Final Report Summary - ANTI-ANGIOGENIC DRUG (Multifunctional Polymeric Nanomicelles Combat Tumor Evasion in Antiangiogenic Cancer Therapy)
Formation of new blood vessel in a process called angiogenesis plays a pivotal role in tumor development and metastases.Angiogenesis supports tumor proliferation and progression, and is often associated with poor disease prognosis. Recent advances in targeting angiogenesis and inhibiting tumor neovascularization led to numerous new antiangiogenic drugs, which are now in clinical use for treating various cancers such as renal cancer, colorectal cancer and several other solid tumors. However, despite the promise, the efficacy of these treatments is relatively limited and similar to chemotherapy, these therapies also show tumor “resistance” over time, through different compensating mechanisms. Ultimately, anti-angiogenic therapy (specific or broad spectrum) aims to starve tumor tissue by damaging its blood supply. As a result of these therapies, tumor tissue becomes hypoxic and eventually necrotic. While tumor death by necrosis is considered a desirable outcome of treatment, paradoxically it also triggers another mechanism of tumor evasion, by the secretion of pro-inflammatory and pro-angiogenic signals from necrotic tissue and also due to re-vascularization. In this project we have successfully fabricated and characterized lung targeted, drug carrying PLGA polymer carriers, using Carbenoxolone, an already approved drug which was recently identified as an antagonist of the necrotic signal HMGB1. We demonstrated the anti-cancer and anti-angiogenic effects of the free drug using both in-vitro and several in-vivo models. We showed that the drug loaded particles maintain the effect of the drug in the lung, proving this treatment to be effective as a targeted prophylactic treatment for lung metastases. Moreover, after setting a novel in-vitro system of mimicking the tumor microenvironment, we conducted a proteomic analysis, and have identified several interesting necrotic signals as possible future therapeutic targets. We are now focusing on our next challenge of modifying our drug carriers to be used as a dual drug release system in vivo for improvement of treatment efficacy. The carriers will combine two drugs: a potent anti-angiogenic drug and an antagonist of a necrotic signal. Using this innovative approach we attempt to significantly improve tumor treatment by minimizing resistance to drug over time.