Combining virotherapy and angiotherapy for the treatment of breast cancer

Abstract

A breast cancer-selective oncolytic adenovirus was engineered to express antagonists of vascular endothelial growth factor (VEGF) and Notch signaling to combine direct anticancer activity with disruption of tumor-associated angiogenesis. Replication of the parental virus, AdEHE2F, is stimulated by estrogen receptor (ER), E2F1 and hypoxia, and it mediates selective lysis of breast cancer cells in vitro and in vivo. Here, we encoded soluble Flt-1 (sFlt1) and soluble Dll4 (sDll4) under control of the E3 promoter. sFlt1 (the extra-cellular domain of VEGF receptor 1) binds VEGF-A and inhibits stimulation of VEGFR2, decreasing angiogenic stimulus. Conversely, sDll4 (the extracellular domain of Delta-like 4) antagonizes Notch signaling to prevent endothelial maturation. We hypothesized that these agents might show additive or synergistic activity. In vitro, sFlt1 inhibited endothelial cell proliferation and sprouting, whereas sDll4 increased the number of vascular branchpoints. In ER-positive ZR75.1 tumors in vivo AdEHE2F showed the potent direct virotherapy with no augmentation owing to sFlt1 or sDll4; however, in ER-negative MDA-231 tumors efficacy was enhanced by encoding sFlt1 or sDll4, with survival time extending to double that of controls. There was also a dramatic decrease in the total number of tumour blood vessels, as well as the number of perfused vessels, suggesting that improved efficacy reflects combined anti-tumour and anti-vascular effects.

The Tumor-Associated Marker, PVRL4 (Nectin-4), Is the Epithelial Receptor for Morbilliviruses

“…Preclinical virotherapeutic studies have been primarily performed using MeV vaccine strains over wild-type strains, due to the exceptional genetic stability and safety record of the vaccine strains [92]. The development of oncolytic virotherapy provides a new approach to cancer therapy by selectively targeting tumor cells using previously identified tumor markers on the tumor surface [93]. …”

Role of Recombinant DNA Technology to Improve Life

“…This technology involves the insertion of DNA fragments from a variety of sources, having a desirable gene sequence via appropriate vector [12]. Manipulation in organism's genome is carried out either through the introduction of one or several new genes and regulatory elements or by decreasing or blocking the expression of endogenous genes through recombining genes and elements [13]. Enzymatic cleavage is applied to obtain different DNA fragments using restriction endo-nucleases for specific target sequence DNA sites followed by DNA ligase activity to join the fragments to fix the desired gene in vector.…”

“…Paradoxically to the view of scientists at the time of Asilomar, the recombinant DNA methods to foster agriculture and drug developments took longer than anticipated because of unexpected difficulties and barriers to achieve the satisfactory results. However, since the mid-1980s, the number of products like hormones, vaccines, therapeutic agents, and diagnostic tools has been developed continually to improve health [13]. …”

“…This further, through tumor angiogenesis disruption acts as anticancer agent. This decreases the total blood vessels numbers and causes a dramatic change along with the perfused vessels which indicates the improved efficacy against the tumor and vascular effects [13]. Efforts have been made to modify the influenza virus genome using recombinant DNA technology for development of vaccines.…”

Recent advances in oncolytic adenovirus therapies for cancer

“…This Armed Onc.Ad demonstrated enhanced anti-tumor effect in two lung cancer xenograft models [22]. When combined, two breast cancer-selective Onc.Ads engineered to express soluble Flt1 (a portion of VEGF receptor 1) or soluble DII4 (Delta-like 4), which negatively regulate Notch signaling to inhibit maturation of endothelium, provided a significant reduction in vascular formation and doubled animal survival in ER-negative breast cancer xenograft models [23]. Endostatin is a potent inhibitor of angiogenesis and has been safely used in replication-deficient Ad vector (Ad-Endo) in clinical trials for patients with advanced solid tumors.…”