Small Molecule Kinase Inhibitor Screen Identifies Polo-Like Kinase 1 as a Target for Neuroblastoma Tumor-Initiating Cells

Loading drugs into carriers such as liposomes can increase the therapeutic ratio by reducing drug concentrations in normal tissues and raising their concentrations in tumors. Although this strategy has proven advantageous in certain circumstances, many drugs are highly hydrophobic and nonionizable and cannot be loaded into liposomes through conventional means. We hypothesized that such drugs could be actively loaded into liposomes by encapsulating them into specially designed cyclodextrins. To test this hypothesis, two hydrophobic drugs that had failed phase II clinical trials because of excess toxicity at deliverable doses were evaluated. In both cases, the drugs could be remotely loaded into liposomes after their encapsulation (preloading) into cyclodextrins and administered to mice at higher doses and with greater efficacy than possible with the free drugs.T here is currently wide interest in the development of nanoparticles for drug delivery (1-7). This area of research is particularly relevant to cancer drugs, wherein the therapeutic ratio (dose required for effectiveness to dose causing toxicity) is often low. Nanoparticles carrying drugs can increase this therapeutic ratio over that achieved with the free drug through several mechanisms. In particular, drugs delivered by nanoparticles are thought to selectively enhance the concentration of the drugs in tumors as a result of the enhanced permeability and retention (EPR) effect (8-18). The enhanced permeability results from a leaky tumor vascular system, whereas the enhanced retention results from the disorganized lymphatic system that is characteristic of malignant tumors.Much current work in this field is devoted to designing novel materials for nanoparticle generation. This new generation of nanoparticles can carry drugs-particularly those that are insoluble in aqueous medium-that are difficult to incorporate into conventional nanoparticles such as liposomes. However, the older generation of nanoparticles has a major practical advantage in that they have been extensively tested in humans and approved by regulatory agencies such as the Food and Drug Administration in the United States and the European Medicines Agency in Europe. Unfortunately, many drugs cannot be easily or effectively loaded into liposomes, thereby compromising their general use.In general, liposomal drug loading is achieved by either passive or active methods (9,(19)(20)(21)(22). Passive loading involves dissolution of dried lipid films in aqueous solutions containing the drug of interest. This approach can only be used for water-soluble drugs, and the efficiency of loading is often low. In contrast, active loading can be extremely efficient, resulting in high intraliposomal concentrations and minimal wastage of precious chemotherapeutic agents (9,23,24). In active loading, drug internalization into preformed liposomes is typically driven by a transmembrane pH gradient. The pH outside the liposome allows some of the drug to exist in an unionized form, able to migrate across the lipid bi...

show abstract

“…4B). This efficacy was previously observed in other murine models (41,47,(56)(57)(58)(59), and provided the rationale for the clinical trials.…”

Section: Chemically Modified β-Cyclodextrins Can Encapsulate Small Hysupporting

confidence: 70%

Remote loading of preencapsulated drugs into stealth liposomes

Sur

Fries

Kinzler

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

122

View full text Add to dashboard Cite

show abstract

“…Since TIC cells are essential for tumor initiation, tumor maintenance, and tumor growth (Cheng & O'Neill, 2009; Ricci‐Vitiani et al , 2009; Grinshtein et al , 2011; Beck & Blanpain, 2013; Bansal et al , 2016; Zhang et al , 2016), increased TIC activity is expected to accelerate tumor growth in vivo (Grinshtein et al , 2011; Beck & Blanpain, 2013; Bansal et al , 2016). To test the effect of FUT9 on this process, we generated a xenograft model of colorectal cancer in immune‐deficient NOD/SCID gamma mice.…”

Section: Resultsmentioning

confidence: 99%

“…TICs represent a higher proportion of the overall cell population in a tumor at earlier stages of tumor development. At later stages however, TICs are gradually outgrown by the rest of the tumor cells (Fig 4E), but they are still required for efficient tumor growth and maintenance (Cheng & O'Neill, 2009; Ricci‐Vitiani et al , 2009; Grinshtein et al , 2011; Beck & Blanpain, 2013; Bansal et al , 2016; Zhang et al , 2016). Since our experimental data suggest that FUT9 provides an advantage for TIC populations, while its reduced activity benefits other tumor cells, its relative abundance should be expected to gradually drop with tumor progression, mirroring a decrease in the proportional representation of TICs.…”

Section: Discussionmentioning

confidence: 99%

An integrated computational and experimental study uncovers FUT 9 as a metabolic driver of colorectal cancer

Auslander

Cunningham

Toosi

et al. 2017

Molecular Systems Biology

View full text Add to dashboard Cite

Metabolic alterations play an important role in cancer and yet, few metabolic cancer driver genes are known. Here we perform a combined genomic and metabolic modeling analysis searching for metabolic drivers of colorectal cancer. Our analysis predicts FUT9, which catalyzes the biosynthesis of Ley glycolipids, as a driver of advanced‐stage colon cancer. Experimental testing reveals FUT9's complex dual role; while its knockdown enhances proliferation and migration in monolayers, it suppresses colon cancer cells expansion in tumorspheres and inhibits tumor development in a mouse xenograft models. These results suggest that FUT9's inhibition may attenuate tumor‐initiating cells (TICs) that are known to dominate tumorspheres and early tumor growth, but promote bulk tumor cells. In agreement, we find that FUT9 silencing decreases the expression of the colorectal cancer TIC marker CD44 and the level of the OCT4 transcription factor, which is known to support cancer stemness. Beyond its current application, this work presents a novel genomic and metabolic modeling computational approach that can facilitate the systematic discovery of metabolic driver genes in other types of cancer.

show abstract

“…High-throughput screening was performed at the SMART Facility of the Lunenfeld-Tanenbaum Research Institute (Toronto, Canada), as described previously (30,31). Drug "hits" were defined as compounds that caused a signal decrease of at least 75% at a screening dose of 1 mmol/L as compared with controls.…”

Section: High-throughput Screening and Secondary Validationmentioning

confidence: 99%

Disulfiram when Combined with Copper Enhances the Therapeutic Effects of Temozolomide for the Treatment of Glioblastoma

Lun

Wells

Grinshtein

et al. 2016

Clinical Cancer Research

Self Cite

163

119

View full text Add to dashboard Cite

Purpose: Glioblastoma is one of the most lethal cancers in humans, and with existing therapy, survival remains at 14.6 months. Current barriers to successful treatment include their infiltrative behavior, extensive tumor heterogeneity, and the presence of a stem-like population of cells, termed brain tumor-initiating cells (BTIC) that confer resistance to conventional therapies.Experimental Design: To develop therapeutic strategies that target BTICs, we focused on a repurposing approach that explored already-marketed (clinically approved) drugs for therapeutic potential against patient-derived BTICs that encompass the genetic and phenotypic heterogeneity of glioblastoma observed clinically.Results: Using a high-throughput in vitro drug screen, we found that montelukast, clioquinol, and disulfiram (DSF) were cytotoxic against a large panel of patient-derived BTICs. Of these compounds, disulfiram, an off-patent drug previously used to treat alcoholism, in the presence of a copper supplement, showed low nanomolar efficacy in BTICs including those resistant to temozolomide and the highly infiltrative quiescent stem-like population. Low dose DSF-Cu significantly augmented temozolomide activity in vitro, and importantly, prolonged in vivo survival in patient-derived BTIC models established from both newly diagnosed and recurrent tumors. Moreover, we found that in addition to acting as a potent proteasome inhibitor, DSF-Cu functionally impairs DNA repair pathways and enhances the effects of DNA alkylating agents and radiation. These observations suggest that DSF-Cu inhibits proteasome activity and augments the therapeutic effects of DNA-damaging agents (temozolomide and radiation).Conclusions: DSF-Cu should be considered as an adjuvant therapy for the treatment of patients with glioblastoma in both newly diagnosed and recurrent settings.

show abstract

Small Molecule Kinase Inhibitor Screen Identifies Polo-Like Kinase 1 as a Target for Neuroblastoma Tumor-Initiating Cells

Cited by 91 publications

References 31 publications

Remote loading of preencapsulated drugs into stealth liposomes

Remote loading of preencapsulated drugs into stealth liposomes

An integrated computational and experimental study uncovers FUT 9 as a metabolic driver of colorectal cancer

Disulfiram when Combined with Copper Enhances the Therapeutic Effects of Temozolomide for the Treatment of Glioblastoma

Contact Info

Product

Resources

About