Despite the promise of RNA interference (RNAi) approach for targeting undruggable targets, major challenges remain including specific delivery of siRNA into cell types of interest in vivo, poor stability and off-target effects. We have been at the forefront of addressing these issues and my laboratory has pioneered many studies using RNAi approaches for cancer treatment and has made key discoveries related to RNAi biology. We were among the first to demonstrate that RNAi processing machinery is deregulated in a high proportion of ovarian and other cancers (Merritt et al., New Engl J Med 2008). To achieve systemic delivery of RNAi therapeutics, we systematically identified safe and effective methods for siRNA delivery. After extensive testing, our first successful platform utilized the neutral DOPC nanoliposomal delivery system (Landen et al., Cancer Res 2005; Ahmed et al., Cancer Cell 2010), which has subsequently been tested in multiple tumor model systems (Liu et al., Nature 2015; Kim et al., Cell 2013). With a robust portfolio of preclinical studies and all of the requisite safety studies based on FDA guidance, a first-in-human phase I clinical trial with EPHARNA (EphA2 targeted siRNA in DOPC) is nearing completion for patients with solid tumors. We have made great strides in applying this technology for cancer therapy. However, despite the promise of synthetic delivery systems that we and others have developed, novel and biocompatible delivery strategies that are independent of reliance on vascular leakiness are highly desirable. In this project, we propose to develop a biomimetic exosomal system that will enable active delivery of cancer therapeutics to the tumor microenvironment. These naturally occurring particles represent a promising, and safe alternative approach for delivering RNAi therapeutics. We will package RNAi cargos into these particles and engineer their surface membrane to actively target distinct cell types. Finally, we will develop this approach for enhancing anti-tumor immune response in ovarian and other cancers. If successful, this biomimetic exosomal system can be rapidly applied more broadly to other ?undruggable? targets. Support through the R35 mechanism will greatly facilitate this undertaking, which would not otherwise be possible.
Despite the promise of synthetic delivery systems that we and others have developed, novel and biocompatible delivery strategies that are independent of reliance on vascular leakiness are needed. In this proposal, we aim to develop a biomimetic exosomal system that will enable active delivery of cancer therapeutics. These naturally occurring particles represent a promising, safe alternative approach to delivering RNAi therapeutics. We will package non-coding RNA cargos into these particles and engineer their surface membrane to actively target distinct cell types in the tumor microenvironment.
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| Zhang, Lin; Peng, Dan; Sood, Anil K et al. (2018) Shedding Light on the Dark Cancer Genomes: Long Noncoding RNAs as Novel Biomarkers and Potential Therapeutic Targets for Cancer. Mol Cancer Ther 17:1816-1823 |
| Villar-Prados, Alejandro; Wu, Sherry Y; Court, Karem A et al. (2018) Predicting novel therapies and targets: Regulation of Notch3 by the bromodomain protein BRD4. Mol Cancer Ther : |
| Allen, Julie K; Armaiz-Pena, Guillermo N; Nagaraja, Archana S et al. (2018) Sustained Adrenergic Signaling Promotes Intratumoral Innervation through BDNF Induction. Cancer Res 78:3233-3242 |
| Chen, Xiuhui; Mangala, Lingegowda S; Rodriguez-Aguayo, Cristian et al. (2018) RNA interference-based therapy and its delivery systems. Cancer Metastasis Rev 37:107-124 |
| Umamaheswaran, Sujanitha; Dasari, Santosh K; Yang, Peiying et al. (2018) Stress, inflammation, and eicosanoids: an emerging perspective. Cancer Metastasis Rev 37:203-211 |
| Yang, Hailing; Mao, Weiqun; Rodriguez-Aguayo, Cristian et al. (2018) Paclitaxel Sensitivity of Ovarian Cancer Can be Enhanced by Knocking Down Pairs of Kinases that Regulate MAP4 Phosphorylation and Microtubule Stability. Clin Cancer Res 24:5072-5084 |
| Inoue, Kazuki; Deng, Zhonghao; Chen, Yufan et al. (2018) Bone protection by inhibition of microRNA-182. Nat Commun 9:4108 |
| Dal Molin, Graziela Z; Omatsu, Kohei; Sood, Anil K et al. (2018) Rucaparib in ovarian cancer: an update on safety, efficacy and place in therapy. Ther Adv Med Oncol 10:1758835918778483 |
| Dalton, Heather J; Pradeep, Sunila; McGuire, Michael et al. (2017) Macrophages Facilitate Resistance to Anti-VEGF Therapy by Altered VEGFR Expression. Clin Cancer Res 23:7034-7046 |
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