Atu027 Prevents Pulmonary Metastasis in Experimental and Spontaneous Mouse Metastasis Models

Abstract

Purpose: Atu027, a novel RNA interference therapeutic, has been shown to inhibit lymph node metastasis in orthotopic prostate cancer mouse models. The aim of this study is to elucidate the pharmacologic activity of Atu027 in inhibiting hematogenous metastasis to the target organ lung in four different preclinical mouse models.Experimental Design: Atu027 compared with vehicle or control small interfering RNA lipoplexes was tested in two experimental lung metastasis models (Lewis lung carcinoma, B16V) and spontaneous metastasis mouse models (MDA-MB-435, MDA-MB-231, mammary fat pad). Different dosing schedules (repeated low volume tail vein injections) were applied to obtain insight into effective Atu027 treatment. Primary tumor growth and lung metastasis were measured, and tissues were analyzed by immunohistochemistry and histology. In vitro studies in human umbilical vein endothelial cells were carried out to provide an insight into molecular changes on depletion of PKN3, in support of efficacy results.Results: Intravenous administration of Atu027 prevents pulmonary metastasis. In particular, formation of spontaneous lung metastasis was significantly inhibited in animals with large tumor grafts as well as in mice with resected primary mammary fat pad tumors. In addition, we provide evidence that an increase in VE-cadherin protein levels as a downstream result of PKN3 target gene inhibition may change endothelial function, resulting in reduced colonization and micrometastasis formation.Conclusion: Atu027 can be considered as a potent drug for preventing lung metastasis formation, which might be suitable for preventing hematogenous metastasis in addition to standard cancer therapy.

Examining the role of Rac1 in tumor angiogenesis and growth: a clinically relevant RNAi-mediated approach

“…Strategies to target tumor-associated cells without affecting normal cells may offer a larger therapeutic window. As a number of targeted delivery systems that specifically deliver siRNA to tumor sides are currently under preclinical and clinical development [33,35,36], this approach may soon appear applicable.…”

Systemic delivery of therapeutic small interfering RNA using a pH-triggered amphiphilic poly-l-lysine nanocarrier to suppress prostate cancer growth in mice

“…Recently, highly sequence-specific gene-silencing via the RNA interference (RNAi) mechanism has become a powerful method for down-regulating the expression of disease-related genes ( [Elbashir et al, 2001], [Bumcrot et al, 2006] and [De Fougerolles et al, 2007]). RNAi-induced silencing of cancerous genes related to tumour transformation, development, and metastasis has been considered as a promising strategy for cancer gene therapy ( [Dassie et al, 2009], [Kortylewski et al, 2009] and [Santel et al, 2011]). Synthetic siRNA is one of the approaches used to therapeutically affect this post-transcriptional mechanism ( [Elbashir et al, 2001], [Bumcrot et al, 2006] and [De Fougerolles et al, 2007]).…”

Systemic Delivery of Small RNA Using Lipid Nanoparticles

“…13) Atu027 is approximately 100 nm lipoplexes composed of liposomes and siRNA targeting protein kinase N3 (PKN3) and is being studied as an anticancer siRNA agent in phase II clinical trials. 7,14,15) The liposomes of Atu027 are composed of…”