Efficient Intravenous Tumor Targeting Using the αvβ6 Integrin-Selective Precision Virotherapy Ad5NULL-A20

We previously developed a refined, tumor-selective adenovirus, Ad5NULL-A20, harboring tropism ablating mutations in each major capsid protein, to ablate all native means of infection. We incorporated a 20-mer peptide (A20) in the fiber knob for selective infection via αvβ6 integrin, a marker of aggressive epithelial cancers. Methods: To ascertain the selectivity of Ad5NULL-A20 for αvβ6-positive tumor cell lines of pancreatic and breast cancer origin, we performed reporter gene and cell viability assays. Biodistribution of viral vectors in mice harboring xenografts with low, medium, and high αvβ6 levels was quantified by qPCR for viral genomes 48 h post intravenous administration. Results: Ad5NULL-A20 vector transduced cells in an αvβ6-selective manner, whilst cell killing mediated by oncolytic Ad5NULL-A20 was αvβ6-selective. Biodistribution analysis following intravenous administration into mice bearing breast cancer xenografts demonstrated that Ad5NULL-A20 resulted in significantly reduced liver accumulation coupled with increased tumor accumulation compared to Ad5 in all three models, with tumor-to-liver ratios improved as a function of αvβ6 expression. Conclusions: Ad5NULL-A20-based virotherapies efficiently target αvβ6-integrin-positive tumors following intravenous administration, validating the potential of Ad5NULL-A20 for systemic applications, enabling tumor-selective overexpression of virally encoded therapeutic transgenes.

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Efficient Intravenous Tumor Targeting Using the αVβ6 Integrin Selective Precision Virotherapy Ad5NULL-A20

10.20944/preprints202103.0779.v1 ◽

2021 ◽

Author(s):

James A Davies ◽

Gareth Marlow ◽

Hanni K Uusi-Kerttula ◽

Gillian Seaton ◽

Luke Piggott ◽

...

Keyword(s):

Breast Cancer ◽

Intravenous Administration ◽

Viral Vectors ◽

Major Capsid Protein ◽

Positive Tumor Cell ◽

Viral Genomes ◽

Epithelial Cancers ◽

Tumor Accumulation ◽

Breast Cancer Xenografts ◽

Tumor Selective

Background: We previously developed a refined, tumor selective adenovirus, Ad5NULL-A20, har-boring tropism ablating mutations in each major capsid protein, to ablate all native means of infection. We incorporated a 20mer peptide (A20) in the fiber knob for selective infection via αvβ6 integrin, a marker of aggressive epithelial cancers. Methods: To ascertain the selectivity of Ad5NULL-A20 for αvβ6 positive tumor cell lines of pancreatic and breast cancer origin, we performed reporter gene and cell viability assays. Biodistribution of viral vectors in mice harboring xenografts with low, medium, and high αvβ6 levels was quantified by qPCR for viral genomes 48 hours post intravenous administration. Results: Ad5NULL-A20 vector transduced cells in an αvβ6 selective manner, whilst cell killing me-diated by oncolytic Ad5NULL-A20 was αvβ6 selective. Biodistribution analysis following intrave-nous administration into mice bearing breast cancer xenografts demonstrated that Ad5NULL-A20 resulted in significantly reduced liver accumulation coupled with increased tumor accumulation compared to Ad5 in all three models, with tumor: liver ratios improved as a function of αvβ6 expression. Conclusions: Ad5NULL-A20 based virotherapies efficiently target αvβ6 integrin positive tumors following intravenous administration, validating the potential of Ad5NULL-A20 for systemic ap-plications, enabling tumor selective overexpression of virally encoded therapeutic transgenes.

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Analysis of the 17BE2 and progesterone (P4)-dependent ESR1 and PGR cistromes in MCF-7 cell-derived mouse breast cancer xenografts

Signaling Pathways Project Datasets ◽

10.1621/gozuaxz6vk ◽

2019 ◽

Author(s):

H Mohammed

Keyword(s):

Breast Cancer ◽

Mouse Breast Cancer ◽

Breast Cancer Xenografts ◽

Mcf 7

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Faculty Opinions recommendation of Subcutaneous versus intravenous administration of (neo)adjuvant trastuzumab in patients with HER2-positive, clinical stage I-III breast cancer (HannaH study): a phase 3, open-label, multicentre, randomised trial.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.717955064.793462779 ◽

2012 ◽

Author(s):

Nancy Lin ◽

Ines Vaz-Luis

Keyword(s):

Breast Cancer ◽

Intravenous Administration ◽

Clinical Stage ◽

Randomised Trial ◽

Stage I ◽

Her2 Positive ◽

Open Label ◽

Phase 3 ◽

Adjuvant Trastuzumab

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Preclinical Molecular Imaging of the Translocator Protein (TSPO) in a Metastases Model Based on Breast Cancer Xenografts Propagated in the Murine Brain

Current Molecular Medicine ◽

10.2174/1566524011207040458 ◽

2012 ◽

Vol 12 (4) ◽

pp. 458-466

Author(s):

Shelby K. Wyatt ◽

H. Charles Manning ◽

Mingfeng Bai ◽

Moneeb Ehtesham ◽

Khubaib Y. Mapara ◽

...

Keyword(s):

Breast Cancer ◽

Molecular Imaging ◽

Translocator Protein ◽

Model Based ◽

Murine Brain ◽

Breast Cancer Xenografts

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Selective Targeting of Breast Cancer by Tafuramycin a Using SMA-Nanoassemblies

Molecules ◽

10.3390/molecules26123532 ◽

2021 ◽

Vol 26 (12) ◽

pp. 3532

Author(s):

Ibrahim M. El-Deeb ◽

Valeria Pittala ◽

Diab Eltayeb ◽

Khaled Greish

Keyword(s):

Breast Cancer ◽

Progesterone Receptors ◽

In Vivo Studies ◽

Chemotherapy Agent ◽

Anticancer Effects ◽

Tumor Tissues ◽

Potential Strategy ◽

Tumor Accumulation

Triple-negative breast cancer (TNBC) is a heterogeneous subtype of tumors that tests negative for estrogen receptors, progesterone receptors, and excess HER2 protein. The mainstay of treatment remains chemotherapy, but the therapeutic outcome remains inadequate. This paper investigates the potential of a duocarmycin derivative, tafuramycin A (TFA), as a new and more effective chemotherapy agent in TNBC treatment. To this extent, we optimized the chemical synthesis of TFA, and we encapsulated TFA in a micellar system to reduce side effects and increase tumor accumulation. In vitro and in vivo studies suggest that both TFA and SMA–TFA possess high anticancer effects in TNBC models. Finally, the encapsulation of TFA offered a preferential avenue to tumor accumulation by increasing its concentration at the tumor tissues by around four times in comparison with the free drug. Overall, the results provide a new potential strategy useful for TNBC treatment.

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Integrated transcription factor profiling with transcriptome analysis identifies L1PA2 transposons as global regulatory modulators in a breast cancer model

Scientific Reports ◽

10.1038/s41598-021-86395-9 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Jiayue-Clara Jiang ◽

Joseph A. Rothnagel ◽

Kyle R. Upton

Keyword(s):

Breast Cancer ◽

Transcription Factor ◽

Transcriptional Regulation ◽

Disease Diagnosis ◽

Integrated Analysis ◽

Regulatory Sequences ◽

Cancer Model ◽

Mcf7 Cells ◽

Epithelial Cancers ◽

Breast Cancer Model

AbstractWhile transposons are generally silenced in somatic tissues, many transposons escape epigenetic repression in epithelial cancers, become transcriptionally active and contribute to the regulation of human gene expression. We have developed a bioinformatic pipeline for the integrated analysis of transcription factor binding and transcriptomic data to identify transposon-derived promoters that are activated in specific diseases and developmental states. We applied this pipeline to a breast cancer model, and found that the L1PA2 transposon subfamily contributes abundant regulatory sequences to co-ordinated transcriptional regulation in breast cancer. Transcription factor profiling demonstrates that over 27% of L1PA2 transposons harbour co-localised binding sites of functionally interacting, cancer-associated transcription factors in MCF7 cells, a cell line used to model breast cancer. Transcriptomic analysis reveals that L1PA2 transposons also contribute transcription start sites to up-regulated transcripts in MCF7 cells, including some transcripts with established oncogenic properties. In addition, we verified the utility of our pipeline on other transposon subfamilies, as well as on leukemia and lung carcinoma cell lines. We demonstrate that the normally quiescent regulatory activities of transposons can be activated and alter the cancer transcriptome. In particular, the L1PA2 subfamily contributes abundant regulatory sequences, and likely plays a global role in modulating breast cancer transcriptional regulation. Understanding the regulatory impact of L1PA2 on breast cancer genomes provides additional insights into cancer genome regulation, and may provide novel biomarkers for disease diagnosis, prognosis and therapy.

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