Abstract 2139: Effect of telmisartan on triple negative breast cancer (TNBC) and lung cancer tumor progression and intratumoral distribution of nanoparticles.

Abstract

Abstract Introduction: The intratumoral distribution of tumor targeted nanoparticles (NP) is hindered by dense collagen network and highly fibrous interstitium. Use of antifibrotic agents can decrease tumor interstitial fibrosis and promote NP intratumoral distribution. The objective of this study was to evaluate the effect of Telmisartan (TEL, AT1 blocker/PPAR-γ agonist) and Losartan (LOS, AT1 blocker) on NPs intratumoral distribution and anticancer effects in TNBC and lung cancer. Methods: Anticancer effect of TEL (5 mg/kg) and LOS (20 mg/kg) by inhalation and oral route were evaluated using Non-small cell lung cancer (A549 orthotopic and metastatic model) and triple negative breast cancer (TNBC, MDA-MB-231 orthotopic model) in Nu/nu mice. Also, to study intratumoral distribution, fluorescent polystyrene NP (FPNP) were administered intravenously followed by fluorescent microscopy. Tumor fibrous nature was characterized by estimating collagen-1, transforming growth factor beta1 (TGF-β;1) expression by IHC and ELISA. Collagen deposition in the tumor interstitium was studied by Masson's Trichome staining. To correlate the AT1 receptor blockage to anticancer effects, expression of VEGF, cleaved caspase-3, MMP-9 and microvessel densities (CD31) were quantified by IHC and western blotting. Epithelial Mesenchymal transition (EMT) mediated tumor metastasis was characterized by expressions of E-Cadherin and Vimentin. Results: TEL showed significant antitumor effects in both lung and TNBC tumor models. TEL at 1/4th dose produced superior anticancer effects than LOS. Survival rate was extended with TEL compare to LOS & untreated control. Further, Paclitaxel-NP produced better tumor regression in inhalation with TEL compared to single agent treatment and control. The fibrous nature of lung tumors and TNBC was decreased significantly (p<0.05) with TEL and LOS treatment based on expression of collagen-1 and TGF-β;1. This allowed better FPNP distribution into the tumors compared to control. Further, compared to control tumors, LOS and TEL treated group resulted in 5.33 and 14.33 fold increase in NP distribution. Similarly, Paclitaxel-NP distribution was superior in combination with TEL & LOS treatment, which in turn exhibited synergistic anticancer effects. TEL treatment resulted in the decreased metastatic tumor nodules and tumor volumes. The metastatic markers MMP-9 & vimentin levels were significantly decreased (p<0.001) in TEL group compared to LOS & control, suggesting the promising effects of TEL in tumor anti-metastasis. Further, our study also demonstrated the safety of TEL upon inhalation route. Conclusion: Telmisartan showed significant anticancer effects in Lung cancer and TNBC. Telmisartan could be an ideal candidate for combination therapy to improve the NPs intratumoral distribution and anticancer effects in various cancer types. Citation Format: Chandraiah Godugu, Apurva R. Patel, Srujan Marepally, Ravi Doddapaneni, Mandip Singh Sachdeva, Mahavir B. Chougule. Effect of telmisartan on triple negative breast cancer (TNBC) and lung cancer tumor progression and intratumoral distribution of nanoparticles. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2139. doi:10.1158/1538-7445.AM2013-2139