Study may provide novel targetable mechanisms of therapeutic resistance to anti-VEGF therapies

The cover for issue 1 of Oncotarget features Figure 5, "APLN overexpression correlates with worsened prognosis in ovarian cancer patients treated with bevacizumab," by Jaiprasart, et al.

To establish a molecular signature of this resistance in ovarian cancer, the authors developed preclinical tumor models of adaptive resistance to chronic anti-VEGF treatment.

These findings link signature gene expressions with anti-VEGF response, and may thus provide novel targetable mechanisms of clinical resistance to anti-VEGF therapies.

Dr. Sukyung Woo from the Department of Pharmaceutical Sciences, College of Pharmacy, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA as well as the Gynecologic Cancers Research Program, Peggy and Charles Stephenson Cancer Center, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA said, "Ovarian cancer is the principal cause of gynecological-cancer-related deaths in women in the United States"

Figure 5: APLN overexpression correlates with worsened prognosis in ovarian cancer patients treated with bevacizumab. (A) APLN expression in patients in APLN-low and APLN-high groups. (B) Kaplan-Meier analysis of disease-free survival (DFS) in patients in APLN-low and APLN-high groups (Median DFS of 14.1 vs. 41.2 months; P = 0.05). (C) APLNR expression in patients in APLNR-low and APLNR-high groups (P < 0.001). (D) Kaplan-Meier analysis of DFS in patients in APLNR-low and APLNR-high groups (P = 0.22). Statistical analysis was performed using Two-tailed unpaired t-test for gene expression levels in A., C and Log-rank test was used for statistical analysis of survival outcome in B., D.

Increased tumor angiogenesis in ovarian cancer is also critical to ovarian cancer metastasis and ascites development.

Several studies have shown that a high level of vascular endothelial growth factor, a key regulator of tumor angiogenesis, is associated with poor prognosis in patients with ovarian cancer.

In the present study, the scientists developed preclinical xenograft models of ovarian cancer that acquire adaptive resistance to anti-VEGF therapeutics.

Using these tumors, they utilized unbiased approaches to identify not only a distinct gene signature associated with resistance development, but also the source of resistance.

The Woo Research Team concluded:

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. These pathways may function as important alternative angiogenic signaling pathways in the presence of VEGF blockade. 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.