors of obese animals overexpressed several inflammatory and angiogenic molecules, including IL-6. Blocking IL-6 in those mice boosted response to anti-VEGF therapy so that it was comparable to that seen in lean animals. In a triple-negative breast cancer model, meanwhile, obese animals had higher levels of FGF-2 but not IL-6. In these mice, FGF-2 inhibition increased treatment response to levels seen in lean animals.

The researchers note that their results could be clinically tested soon, since several inhibitors of those pathways are available. One of the drugs they used to inhibit FGF-2 was metformin, a widely used type 2 diabetes drug that can also suppress the growth of certain cancers.

The original release from which this summary is derived can be accessed here.

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