Mentor Name: Eric Raabe

Malignant rhabdoid tumor (MRT) is an aggressive tumor arising in soft tissues in infants and young children. MRT has a dismal prognosis, with a small minority of patients surviving long-term. Like atypical teratoid rhabdoid tumor (ATRT), a hallmark of MRT is loss of the SMARCB1 protein, leading to disruption of the function of the mammalian SWI/SNF chromatin remodeling complex. The SWI/SNF complex is a macromolecular motor that generally functions to derepress chromatin and activate pro-differentiation pathways. MRT has epigenetic disfunction in that it remains locked in a stem-cell state, yet also is highly proliferative. LP-184 is a novel acylfulvene alkylating agent that has remarkable activity against ATRT, with IC50 that are 10 times lower than those of other brain tumors. LP-184 administered weekly extends survival of mice bearing orthotropic xenografts. We hypothesize that LP-184 will have similar activity in MRT and will demonstrate single-agent efficacy in vitro and in vivo. Spironolactone is a potassium-sparing diruetic medication that is commonly used in pediatric patients. Spironolactone binds to the DNA repair protein ERCC3/XP-B and targets it for ubiquitination and degradation. We find that spironolactone degrades ERCC3 and potentiates LP-184 activity in vitro and in vivo in ATRT. We further hypothesize that spironolactone will similarly increase the efficacy of LP-184 in MRT, without increasing toxicity in mice.