Activation of Apelin Signaling Decreases VEGF Inhibitor Efficacy in Ovarian Cancer Treatment

The activation of apelin/APJ signaling significantly decreased the efficacy of VEGF inhibitors in endothelial cells, while disease-free survival (DFS) rates of patients with ovarian cancer treated with bevacizumab (Avastin) significantly decreased with increased expression of apelin, according to a study published in Oncotarget.¹

The researchers discovered that high levels of apelin correlated with shorter DFS compared to lower levels of apelin (median DFS, 14.1 months vs 41.2 months). This data confirmed the researchers’ work that patients with ovarian cancer treated with bevacizumab and high expression of the apelin/APJ pathway correlates with “worsened prognosis.”

“We have used in vivo tumor models that gain adaptive resistance to VEGF-targeting therapeutics to discover a unique molecular signature associated with the anti-VEGF resistance phenotype,” wrote Pharavee Jaiprasart and colleagues. “These pathways may function as important alternative angiogenic signaling pathways in the presence of VEGF blockade.”

Jaiprasart and colleagues categorized tumors that responded and regrew into 4 categories: bevacizumab- or sorafenib (Nexavar)-resistant and -sensitive. The resistant tumors saw regrowth starting around week 4-5, with 70% of tumors treated with bevacizumab experiencing progression and 50% of tumors treated with sorafenib progressing despite treatment.

“Together, these data show that the tumors that gained adaptive resistance with restored tumor progression, resumed angiogenesis and cell proliferation despite continued anti-VEGF treatment,” wrote the researchers.

With the rapid development of resistance to anti-VEGF treatment, a new method of treatment is required to continuously and effectively treat patients with ovarian cancer. Despite anti-VEGF treatment, tumors that developed resistance continued angiogenesis and cell proliferation.

In turn, the researchers developed preclinical xenograft models of “ovarian cancer that acquire adaptive resistance to anti-VEGF therapeutics,”² and used Ingenuity Pathway Analysis (IPA) to successfully identify signaling transduction pathways with resistant tumors, which were also involved in cancer progression.

The researchers also discovered that the addition of apelin to the presence of VEGF, which increased the migration and invasion of EaHY.926 cells, either maintained or increased the levels of phenotypes in the apelin/APJ pathway compared to the control group. This data suggests that the activated apelin/APJ pathway in endothelial cells decreases the efficacy of anti-VEGF treatments.

“Another important step forward would be to ascertain mechanisms by which tumors mediate resistance to anti-angiogenic drugs,” wrote Jaiprasart and colleagues. “Identification of such novel targets would enable the use of combination therapies to counteract the existing bypass mechanisms.”

The researchers were fairly limited with their lack of model systems that imitate tumor environment and cancer cells, rendering the analysis of resistance mechanisms of non-cancer cells targeting agents difficult. Even more, the commonly utilized in vitro model of studying resistance mechanisms does not apply to anti-angiogenic drugs, therefore the researchers were forced to use the in vivo model.

The study also pointed out a number of previous studies that align well with their findings, validating the work produced from this study. The activation of pro-angiogenic factors and signaling pathways in resistant tumors was previously reported by other studies, while endothelial cells, when treated with VEGF therapies in the presence of activated apelin signaling, do not respond effectively.

“These pathways may function as important alternative angiogenic signaling pathways in the presence of VEGF blockade,” wrote the researchers. “The present study has thus paved the way for the development of new combination or sequential treatment strategies that may help to counteract the resistance mechanisms.”

References:

1. Jaiprasart P, Dogra S, Neelakantan D, et al. Identification of signature genes associated with therapeutic resistance to anti-VEGF therapy. Oncotarget. https://doi.org/10.18632/oncotarget.27307.

2. Identification of signature genes associated with therapeutic resistance to anti-VEGF therapy [news release]. EurekAlert! Science News; January 8, 2020. https://www.eurekalert.org/pub_releases/2020-01/ijl-ios010820.php. Accessed January 20, 2020.