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Non-Viral Delivery of Genome-Editing Nucleases for Gene Therapy
Published in Yashwant Pathak, Gene Delivery, 2022
The siRNA based lipid vectors showed targeted delivery of siRNA to silence the target genes with a nanoparticle size of 200nm [64]. It was first discovered in 2005 to treat hepatitis B virus (HBV) in a mouse model HBV replication [65]. In two separate clinical trials, efficacy of LNP-based siRNA delivery has been evaluated in patients with hepatocellular carcinoma. Tekmira pharmaceuticals corporation investigated the antitumor activity of drug TKM-080301 targeted to suppress the polo-like kinase 1 (PLK1). On the other hand, Alnylam pharmaceuticals developed ALN-VSP02 to target KIF11 (which encodes kinesin spindle protein) and VEGF. In addition, ALN-TTR02 (Alnylam pharmaceuticals) based siRNA formulations are shown to have the ability of silencing the transthyretin (TTR) in TTR-mediated amyloidosis. Patisiran is a second-generation SNALP formulation ALN-TTR02, which is a DLinDMA analogue. In preclinical studies, it showed a tenfold increase in therapeutic activity [1, 66].
Targeting Subgroup-specific Cancer Epitopes for Effective Treatment of Pediatric Medulloblastoma
Published in Surinder K. Batra, Moorthy P. Ponnusamy, Gene Regulation and Therapeutics for Cancer, 2021
Sidharth Mahapatra, Naveenkumar Perumall
Polo-like kinase 1 (PLK1) facilitates mitotic entry and exit. Overexpression leads to aneuploidy, chromosomal instability, and neoplastic transformation [99]. Likewise, a small molecule inhibitor of PLK1 (BI 2536) suppressed colony and tumor sphere formation, inhibited cell growth, and increased apoptosis in vitro; moreover, PLK1 inhibition enhanced radiosensitivity of high-MYC expressing medulloblastoma cell lines [100]. Finally, the CDK4/6 inhibitor, palbociclib, was shown to decrease tumor cell proliferation, to increase apoptosis, and to improve survival in an orthotopic mouse model of MYC-overexpressing Group 3 MB [101].
Antitubulin Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
The Polo-Like Kinases (PLKs) are a family of conserved serine/threonine kinases that are important regulators of the cell cycle through G2 and some phases of mitosis, including mitotic entry and exit, and cytokinesis. The “Polo” domain is named after the original protein encoded by the Polo gene of Drosophila melanogaster. These proteins are involved in the formation of, and modifications to, the mitotic spindle, and in the activation of CDK/Cyclin complexes during the M phase of the cell cycle. The PLKs are characterized by an amino terminal catalytic domain, and a carboxy terminal noncatalytic domain consisting of three blocks of conserved sequences known as Polo boxes which form one single functional domain. Mammalian PLKs include PLK1 (also known as STPK13), PLK2 (also known as SNK), PLK3 (also known as CNK, FNK, and PRK), PLK4 (also known as SAK or STK18), and PLK5. In particular, PLK1 acts in concert with Cyclin-dependent kinase 1 (Cyclin B1) and the Aurora kinases to orchestrate a wide range of critical cell-cycle events.
Virtual screening and zebrafish models in tandem, for drug discovery and development
Published in Expert Opinion on Drug Discovery, 2023
David Hernández-Silva, Francisca Alcaraz-Pérez, Horacio Pérez-Sánchez, Maria Luisa Cayuela
Rapid development. Polo-like kinase 1 (PLK1) [90], one of the most important regulators of mitosis, is a target for cancer therapy given its abnormally heightened activity in several tumors. The first 10 mitoses of zebrafish embryonic cleavages take place every∼30 minutes, providing a rapid assay to evaluate mitosis inhibitors, even those targeting Plk1. A computational virtual screen of∼60,000 compounds against the human Plk1 3-D structure, which is highly conserved between zebrafish and humans, identified 370 candidates with the top free-energy scores. The candidates underwent a zebrafish assay, and three were shown to inhibit cell division in the first 40 minutes after being added to the embryos. One of the three, named I2, went on to demonstrate the effective inhibition of PC3 prostate cancer growth in the Xenograft mouse model in vivo. The IC50 values of I2 in these assays are compatible with those of ON-01910, a Plk1 inhibitor currently in Phase III clinical trials. Importantly, the authors compared results from a random screen using the ChemBridge DiverSet chemical library (from 5376 compounds) with a computation-based pre-screen computation, which was seen to increase the efficiency of identifying mitosis inhibitors by approximately 11-fold [90].
Hepatocellular carcinoma (HCC): the most promising therapeutic targets in the preclinical arena based on tumor biology characteristics
Published in Expert Opinion on Therapeutic Targets, 2021
Haichuan Wang, Xin Chen, Diego F. Calvisi
Amplification of two-pore channel 2 (TPC2) occurs in ~6% of HCC samples based on the TCGA database. Muller et al. developed simplified analogs of the alkaloid tetrandrine as potent TPC2 inhibitors by screening a library of synthesized benzyltetrahydroisoquinoline derivatives. Notably, they found a TPC2 inhibitor with anti-tumor efficacy in mice [108]. Han et al. developed a miR122a-based approach to target telomerase reverse transcriptase (TERT) through the post-transcriptional enhancement of the ribozyme improved trans-splicing [109]. In addition, the Ser/Thr kinase polo-like kinase 1 (PLK1) plays a pivotal role in cell-cycle regulation, and targeting PLK1 with a selective PLK1 kinase inhibitor exhibited profound anti-tumor efficacy in a xenograft mouse HCC model [110]. The transcription factor Late SV40 factor (LSF) promotes hepatocarcinogenesis by regulating the major hallmarks of cancer, including cell invasion, angiogenesis, chemoresistance, and senescence [111]. The LSF inhibitors, factor quinolinone inhibitor 1 (FQI1) and FQI2, have shown compelling therapeutic effects on the HCC lesions from Alb/c-Myc transgenic mice [112]. Several microRNAs, such as miR122 [113], miR21 [114], and miR218 [115], have been identified as effective targets for HCC treatment. With the advances in the pharmacological field, targeting specific microRNAs might also be beneficial for HCC treatment.
Comparison of cationic liposome and PAMAM dendrimer for delivery of anti-Plk1 siRNA in breast cancer treatment
Published in Pharmaceutical Development and Technology, 2020
Upendra Bulbake, Nagavendra Kommineni, Maksim Ionov, Maria Bryszewska, Wahid Khan
Polo-like kinase 1 is a serine/threonine kinase enzyme encoded by the Plk1 gene (Barr et al. 2004). Activity of Plk1 gene is elevated in proliferating cancer cells (Strebhardt and Ullrich 2006). The significance of Plk1 in tumor and for envisaging effects in patients with cancer results from its involvement in oncogenic transformation (Zhang et al. 2013). The supression of Plk1 with anti-PLk1 siRNA (siPlk1) leads to mitotic arrest, apoptosis and inhibition of tumor growth (Spa¨nkuch-Schmitt et al. 2002). However, delivery of siRNA is difficult because they are highly negatively charged molecules thus they are not able cross cell membranes easily. Moreover, due to their short circulation half-life, degradation by RNase enzyme and poor serum stability, it requires effective delivery system to overcome the number of cellular barriers (Kim and Rossi 2007). TKM-080301 is a lipid nanoparticle formulation of siPlk1 present in phase I clinical trial for the treatment of hepatocellular carcinoma (Bulbake et al. 2017). Patients receive single dose of TKM-080301 given directly into the liver through Hepatic Arterial Infusion (HAI). However, drugs used thus far in HAI have limited efficacy.