Clinical experiences with systemically administered siRNA-based therapeutics in cancer

Zuckerman, Jonathan E.; Davis, Mark E.

doi:10.1038/nrd4685

Cited by 354 publications

(271 citation statements)

References 93 publications

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“…By improving the in vivo delivery of RNAi agents (e.g., siRNA) to solid tumor tissues through the enhanced permeability and retention (EPR) effect (6), nanotechnology has drastically facilitated the clinical translation of RNAi for cancer therapy (5). However, RNAi nanoparticles (NPs) at the clinical stage for cancer treatment (7,8) may still face challenging obstacles, such as suboptimal systemic delivery of siRNA into target tumor cells.…”

mentioning

confidence: 99%

“…RNAi is a powerful means for specific silencing of virtually any target gene of interest, thus offering an enormous opportunity to treat cancers and suppress metastases (5). By improving the in vivo delivery of RNAi agents (e.g., siRNA) to solid tumor tissues through the enhanced permeability and retention (EPR) effect (6), nanotechnology has drastically facilitated the clinical translation of RNAi for cancer therapy (5).…”

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confidence: 99%

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Theranostic near-infrared fluorescent nanoplatform for imaging and systemic siRNA delivery to metastatic anaplastic thyroid cancer

Liu

Gunda

Zhu

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Anaplastic thyroid cancer (ATC), one of the most aggressive solid tumors, is characterized by rapid tumor growth and severe metastasis to other organs. Owing to the lack of effective treatment options, ATC has a mortality rate of ∼100% and median survival of less than 5 months. RNAi nanotechnology represents a promising strategy for cancer therapy through nanoparticle (NP) -mediated delivery of RNAi agents (e.g., siRNA) to solid tumors for specific silencing of target genes driving growth and/or metastasis. Nevertheless, the clinical success of RNAi cancer nanotherapies remains elusive in large part because of the suboptimal systemic siRNA NP delivery to tumors and the fact that tumor heterogeneity produces variable NP accumulation and thus, therapeutic response. To address these challenges, we here present an innovative theranostic NP platform composed of a near-infrared (NIR) fluorescent polymer for effective in vivo siRNA delivery to ATC tumors and simultaneous tracking of the tumor accumulation by noninvasive NIR imaging. The NIR polymeric NPs are small (∼50 nm), show long blood circulation and high tumor accumulation, and facilitate tumor imaging. Systemic siRNA delivery using these NPs efficiently silences the expression of V-Raf murine sarcoma viral oncogene homolog B (BRAF) in tumor tissues and significantly suppresses tumor growth and metastasis in an orthotopic mouse model of ATC. These results suggest that this theranostic NP system could become an effective tool for NIR imaging-guided siRNA delivery for personalized treatment of advanced malignancies.T hyroid cancer has been continuously increasing in worldwide incidence for the past few decades and is now the fifth most common malignancy in females (1). Notably, the most aggressive form of thyroid cancer, anaplastic thyroid cancer (ATC), has a mortality rate of nearly 100%, with median survival time of 3-5 months, mainly because of local invasion and metastasis to lung, lymph nodes (LNs), and other tissues (2). The mechanisms that mediate metastasis in ATC strongly depend on the activation of genetic mutations, such as V-Raf murine sarcoma viral oncogene homolog B (BRAF), TP53, RAS, PIK3CA, and AKT1 (3). Current treatments for ATC rely on various combinations of surgical resection with adjuvant therapies, such as chemotherapy and radiotherapy, but have shown only limited survival benefits (4). Therefore, there are compelling reasons to establish new strategies for more effective treatment of metastatic ATC.RNAi is a powerful means for specific silencing of virtually any target gene of interest, thus offering an enormous opportunity to treat cancers and suppress metastases (5). By improving the in vivo delivery of RNAi agents (e.g., siRNA) to solid tumor tissues through the enhanced permeability and retention (EPR) effect (6), nanotechnology has drastically facilitated the clinical translation of RNAi for cancer therapy (5). However, RNAi nanoparticles (NPs) at the clinical stage for cancer treatment (7, 8) may still face challenging obstacles, such ...

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confidence: 99%

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confidence: 99%

Theranostic near-infrared fluorescent nanoplatform for imaging and systemic siRNA delivery to metastatic anaplastic thyroid cancer

Liu

Gunda

Zhu

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Moreover, small noncoding RNA therapeutics are well tolerated in patients with manageable side effects 37. Two miRNA replacement therapies are already involved in phase I clinical trials: MRX34 in patients with advanced liver cancer and TargomiR (miR‐26 mimic) in patients with malignant pleural mesothelioma and nonsmall‐cell lung cancer 11, 12.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA therapy inhibits hepatoblastoma growth in vivo by targeting β‐catenin and Wnt signaling

Indersie

Lesjean

Hooks

et al. 2017

Hepatology Communications

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Hepatoblastoma (HBL) is the most common pediatric liver cancer. In this malignant neoplasm, beta‐catenin protein accumulates and increases Wnt signaling due to recurrent activating mutations in the catenin‐beta 1 (CTNNB1) gene. Therefore, beta‐catenin is a key therapeutic target in HBL. However, controlling beta‐catenin production with therapeutic molecules has been challenging. New biological studies could provide alternative therapeutic solutions for the treatment of HBL, especially for advanced tumors and metastatic disease. In this study, we identified microRNAs (miRNAs) that target beta‐catenin and block HBL cell proliferation in vitro and tumor growth in vivo. Using our dual‐fluorescence‐FunREG system, we screened a library of 1,712 miRNA mimics and selected candidates inhibiting CTNNB1 expression through interaction with its untranslated regions. After validating the regulatory effect of nine miRNAs on beta‐catenin in HBL cells, we measured their expression in patient samples. Let‐7i‐3p, miR‐449b‐3p, miR‐624‐5p, and miR‐885‐5p were decreased in tumors compared to normal livers. Moreover, they inhibited HBL cell growth and Wnt signaling activity in vitro partly through beta‐catenin down‐regulation. Additionally, miR‐624‐5p induced cell senescence in vitro, blocked experimental HBL growth in vivo, and directly targeted the beta‐catenin 3′‐untranslated region. Conclusion: Our results shed light on how beta‐catenin‐regulating miRNAs control HBL progression through Wnt signaling inactivation. In particular, miR‐624‐5p may constitute a promising candidate for miRNA replacement therapy for HBL patients. (Hepatology Communications 2017;1:168‐183)

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“…Davis group studies revealed that targeting is important for the specific delivery of siRNAs to the diseased cells [109]. However, further phase clinical trials were stopped due to the drug instability which was supposedly thought to be due to the presence of the transferrin ligand [110].…”

Section: Cyclodextrin Containing Polycations and Targeting Ligandsmentioning

confidence: 99%

Functionalized non-viral cationic vectors for effective siRNA induced cancer therapy

Gupta

Puri

Shapiro

2017

DNA and RNA Nanotechnology

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RNA interference (RNAi) has been regarded as a vital asset in the field of therapeutics as it has the capability to silence various disease causing genes including those that cause cancer. Small non-coding RNA molecules such as short interfering RNAs (siRNAs) are one of the extensively studied RNAi inducers for gene modulations. However, the delivery of RNAi inducers including siRNAs is compromised due to the barriers imposed by the biological system such as degradation by nucleases, rapid clearance, high anionic charge, immunogenicity and off-target effects. Viral vectors, in general exhibit high transfection efficiencies but are expensive and likely to confer immunological and safety issues. Therefore, non-viral cationic vectors (NVCVs) have received considerable attention to not only address these issues but also for developing efficacious siRNA delivery vectors. In this review, we will first discuss the historical development of various NVCVs and then will discuss functionalized NVCVs with linkers that provide stability, as well as respond to the cancer cell environment and with cancer cell receptor specific ligands to explicitly target them for improved siRNA efficacy. Multifunctional NVCVs (MNVCVs) that employ multiple synergistically working components to aid siRNA delivery efficacy are also discussed.

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Clinical experiences with systemically administered siRNA-based therapeutics in cancer

Cited by 354 publications

References 93 publications

Theranostic near-infrared fluorescent nanoplatform for imaging and systemic siRNA delivery to metastatic anaplastic thyroid cancer

Theranostic near-infrared fluorescent nanoplatform for imaging and systemic siRNA delivery to metastatic anaplastic thyroid cancer

MicroRNA therapy inhibits hepatoblastoma growth in vivo by targeting β‐catenin and Wnt signaling

Functionalized non-viral cationic vectors for effective siRNA induced cancer therapy

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