Biomedical subjects

Justin D Lathia

Publications and source records attributed to Justin D Lathia.

7 recordsLinked to original sources

PubMed2026

Development and characterization of triazole-based WDR5 inhibitors for the treatment of glioblastoma.

Glioblastoma (GBM) cancer stem cells (CSCs) contribute to tumor recurrence, treatment resistance, and dismal clinical outcomes. Genetic and pharmacological evidence suggests that the nuclear scaffolding protein WD-repeat containing protein 5 (WDR5) is a therapeutic vulnerability of the CSC population. However, previously reported WDR5 inhibitors display low permeability and are unable to penetrate the blood-brain barrier (BBB), limiting their utility in GBM. Herein, we report the structure-guided development of a series of triazole-based WDR5 WIN-site inhibitors designed to increase passive brain penetration. We identified triazole-based WDR5 inhibitors that are potent, passively permeable, and in some cases more brain penetrant than other scaffolds. We phenotypically assessed our WDR5 inhibitors in a panel of patient-derived CSC models and uncovered unique WDR5-regulated metabolic genes in GBM. We also evaluated their antiproliferative activity against CSCs both in vitro and in vivo. Finally, to identify potential combination opportunities, we screened a 2,100-compound chemical probe library and identified that the ATAD2 inhibitor BAY-850 synergizes with WDR5 inhibitors to enhance CSC killing. Our work diversifies the chemical matter targeting WDR5, clarifies the in vitro consequences of WIN-site inhibition in CSCs, and encourages the future development of next-generation WDR5 inhibitors with the potential to achieve in vivo efficacy in the brain.

Humans↗

PubMed2025

Connexin 43 drives glioblastoma cancer stem cell phenotypes through a WNK lysine-deficient protein kinase 1-c-MYC signaling axis.

The coordination of cellular processes such as growth and survival relies on communication between cells through gap junctions. Connexin proteins comprise gap junctions and also function to mediate protein-protein interactions and communication with the extracellular space via hemichannels. Despite their essential roles, connexin function in cancer is context dependent, with connexin 43 (Cx43) reported to both promote and suppress tumor growth in glioblastoma, the most common primary malignant brain tumor. Here, we detect primarily intracellular expression of Cx43 in glioblastoma patient-derived cancer stem cells and demonstrate that Cx43 is essential for their survival, self-renewal, and tumor initiation. Mechanistically, Cx43 depletion reduces c-MYC expression through reduced levels of the upstream mediator WNK lysine-deficient protein kinase 1 (WNK1). WNK1 depletion phenocopies Cx43 knockdown and reduces c-MYC expression and tumor initiation. Together, these results define a signaling axis downstream of Cx43 that promotes tumor growth and cancer stem cell phenotypes in glioblastoma.

Connexin 43↗

PubMed2006

Integrins are markers of human neural stem cells.

The identification of markers for the isolation of human neural stem cells (hNSCs) is essential for studies of their biology and therapeutic applications. This study investigated expression of the integrin receptor family by hNSCs as potential markers. Selection of alpha6(hi) or beta1(hi) cells by fluorescence-activated cell sorting led to an enrichment of human neural precursors, as shown by both neurosphere forming assays and increased expression of prominin-1, sox2, sox3, nestin, bmi1, and musashi1 in the beta1(hi) population. Cells expressing high levels of beta1 integrin also expressed prominin-1 (CD133), a marker previously used to isolate hNSCs, and selection using integrin beta1(hi) cells or prominin-1(hi) cells was found to be equally effective at enriching for hNSCs from neurospheres. Therefore, integrin subunits alpha6 and beta1 are highly expressed by human neural precursors and represent convenient markers for their prospective isolation.

AC133 Antigen↗

PubMed2006

Inflammation stimulates myelination by transplanted oligodendrocyte precursor cells.

Inflammation associated with CNS demyelination provides an important stimulus for the activation of endogenous oligodendrocyte precursor cells (OPCs) and subsequent remyelination. This view is largely based on "loss-of-function" studies, whereby remyelination is impaired following depletion of inflammatory cells or mediators. However, "gain-of-function" approaches, asking whether inflammation directly enhances remyelination, have received less attention. We have addressed this issue using a model in which OPCs transplanted into the adult rat retina myelinate retinal ganglion cell axons around the point of injection. Inflammation (characterized by increased expression of the macrophage marker ED1 and the astrocyte marker GFAP, and the up-regulation of multiple cytokines) was induced in the retina by the administration of the TLR-2 ligand zymosan. Myelination, revealed by MBP+ myelin sheaths, was substantially increased when OPCs were injected into the inflamed retina compared to that achieved following transplantation into the normal, noninflamed retina. Our results have important implications for the development of immunomodulatory treatments for acute demyelinating disease and for the therapeutic creation of proremyelination environments in chronic demyelinating disease.

Animals↗

PubMed2004

Ultrasound degradation of novel polymer contrast agents.

This report describes an investigation into factors affecting the degradation of novel poly(lactic-co-glycolic acid) (PLGA) contrast agents. Contrast agents fabricated by two different methods and varying in acoustic properties were compared. The effect of ultrasound frequency (5 and 10 MHz) on degradation of the microcapsules was also studied. High-performance liquid chromatography was used to quantify the production of lactic and glycolic acid to monitor agent degradation. The degradation pattern from the microcapsules was found to be closely related to capsule morphology; the more acoustically efficient capsules (maximum enhancement of 25 dB at 5 MHz with 0.004 mg/mL) degraded at a faster rate than those with lower acoustical efficiency (maximum enhancement of 25 dB at 5 MHz only achieved with 0.6 mg/mL). The capsules also degraded fastest when insonated at the frequency at which they gave highest backscatter. In addition, despite the use of a 50:50 PLGA copolymer, more glycolic than lactic acid was released at early time points, which reflects the greater hydrophilicity of the glycolic acid residues, and greater degradation rate of glycolic acid repeat units. The results from this study provided unique insight into the degradation behavior of hollow PLGA microcapsules, and their potential in ultrasound diagnosis and therapy.

Biocompatible Materials↗

PubMed2004

Polymeric contrast agent with targeting potential.

The Arg-Gly-Asp (RGD) peptide sequence was conjugated to poly (lactid acid), (PLA), microcapsules. These hollow, biodegradable PLGA microcapsules were developed in our laboratory for use as ultrasound contrast agents. By modifying the surface of the agent with a targeting ligand, it can be targeted to a specific address within the body. This application is ideal for both targeted imaging and/or targeted drug delivery. Integrins are membrane-spanning proteins in cells that play a vital role in cell attachment and many other processes. The RGD peptide sequence targets integrins expressed during angiogenesis, alphavbeta3 and alphavbeta5. The integrins specific to angiogenesis are more active during cancer and can be used as receptors for the RGD-conjugated contrast agents. Although the generic RGD sequence is not specific to only alphavbeta3 and alphavbeta5 integrins, it is an excellent candidate for proof of concepts studies such as described here. Preliminary in vitro results indicate that the modified capsules remain highly echogenic (maximum enhancement of 20 dB in vitro) and adhere specifically to a breast cancer cell line MDA-MB-231 in static experiments. However, no adherence is seen with either unmodified capsules (negative control), or when cells that have been pre-saturated with RGD ligand are contacted with modified capsules (positive control). Specific targeting of ultrasound contrast agents could lead the way to imaging as a method for discrimination of malignant from benign.

Analysis of Variance↗

PubMed2004

Effect of shell type on the in vivo backscatter from polymer-encapsulated microbubbles.

This study compared in vivo enhancement from four different polymer-encapsulated ultrasound (US) contrast agents. The agents were produced with a rigid shell composed of the biodegradable block copolymer poly[D,L-lactide-co-glycolide] (PLGA) with the lactic and glycolic acid ratios 50:50, 75:25, 85:15 and 100:0 (i.e., increasingly hydrophobic shell compositions). Approximately the same bubble diameter (1.2 microm) and concentration (0.4 g/mL) were obtained for each agent. In four rabbits, audio Doppler signals were acquired from a 10 MHz cuff transducer placed around a surgically exposed vessel (contrast dose: 0.0125 to 0.15 mL/kg). In vivo dose responses were calculated off-line (in dB). Nine rabbit kidneys were imaged during contrast administration (0.1 mL/kg) in power Doppler and grey-scale pulse inversion harmonic (PIHI) modes using an HDI 5000 scanner (Philips Medical Systems, Bothell, WA). Time-intensity curves were produced and the time-to-peak, peak intensity, slope, area under the curve (AUC) and total duration of enhancement for each agent were compared. All agents produced marked Doppler enhancement with increasing duration from the 50:50 agent (48 +/- 10 s) to the 75:25 agent (166 +/- 46 s), the 85:15 agent (403 +/- 83 s) and with the 100:0 agent (603 +/- 93 s) lasting longest (p < 0.02). No other parameters changed significantly, except the AUC of the 85:15 agent, which was greater than that of the 50:50 agent (190.75 vs. 61.58; p = 0.02). The in vivo dose-response curves were similar for all agents, with mean enhancement up to 20.6 +/- 1.11 dB (p = 0.17). In conclusion, contrast duration increases by an order of magnitude as the lactic acid component in the polymer-encapsulated bubbles increases and the shell, thus, becomes increasingly hydrophobic.

Animals↗