THER-14. SMALL MOLECULE INHIBITOR TARGETING SELF-RENEWAL AS A THERAPEUTIC OPTION FOR RECURRENT MEDULLOBLASTOMA

Medulloblastoma (MB) is the most common pediatric brain tumor malignancy, and one of the leading causes of childhood cancer mortality. Often associated with tumor recurrence, relapsed MB patients are limited to palliation outwith the paucity of clinical trials available, carrying a mortality rate approaching 100%. Selectively targeting the MB stem cell population that evade conventional chemoradiotherapy and drive recurrence, can reduce the self-renewal and proliferative properties characteristic of aggressive cancer stem cells. Previous work identified BMI1, a master stem cell regulatory protein and epigenetic modifier, as a novel therapeutic target of developmental pathways active during tumorigenesis. Given that small molecule inhibitors targeting BMI1 correlated with diminished tumorigenic potential in other cancers, through industry partnership, we employ PTC596, a BMI1 inhibitor, providing extensive evidence of an efficacious therapy for treatment-refractory and recurrent MB through translational inhibition of BMI1. PTC596 effectively decreases the endogenous levels of BMI1 in our primary patient-derived MB cells, while abrogating the self-renewal capacity of MB stem cells. Novel to this work is the combinatorial MB patient-derived xenograft (PDX) mouse model, where tumor-bearing immune deficient mice were treated with standard chemoradiotherapy along with PTC596. Remarkably, an even greater survival benefit and reduction in tumor burden was seen in both concurrently and sequentially treated PDX cohorts. Such promising preclinical results have rapidly translated to the clinic with impending implementation of a North American clinical trial for children with recurrent MB. As BMI1 is implicated in the maintenance of aggressive childhood and adult brain tumors, BMI1-targeted therapies offer great clinical interest, with the potential of providing avenues for de-escalating therapies that otherwise cause severe neurological and psychosocial sequelae.