HIF2α-Targeted RNAi Therapeutic Inhibits Clear Cell Renal Cell Carcinoma

Wong, So C.; Cheng, Weijun; Hamilton, Holly L.; Nicholas, Anthony L.; Wakefield, Darren H.; Almeida, Aaron; Blokhin, Andrei V.; Carlson, Jeffrey; Neal, Zane C.; Субботин, Владимир; Zhang, Guofeng; Hegge, Julia; Bertin, Stephanie; Trubetskoy, Vladimir S.; Rozema, David B.; Lewis, David L.; Kanner, Steven B.

doi:10.1158/1535-7163.mct-17-0471

Cited by 24 publications

(10 citation statements)

References 43 publications

(73 reference statements)

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“…Furthermore, studies on pre-neoplastic kidney lesions of patients with VHL disease also support the key role of HIF2A in the transformation of dysplastic cells, as the HIF2A expression was increased while that of HIF1A was decreased, as assessed by IHC (71,72). The association between high levels of HIF2A and ccRCC progression has also been observed in cell lines representing various stages of RCC progression (73,74) or in mouse xenograft models (77). In a clinical study, Kamai et al analyzed tumor samples obtained from 129 patients with ccRCC, and found that increased expression of the HIF2A protein (measured by western blot analysis) was associated with worse clinical status, local and distant metastasis, and shorter OS (78).…”

Section: Discussionmentioning

confidence: 86%

Prognostic significance of VHL, HIF1A, HIF2A, VEGFA and p53 expression in patients with clear‑cell renal cell carcinoma treated with sunitinib as first‑line treatment

et al. 2019

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Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cell cancer, characterized by the highest mortality rate among other RCC subtypes due to the occurrence of metastasis and drug resistance following surgery. The Von Hippel-Lindau tumor suppressor (VHL)-hypoxia-inducible factor 1 subunit α (HIF1A)/hypoxia-inducible factor 2α (HIF2A)-vascular endothelial growth factor A (VEGFA) protein axis is involved in the development and progression of ccRCC, whereas sunitinib, a tyrosine kinase inhibitor, blocks the binding of VEGFA to its receptor. The aim of the present study was to examine the possible association of the gene expression of VHL, HIF1A, HIF2A, VEGFA and tumor protein P53 ( P53 ) in cancer tissue with the outcome of ccRCC patients who were treated with sunitinib as first-line therapy following nephrec-tomy. A total of 36 ccRCC patients were enrolled, 11 of whom were administered sunitinib post-operatively. Tumor and control samples were collected, and mRNA and protein levels were assessed by reverse transcription-quantitative polymerase chain reaction and western blot analysis, respectively. High mRNA and protein expression levels of HIF2A and VEGFA were found to be associated with shorter overall survival (OS) and progression-free survival (PFS) rates, as well as with unfavorable risk factors of cancer recurrence and mortality. Resistance to sunitinib was also observed; the OS and PFS rates were shorter (median OS and PFS: 12 and 6 months, respectively, vs. undetermined). Sunitinib resistance was associated with high HIF2A and VEGFA protein levels (b=0.57 and b=0.69 for OS and PFS, respectively; P<0.001). Taken together, the findings of this study suggest that the protein levels of HIF2A and VEGFA in tumor tissue may serve as independent prognostic factors in ccRCC. ccRCC patients with increased intratumoral HIF2A and VEGFA protein levels, and unaltered VHL protein levels, are not likely to benefit from sunitinib treatment following nephrectomy; however, this hypothesis requires verification by large-scale replication studies.

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Section: Discussionmentioning

confidence: 86%

Prognostic significance of VHL, HIF1A, HIF2A, VEGFA and p53 expression in patients with clear‑cell renal cell carcinoma treated with sunitinib as first‑line treatment

et al. 2019

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“…Polymeric materials are not as clinically advanced for nucleic acid delivery as ionizable lipids, with few formulations used for the delivery of therapeutic siRNA. 47,48 Relative to lipids, polymeric materials face additional challenges related to polydispersity and clearance or biodegradation for large molecular weight polymers. Low-molecular-weight polyethyleneimine (PEI) modified with fatty chains has been used for siRNA and mRNA delivery to reduce toxicity of high-molecular weight PEI.…”

Section: Reviewmentioning

confidence: 99%

Delivering the Messenger: Advances in Technologies for Therapeutic mRNA Delivery

et al. 2019

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mRNA has broad potential as a therapeutic. Current clinical efforts are focused on vaccination, protein replacement therapies, and treatment of genetic diseases. The clinical translation of mRNA therapeutics has been made possible through advances in the design of mRNA manufacturing and intracellular delivery methods. However, broad application of mRNA is still limited by the need for improved delivery systems. In this review, we discuss the challenges for clinical translation of mRNA-based therapeutics, with an emphasis on recent advances in biomaterials and delivery strategies, and we present an overview of the applications of mRNA-based delivery for protein therapy, gene editing, and vaccination. mRNA holds the potential to revolutionize vaccination, protein replacement therapies, and the treatment of genetic diseases. Since the first pre-clinical studies in the 1990s, 1 significant progress in the clinical translation of mRNA therapeutics has been made through advances in the design of mRNA manufacturing and intracellular delivery methods. 2 The translatability and stability of mRNA as well as its immunostimulatory activity are the key factors to be optimized for specific therapeutic application. 3 Increased translation and stability can be affected by many regions of the RNA. mRNA 5 0 and 3 0 UTRs are responsible for recruiting RNA-binding proteins and microRNAs, and they can profoundly affect translational activity. 2,4 The modification of rare codons in protein-coding sequences with synonymous frequently occurring codons, so-called codon optimization, can result in order-of-magnitude changes in expression levels. 5,6 Modification of the 5 0 mRNA cap can also enhance mRNA translation by inhibiting RNA decapping and improving resistance to enzymatic degradation. 7 Chemical modification of RNA bases can be used to modify mRNA immunostimulatory activity. 8,9 The importance of immunostimulation can depend on the application, 10 and, in some cases, it may actually improve performance, as in the case of vaccines. 11Finally, methods and vehicles for intracellular delivery remain the major barrier to the broad application of mRNA therapeutics. 12 With some exceptions, the intracellular delivery of mRNA is generally more challenging than that of small oligonucleotides, and it requires encapsulation into a delivery nanoparticle, in part due to the significantly larger size of mRNA molecules (300-5,000 kDa, 1-15 kb) as compared to other types of RNAs (small interfering RNAs [siRNAs], 14 kDa; antisense oligonucleotides [ASOs], 4-10 kDa). 10,13 In this review, we discuss the challenges for clinical translation of mRNAbased therapeutics, with an emphasis on recent advances in biomaterials and delivery strategies, and we present an overview of the applications of mRNA-based delivery for protein therapy, gene editing, and vaccination. Materials for mRNA Delivery Structural Aspects of Material DesignAmong the many barriers to function, mRNA must cross the cell membrane in order to reach the cytoplasm (Figure 1). The cell me...

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“…Subsequently, the siRNA drug was delivered in cytosol via disruption of disulfide bond. Moving forward, Arrowhead had developed a better alternative, called TRiM (Targeted RNAi Molecule) technology [ 168 ] with enhanced pharmacokinetic performance and built‐in targeting ligands, namely, GalNAc, αvβ6 ligands, and RGD peptides to deliver nucleic acids in hepatocytes, lung epithelial cells, and cancer cells, respectively.…”

Section: Discussionmentioning

confidence: 99%

Charge‐Conversion Strategies for Nucleic Acid Delivery

Dutta

Das

Medeiros

et al. 2021

Adv Funct Materials

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Nucleic acids are considered as one of the most potent therapeutic modalities, as their roles go beyond storing genetic information and chemical energy or as signal transducers. Attenuation or expression of desired genes through nucleic acids have profound implications in gene therapy, gene editing, and even in vaccine development. Although nucleic acid therapeutics bring in overwhelming possibilities toward the development of molecular medicines, there are significant loopholes in their effective clinical translation. One of the major pitfalls lies in the traditional design concepts of nucleic acid drug carriers, namely, cationic charge induced cytotoxicity. Targeting this bottleneck, several innovative carrier designs have been proposed accommodating charge‐conversion approaches, whereby built‐in functionalities convert from cationic to neutral or anionic, or even from anionic to cationic enabling the carrier to overcome several critical barriers for therapeutics delivery, such as serum deactivation, instability in circulation, low transfection, and poor endosomal escape. This review will critically analyze various molecular designs of charge‐converting nanocarriers in a classified approach for the successful delivery of nucleic acids. Accompanied by the narrative on recent clinical nucleic acid candidates, the review concludes with a discussion on the pitfalls and scope of these emerging approaches.

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HIF2α-Targeted RNAi Therapeutic Inhibits Clear Cell Renal Cell Carcinoma

Cited by 24 publications

References 43 publications

Prognostic significance of VHL, HIF1A, HIF2A, VEGFA and p53 expression in patients with clear‑cell renal cell carcinoma treated with sunitinib as first‑line treatment

Prognostic significance of VHL, HIF1A, HIF2A, VEGFA and p53 expression in patients with clear‑cell renal cell carcinoma treated with sunitinib as first‑line treatment

Delivering the Messenger: Advances in Technologies for Therapeutic mRNA Delivery

Charge‐Conversion Strategies for Nucleic Acid Delivery

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