Mitotic Checkpoints and the Role of WEE1 Inhibition in Head and Neck Squamous Cell Carcinoma.

ABSTRACT: The WEE1 kinase family plays a crucial role in cell cycle regulation and DNA damage response pathways in malignant cells. Inhibition of WEE1 effectively overrides G2 cell cycle arrest and results in the accumulation of extensive DNA damage within dividing cells, potentiating mitotic catastrophe and cell death. As such, the development of WEE1 inhibitors as antineoplastic therapeutics has gained increasing interest in recent years. In particular, the role of WEE1 inhibitors for treatment of head and neck squamous cell carcinomas remains an area of active research with both preclinical and clinical studies investigating their use as both single-agent therapy and chemosensitizers when used in tandem with traditional chemotherapy, particularly in the context of TP53-mutant tumors. Here, we review the relevant available preclinical and clinical data on hand investigating the efficacy of WEE1 inhibitors for the treatment of head and neck cancers.

Direct Comparison of B Cell Surface Receptors as Therapeutic Targets for Nanoparticle Delivery of BTK Inhibitors.

Targeting different cell surface receptors with nanoparticle (NP)-based platforms can result in differential particle binding properties that may impact their localization, bioavailability, and, ultimately, the therapeutic efficacy of an encapsulated payload. Conventional in vitro assays comparing the efficacy of targeted NPs often do not adequately control for these differences in particle-receptor binding, potentially confounding their therapeutic readouts and possibly even limiting their experimental value. In this work, we characterize the conditions under which NPs loaded with Bruton's Tyrosine Kinase (BTK) inhibitor differentially suppress primary B cell activation when targeting either CD19 (internalizing) or B220 (noninternalizing) surface receptors. Surface binding of fluorescently labeled CD19- and B220-targeted NPs was analyzed and quantitatively correlated with the number of bound particles at given treatment concentrations. Using this binding data, suppression of B cell activation was directly compared for differentially targeted (CD19 vs B220) NPs loaded with a BTK inhibitor at a range of particle drug loading concentrations. When NPs were loaded with lower amounts of drug, CD19-mediated internalization demonstrated increased inhibition of B cell proliferation compared with B220 NPs. However, these differences were mitigated when particles were loaded with higher concentrations of BTK inhibitor and B220-mediated "paracrine-like" delivery demonstrated superior suppression of cellular activation when cells were bound to lower overall numbers of NPs. Taken together, these results demonstrate that inhibition of B cell activation can be optimized for NPs targeting either internalizing or noninternalizing surface receptors and that particle internalization is likely not a requisite endpoint when designing particles for delivery of BTK inhibitor to B cells.

Invasive pseudomembranous upper airway and tracheal Aspergillosis refractory to systemic antifungal therapy and serial surgical debridement in an Immunocompetent patient.

BACKGROUND: The development of respiratory infections secondary to Aspergillus spp. spores found ubiquitously in the ambient environment is uncommon in immunocompetent patients. Previous reports of invasive upper airway aspergillosis in immunocompetent patients have generally demonstrated the efficacy of treatment regimens utilizing antifungal agents in combination with periodic endoscopic debridement, with symptoms typically resolving within months of initiating therapy. CASE PRESENTATION: A 43-year-old previously healthy female presented with worsening respiratory symptoms after failing to respond to long-term antibiotic treatment of bacterial sinusitis. Biopsy of her nasopharynx and trachea revealed extensive fungal infiltration and Aspergillus fumigatus was isolated on tissue culture. Several months of oral voriconazole monotherapy failed to resolve her symptoms and she underwent mechanical debridement for symptom control. Following transient improvement, her symptoms subsequently returned and failed to fully resolve in spite of increased voriconazole dosing and multiple additional tissue debridements over the course of many years. CONCLUSIONS: Invasive upper airway aspergillosis is exceedingly uncommon in immunocompetent patients. In the rare instances that such infections do occur, combinatorial voriconazole and endoscopic debridement is typically an efficacious treatment approach. However, some patients may continue to experience refractory symptoms. In such cases, continued aggressive treatment may potentially slow disease progression even if complete disease resolution cannot be achieved.