Abstract
Gliomas and meningiomas are the most common brain neoplasms affecting both humans and canines, and identifying druggable targets conserved across multiple brain cancer histologies and comparative species could broadly improve treatment outcomes. While satisfactory cure rates for low grade, non-invasive brain cancers are achievable with conventional therapies including surgery and radiation, the management of non-resectable or recurrent brain tumors remains problematic and necessitates the discovery of novel therapies that could be accelerated through a comparative approach, such as the inclusion of pet dogs with naturally-occurring brain cancers. Evidence supports procaspase-3 as a druggable brain cancer target with PAC-1, a pro-apoptotic, small molecule activator of procaspase-3 that crosses the blood-brain barrier. Procaspase-3 is frequently overexpressed in malignantly transformed tissues and provides a preferential target for inducing cancer cell apoptosis. While preliminary evidence supports procaspase-3 as a viable target in preclinical models, with PAC-1 demonstrating activity in rodent models and dogs with spontaneous brain tumors, the broader applicability of procaspase-3 as a target in human brain cancers, as well as the comparability of procaspase-3 expressions between differing species, requires further investigation. As such, a large-scale validation of procaspase-3 as a druggable target was undertaken across 651 human and canine brain tumors. Relative to normal brain tissues, procaspase-3 was overexpressed in histologically diverse cancerous brain tissues, supporting procaspase-3 as a broad and conserved therapeutic target. Additionally, procaspase-3 expressing glioma and meningioma cell lines were sensitive to the apoptotic effects of PAC-1 at biologically relevant exposures achievable in cancer patients. Importantly, the clinical relevance of procaspase-3 as a potential prognostic variable was demonstrated in human astrocytomas of variable histologic grades and associated clinical outcomes, whereby tumoral procaspase-3 expression was negatively correlated with survival; findings which suggest that PAC-1 might provide the greatest benefit for patients with the most guarded prognoses.
Highlights
In 2018, approximately 23,800 adults and 3,560 children in the US were diagnosed with malignant primary brain or spinal cord tumors, and soberingly, 16,830 adult deaths were attributed to inadequate treatment of these primary CNS tumors [1]
Malignant gliomas in humans remain clinically challenging to treat given the invasive nature of tumor cells into normal surrounding brain parenchyma, which precludes the feasibility of complete surgical resection in most affected patients
Despite a modest therapeutic advance following the introduction of temozolomide therapy in 2005, the median survival time in humans with glioblastoma multiforme (GBM) receiving trimodal therapy is disappointingly short, and has remained static at only 14 months [40]
Summary
In 2018, approximately 23,800 adults and 3,560 children in the US were diagnosed with malignant primary brain or spinal cord tumors, and soberingly, 16,830 adult deaths were attributed to inadequate treatment of these primary CNS tumors [1]. 75% of aggressive brain cancers in humans are classified as malignant gliomas and the prognosis for patients with either anaplastic astrocytoma (grade III) or glioblastoma multiforme (GBM; grade IV) is poor due to the invasive nature of these neoplasms. Even with multimodality therapies including surgery and radiochemotherapy, median survival times for patients diagnosed with anaplastic astrocytoma or GBM are less than 36 or 15 months, respectively [2]. Paralleling the aggressive disease course of invasive malignant gliomas, higher grade meningiomas (WHO grades II and III) referred to as atypical and anaplastic, respectively, remain clinically problematic in a subset of human patients. Of exceptional gravity are the outcomes for patients diagnosed with anaplastic meningiomas, where the average 5-year survival rates range from 30 to 60% [8, 9]
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