Prostate-targeted radiosensitization via aptamer-shRNA chimeras in human tumor xenografts

Ni, Xiaohua; Zhang, Yonggang; Ribas, Judit; Chowdhury, Wasim H.; Castanares, Mark; Zhang, Zhewei; Laiho, Marikki; DeWeese, Theodore L.; Lupold, Shawn E.

doi:10.1172/jci45109

Cited by 125 publications

(116 citation statements)

References 40 publications

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“…Aptamers exhibit specificity and avidity comparable to or exceeding those of antibodies and can be generated against most targets. Recent publications have illustrated the feasibility and therapeutic potential of aptamers as targeting ligands to eradicate tumors (33), sensitize tumor cells to radiation therapy (34), inhibit HIV replication (35,36), and potentiate tumor immunity (37,38). In this study, we show that aptamer-targeted siRNA inhibition of mTOR function in CD8 + T cells potentiates a vaccine-induced memory and an antitumor immunity that are quantitatively comparable, but qualitatively superior, to rapamycin treatment.…”

Section: Introductionmentioning

confidence: 51%

Aptamer-targeted inhibition of mTOR in T cells enhances antitumor immunity

Berezhnoy¹,

Castro²,

Levay³

et al. 2013

J. Clin. Invest.

112

104

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Recent studies have underscored the importance of memory T cells in mediating protective immunity against pathogens and cancer. Pharmacological inhibition of regulators that mediate T cell differentiation promotes the differentiation of activated CD8 + T cells into memory cells. Nonetheless, pharmacological agents have broad targets and can induce undesirable immunosuppressive effects. Here, we tested the hypothesis that aptamer-targeted siRNA inhibition of mTOR complex 1 (mTORC1) function in CD8 + T cells can enhance their differentiation into memory T cells and potentiate antitumor immunity more effectively than the pharmacologic inhibitor rapamycin. To specifically target activated cells, we conjugated an siRNA targeting the mTORC1 component raptor to an aptamer that binds 4-1BB, a costimulatory molecule that is expressed on CD8 + T cells following TCR stimulation. We found that systemic administration of the 4-1BB aptamer-raptor siRNA to mice downregulated mTORC1 activity in the majority of CD8 + T cells, leading to the generation of a potent memory response that exhibited cytotoxic effector functions and enhanced vaccine-induced protective immunity in tumor-bearing mice. In contrast, while treatment with the general mTORC1 inhibitor rapamycin also enhanced antigen-activated CD8 + T cell persistence, the cytotoxic effector functions of the reactivated memory cells were reduced and the alloreactivity of DCs was diminished. Consistent with the immunological findings, mice treated with rapamycin, but not with 4-1BB aptamer-raptor siRNA, failed to reject a subsequent tumor challenge.

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Section: Introductionmentioning

confidence: 51%

Aptamer-targeted inhibition of mTOR in T cells enhances antitumor immunity

Berezhnoy¹,

Castro²,

Levay³

et al. 2013

J. Clin. Invest.

112

104

View full text Add to dashboard Cite

show abstract

“…It is possible to conjugate miRNAs or shRNAs to engineered aptamer to be specifically delivered to a cell type. 142 However, such approach still waits to be used in cardiovascular research. In a more recent study, researchers found that systemic administration of cationic lipid-based nanoparticle encapsulating premiR-107 inhibited tumor growth in a head and neck squamous cell carcinoma model.…”

Section: Aptamers and Nanoparticlesmentioning

confidence: 99%

Non-coding RNAs in Cardiac Remodeling and Heart Failure

Kumarswamy

Thum

2013

Circulation Research

220

151

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Heart failure is a leading cause of death in industrialized nations especially in an aging population. The recent improvements in cardiac revascularization therapy reduced death rates because of myocardial infarction but steadily increased the number of individuals developing cardiac remodeling and heart failure in the future. Conceptual novel approaches entering the clinics to treat cardiac remodeling and heart failure remain scarce. MicroRNAs emerged as powerful and dynamic modifiers of cardiovascular diseases. In this review, the current approaches using microRNAs as novel diagnostic and therapeutic strategies for cardiac remodeling and heart failure are highlighted. Other gene regulatory mechanisms presented include long (>200 bp) noncoding RNAs that function as an additional regulatory machinery of the genome controlling both transcriptional and posttranscriptional events also in the cardiovascular system. (

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“…These anti-DNA PKcs sensitize cells to radiation induced injury [44,54,55] in a similar fashion to RNA inhibition of DNA-PKcs transcripts [56][57][58] . The interaction between epidermal growth factor receptor (EGFR) and the DNA-PKcs has also been explored.…”

Section: Role Of Dna-pkcsmentioning

confidence: 99%

Genotypic characteristics of resistant tumors to pre-operative ionizing radiation in rectal cancer

Ramzan¹

2014

WJGO

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Due to a wide range of clinical response in patients undergoing neo-adjuvant chemoradiation for rectal cancer it is essential to understand molecular factors that lead to the broad response observed in patients receiving the same form of treatment. Despite extensive research in this field, the exact mechanisms still remain elusive. Data raging from DNA-repair to specific molecules leading to cell survival as well as resistance to apoptosis have been investigated. Individually, or in combination, there is no single pathway that has become clinically applicable to date. In the following review, we describe the current status of various pathways that might lead to resistance to the therapeutic applications of ionizing radiation in rectal cancer. Key words: Ionizing radiation; DNA double-strand break; Non-homologous end-joining pathway; DNA-PKcs; Ku proteins; Complete pathological response; Radiation therapy; Apoptosis; Angiogenesis Core tip: Treatment of locally advanced rectal cancer stage Ⅱ and Ⅲ includes neoadjuvant chemo-radiation followed by surgery if clinically feasible. A strategy of observing patients without an operation has been proposed by some surgeons, but this is still the center of much debate. Moreover, the therapeutic effect of ionizing radiation in treatment of rectal cancer varies significantly from one person to another. This has led investigators to identify the molecular targets and pathways in rectal tumors resistant to ionizing radiation in a bid to improve the therapeutic effect of radiation by advanced biomedical and genetic engineering.Ramzan Z, Nassri AB, Huerta S. Genotypic characteristics of resistant tumors to pre-operative ionizing radiation in rectal cancer.

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Prostate-targeted radiosensitization via aptamer-shRNA chimeras in human tumor xenografts

Cited by 125 publications

References 40 publications

Aptamer-targeted inhibition of mTOR in T cells enhances antitumor immunity

Aptamer-targeted inhibition of mTOR in T cells enhances antitumor immunity

Non-coding RNAs in Cardiac Remodeling and Heart Failure

Genotypic characteristics of resistant tumors to pre-operative ionizing radiation in rectal cancer

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