Progress on Kinesin Spindle Protein Inhibitors as Anti-Cancer Agents

RNA interference (RNAi) is a potent and specifi c mechanism for regulating gene expression. Harnessing RNAi to silence genes involved in disease holds promise for the development of a new class of therapeutics. Delivery is key to realizing the potential of RNAi, and lipid nanoparticles (LNP) have proved effective in delivery of siRNAs to the liver and to tumors in animals. To examine the activity and safety of LNP-formulated siRNAs in humans, we initiated a trial of ALN-VSP, an LNP formulation of siRNAs targeting VEGF and kinesin spindle protein (KSP), in patients with cancer. Here, we show detection of drug in tumor biopsies, siRNA-mediated mRNA cleavage in the liver, pharmacodynamics suggestive of target downregulation, and antitumor activity, including complete regression of liver metastases in endometrial cancer. In addition, we show that biweekly intravenous administration of ALN-VSP was safe and well tolerated. These data provide proof-of-concept for RNAi therapeutics in humans and form the basis for further development in cancer. SIGNIFICANCE:The fi ndings in this report show safety, pharmacokinetics, RNAi mechanism of action, and clinical activity with a novel fi rst-in-class LNP-formulated RNAi therapeutic in patients with cancer. The ability to harness RNAi to facilitate specifi c multitargeting, as well as increase the number of druggable targets, has important implications for future drug development in oncology. Cancer Discov; 3(4); 406-17.

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“…17 ) in a 1:1 molar ratio. Both siRNAs were chemically modifi ed to reduce their immunostimulatory potential (refs.…”

Section: Aln-vsp Composition and Preclinical Safety And Activitymentioning

confidence: 99%

First-in-Humans Trial of an RNA Interference Therapeutic Targeting VEGF and KSP in Cancer Patients with Liver Involvement

et al. 2013

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“…Both genes have been extensively investigated as targets of anticancer drugs. 23,24 However, the downstream molecular pathways through which tumor cells undergo cell death in response to mitotic arrest are not well defined. Evidence from microtubule binding drugs suggests that proliferation of non-transformed cells, including hematopoetic precursor cells, might explain the severe myelosuppression and neutropenia observed in patients during therapy.…”

Section: Introductionmentioning

confidence: 99%

Intratumor RNA interference of cell cycle genes slows down tumor progression

et al. 2011

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Small interfering RNAs (siRNAs) are emerging as promising therapeutic tools. However, the widespread clinical application of such molecules as modulators of gene expression is still dependent on several aspects that limit their bioavailability. One of the most promising strategies to overcome the barriers faced by gene silencing molecules involves the use of lipid-based nanoparticles (LNPs) and viral vectors, such as adenoviruses (Ads). The primary obstacle for translating gene silencing technology from an effective research tool into a feasible therapeutic strategy remains its efficient delivery to the targeted cell type in vivo. In this study, we tested the capability of LNPs and Ad to transduce and treat locally tumors in vivo. Efficient knockdown of a surrogate reporter (luciferase) and therapeutic target genes such as the kinesin spindle protein (KIF11) and polo-like kinase 1 were observed. Most importantly, this activity led to a cell cycle block as a consequence and slowed down tumor progression in tumor-bearing animals. Our data indicate that it is possible to achieve tumor transduction with si/short hairpin RNAs and further improve the delivery strategy that likely in the future will lead to the ideal non-viral particle for targeted cancer gene silencing.

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“…Due toEg5's essential function in mitosis, it is now an important target for the development of inhibitors that have antimitotic activity [7][8][9]. Following the discovery of monastrol [10], the first identified Eg5 inhibitor, a plethora of structurally related and unrelated inhibitors of Eg5 have been recently identified [11][12][13]. Earlier, we have described STLC as an Eg5-specific inhibitor which proved more potent than monastrol [14].…”

Section: Introductionmentioning

confidence: 99%

Mutations in the human kinesin Eg5 that confer resistance to monastrol and S-trityl-l-cysteine in tumor derived cell lines

Tcherniuk

Lis

Kozielski

et al. 2010

Biochemical Pharmacology

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. Mutations in the human kinesin Eg5 that confer resistance to monastrol and S-Trityl-L-Cysteine in tumor derived cell lines.. Biochemical Pharmacology, Elsevier, 2010, 79 (6) This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. confirms the target specificity of monastrol and STLC for Eg5. These data also suggest a possible mechanism by which drug resistance may occur in tumors treated with agents targeting Eg5.

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Progress on Kinesin Spindle Protein Inhibitors as Anti-Cancer Agents

Cited by 50 publications

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First-in-Humans Trial of an RNA Interference Therapeutic Targeting VEGF and KSP in Cancer Patients with Liver Involvement

First-in-Humans Trial of an RNA Interference Therapeutic Targeting VEGF and KSP in Cancer Patients with Liver Involvement

Intratumor RNA interference of cell cycle genes slows down tumor progression

Mutations in the human kinesin Eg5 that confer resistance to monastrol and S-trityl-l-cysteine in tumor derived cell lines

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