An In Vivo shRNA-Drug Screen to Identify Novel Targeted Therapy Combinations for KRAS Mutant Cancers

Background: Chronic Myeloid Leukaemia (CML) is associated with the BCRABL1 gene, which plays a central role in the pathogenesis of CML. Thus, it is crucial to suppress the expression of BCR-ABL1 in the treatment of CML. MicroRNA is known to be a gene expression regulator and is thus a good candidate for molecularly targeted therapy for CML. Objective: This study aims to identify the microRNAs from edible plants targeting the 3’ Untranslated Region (3’UTR) of BCR-ABL1. Methods: In this in silico analysis, the sequence of 3’UTR of BCR-ABL1 was obtained from Ensembl Genome Browser. PsRNATarget Analysis Server and MicroRNA Target Prediction (miRTar) Server were used to identify miRNAs that have binding conformity with 3’UTR of BCR-ABL1. The MiRBase database was used to validate the species of plants expressing the miRNAs. The RNAfold web server and RNA COMPOSER were used for secondary and tertiary structure prediction, respectively. Results: In silico analyses revealed that cpa-miR8154, csi-miR3952, gma-miR4414-5p, mdm-miR482c, osa-miR1858a and osa-miR1858b show binding conformity with strong molecular interaction towards 3’UTR region of BCR-ABL1. However, only cpa-miR- 8154, osa-miR-1858a and osa-miR-1858b showed good target site accessibility. Conclusion: It is predicted that these microRNAs post-transcriptionally inhibit the BCRABL1 gene and thus could be a potential molecular targeted therapy for CML. However, further studies involving in vitro, in vivo and functional analyses need to be carried out to determine the ability of these miRNAs to form the basis for targeted therapy for CML.

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IL-2–Targeted Therapy Ameliorates the Severity of Graft-versus-Host Disease: Ex Vivo Selective Depletion of Host-Reactive T Cells and In Vivo Therapy

Biology of Blood and Marrow Transplantation ◽

10.1016/j.bbmt.2011.11.016 ◽

2012 ◽

Vol 18 (4) ◽

pp. 523-535 ◽

Cited By ~ 12

Author(s):

Shai Yarkoni ◽

Tatyana B. Prigozhina ◽

Shimon Slavin ◽

Nadir Askenasy

Keyword(s):

T Cells ◽

Targeted Therapy ◽

Graft Versus Host Disease ◽

Ex Vivo ◽

Host Disease ◽

Graft Versus Host ◽

Selective Depletion

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Recombinant Immunotoxin 4D5scFv-PE40 for Targeted Therapy of HER2-Positive Tumors

Acta Naturae ◽

10.32607/20758251-2015-7-4-93-96 ◽

2015 ◽

Vol 7 (4) ◽

pp. 93-96 ◽

Cited By ~ 2

Author(s):

E. A. Sokolova ◽

O. A. Stremovskiy ◽

T. A. Zdobnova ◽

I. V. Balalaeva ◽

S. M. Deyev

Keyword(s):

Targeted Therapy ◽

Tumor Marker ◽

Cancer Cells ◽

Therapeutic Index ◽

Molecular Profile ◽

Her2 Positive ◽

Pseudomonas Exotoxin A ◽

Recombinant Immunotoxin ◽

Long Run

Recombinant immunotoxins are extremely promising agents for the targeted therapy of tumors with a certain molecular profile. In this work, we studied the properties of a new recombinant HER2-specific immunotoxin composed of the scFv antibody and a fragment of Pseudomonas exotoxin A (4D5scFv-PE40). High affinity of the immunotoxin for the HER2 tumor marker, its selective cytotoxicity against HER2-overexpressing cells, and its storage stability were demonstrated. The 50% inhibitory concentration (IC50) of the 4D5scFv-PE40 immunotoxin for HER2-overexpressing cancer cells was 2.5-3 orders of magnitude lower compared to that for CHO cells not expressing this tumor marker and was 2.5-3 orders of magnitude lower than IC50 of free PE40 for HER2-overexpressing cancer cells. These findings provide a basis for expecting in the long run high therapeutic index values of the 4D5scFv-PE40 immunotoxin for its use in vivo.

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EPCT-06. A PHASE I STUDY OF MULTI-TARGETED THERAPY IN NEWLY DIAGNOSED OR PROGRESSIVE DIFFUSE INTRINSIC PONTINE GLIOMA

Neuro-Oncology ◽

10.1093/neuonc/noaa222.130 ◽

2020 ◽

Vol 22 (Supplement_3) ◽

pp. iii304-iii305

Author(s):

Muhammad Baig ◽

Jason Johnson ◽

Sumit Gupta ◽

Zsila Sadighi ◽

Wafik Zaky ◽

...

Keyword(s):

Targeted Therapy ◽

Maintenance Therapy ◽

Phase I ◽

Phase I Study ◽

Diffusion Tensor ◽

Diffuse Intrinsic Pontine Glioma ◽

Newly Diagnosed ◽

Pontine Glioma ◽

Dose Limiting Toxicity

Abstract BACKGROUND Diffuse intrinsic pontine glioma (DIPG) constitutes 80% of pediatric brain stem tumors with a median survival of 12 months. The PI3K/AKT/mTOR pathway is a key oncogenic driver of this tumor. Targeting the chromatin dysregulation through HDAC inhibition, demonstrated benefit in vivo and vitro studies. We completed the first study as a multi-targeted therapy using SAHA and temsirolimus in pediatric DIPG. METHODS After receiving institutional IRB approval, we enrolled 6 patients on this phase I study using a 3 + 3 statistical design. Patients were divided into stratum 1 and stratum 2, based on newly diagnosed or relapsed DIPG respectively. Stratum I patients received radiation therapy concurrently with vorinostat, followed by maintenance therapy with vorinostat and temsirolimus for 10 cycles (28 day cycle), while in stratum II patients received vorinostat and temsirolimus for 12 cycles. Neuroimaging including diffusion tensor imaging were evaluated where feasible. RESULTS Three patients were enrolled in each of the stratum. One patient in stratum 1 completed therapy, 2 other demonstrated progressive disease (PD) after 4th and 1st cycle of maintenance therapy respectively. In stratum 2 all patients progressed 2 months after the start of therapy. However no dose-limiting toxicity (DLT) was noted. The patient in stratum 1 who completed therapy, remained free of PD 21 months after diagnosis with continued improvements in the volume of enhancing and T2 hyperintense disease. CONCLUSION Although no significant benefit was seen as compared to historical controls during this study, no dose limiting toxicity was noticed with this treatment.

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An Efficient Bivalent Cyclic RGD-PIK3CB siRNA Conjugate for Specific Targeted Therapy against Glioblastoma In Vitro and In Vivo

Molecular Therapy — Nucleic Acids ◽

10.1016/j.omtn.2018.09.002 ◽

2018 ◽

Vol 13 ◽

pp. 220-232 ◽

Cited By ~ 11

Author(s):

Bohong Cen ◽

Yuanyi Wei ◽

Wen Huang ◽

Muzhou Teng ◽

Shuai He ◽

...

Keyword(s):

Targeted Therapy

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MicroRNA in Lung Cancer Metastasis

Cancers ◽

10.3390/cancers11020265 ◽

2019 ◽

Vol 11 (2) ◽

pp. 265 ◽

Cited By ~ 15

Author(s):

Shang-Gin Wu ◽

Tzu-Hua Chang ◽

Yi-Nan Liu ◽

Jin-Yuan Shih

Keyword(s):

Lung Cancer ◽

Targeted Therapy ◽

Cancer Metastasis ◽

Epithelial To Mesenchymal Transition ◽

Cancer Treatments ◽

Mesenchymal Transition ◽

Lung Cancer Metastasis ◽

Targeted Treatments

Tumor metastasis is a hallmark of cancer, with distant metastasis frequently developing in lung cancer, even at initial diagnosis, resulting in poor prognosis and high mortality. However, available biomarkers cannot reliably predict cancer spreading sites. The metastatic cascade involves highly complicated processes including invasion, migration, angiogenesis, and epithelial-to-mesenchymal transition that are tightly controlled by various genetic expression modalities along with interaction between cancer cells and the extracellular matrix. In particular, microRNAs (miRNAs), a group of small non-coding RNAs, can influence the transcriptional and post-transcriptional processes, with dysregulation of miRNA expression contributing to the regulation of cancer metastasis. Nevertheless, although miRNA-targeted therapy is widely studied in vitro and in vivo, this strategy currently affords limited feasibility and a few miRNA-targeted therapies for lung cancer have entered into clinical trials to date. Advances in understanding the molecular mechanism of metastasis will thus provide additional potential targets for lung cancer treatment. This review discusses the current research related to the role of miRNAs in lung cancer invasion and metastasis, with a particular focus on the different metastatic lesions and potential miRNA-targeted treatments for lung cancer with the expectation that further exploration of miRNA-targeted therapy may establish a new spectrum of lung cancer treatments.

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A versatile polyion complex can intelligently respond to a tumor microenvironment to eliminate tumor stem cells for enhanced lung cancer targeted therapy

Biomaterials Science ◽

10.1039/c9bm00812h ◽

2019 ◽

Vol 7 (9) ◽

pp. 3751-3763 ◽

Cited By ~ 2

Author(s):

Jiulong Zhang ◽

Xiufeng Zhao ◽

Chunrong Yang ◽

Ziyuan Huang ◽

Menghao Shi ◽

...

Keyword(s):

Lung Cancer ◽

Stem Cells ◽

Targeted Therapy ◽

Tumor Microenvironment ◽

Antitumor Activity ◽

Tumor Stem Cells ◽

Polyion Complex ◽

Cancer Targeted Therapy

A versatile polyion complex was fabricated which could response to tumor microenvironment and possess remarkable tumor penetrating capability with elevated antitumor activity for LCSCs elimination in vivo.

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