Immunohistochemical characterization of procaspase-3 overexpression as a druggable target with PAC-1, a procaspase-3 activator, in canine and human brain cancers

摘要: Gliomas and meningiomas are the most common brain neoplasms affecting both humans canines, identifying druggable targets conserved across multiple cancer histologies comparative species could broadly improve treatment outcomes. While satisfactory cure rates for low grade, non-invasive cancers achievable with conventional therapies including surgery radiation, management of non-resectable or recurrent tumors remains problematic necessitates discovery novel that be accelerated through a approach, such as inclusion pet dogs naturally-occurring cancers. Evidence supports procaspase-3 target PAC-1, pro-apoptotic, small molecule activator crosses blood-brain barrier. Procaspase-3 is frequently overexpressed in malignantly transformed tissues provides preferential inducing cell apoptosis. preliminary evidence viable preclinical models, PAC-1 demonstrating activity rodent models spontaneous tumors, broader applicability human cancers, well comparability expressions between differing species, requires further investigation. As such, large-scale validation was undertaken 651 canine tumors. Relative to normal tissues, histologically diverse cancerous supporting broad therapeutic target. Additionally, expressing glioma meningioma lines were sensitive apoptotic effects at biologically relevant exposures patients. Importantly, clinical relevance potential prognostic variable demonstrated astrocytomas histologic grades associated outcomes, whereby tumoral expression negatively correlated survival; findings which suggest might provide greatest benefit patients guarded prognoses.