Development of targeted therapies for rhabdoid tumors based on the function of INI1 as a tumor suppressor
Smith, Melissa E.
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Rhabdoid tumors (RTs) are aggressive pediatric malignancies characterized by loss/inactivation of the INI1 tumor suppressor. Current treatments for RTs are rarely curative. Thus, our goals involved further understanding RT biology and developing molecularly-targeted therapies based on INI1's functions.;Cyclin D1 (CD1) is a downstream target of INI1 that is required for RT growth. We hypothesized that therapeutically targeting CD1 or cyclin-dependent kinases (cdks) might inhibit RTs. CD1's main function is to activate cdks 4 and 6. To determine if this function is specifically necessary for rhabdoid tumorigenesis, we crossed Ini1+/- mice that form RTs to knock-in mice containing the CD1K112E mutant that is defective for cdk-activation. Ini1 +/-;CD1K112E/K112E mice did not form RTs indicating that CD1's cdk-dependent functions are required for rhabdoid tumorigenesis. This provided proof of concept that impairing the Cyclin/cdk-axis effectively inhibits RTs. Therefore, we carried out preclinical studies using pan-cdk inhibitor flavopiridol and found that flavopiridol inhibited RT growth in vitro and in a xenograft RT mouse model with efficacy correlated with CD1 down-modulation and regulation of p21CIP.;Genetically engineered mouse models (GEMMs) that develop primary tumors are better predictors of therapeutic efficacy compared to xenograft mouse models. We demonstrated that primary RTs developed in Int1 +/- mice can be measured using positron emission tomography. In a longitudinal study, we found that flavopiridol caused complete regression of some tumors. Other tumors exhibited resistance which, in one tumor, was correlated with amplification of CD1..;In addition to flavopiridol, we have used 4-HPR to target the Cyclin/cdk-axis. To improve 4-HPR's efficacy against RTs, we synthesized novel derivatives and performed structure-activity-relationship studies. We found that 4-HPR's para-hydroxy group was required for activity and that potency was correlated with CD1 down-modulation and induction of apoptosis.;Overall, our studies demonstrate that targeting the Cyclin/cdk-axis inhibits RTs in preclinical models, and that a RT GEMM can be used for more predictive therapeutic testing and for studying natural drug resistance. Our studies also provide insights into the roles of INI1 and CD1 in tumorigenesis and the mechanisms of chemotherapeutic action in RTs, which will allow us to develop better-targeted therapies for RTs and other INI1-negative tumors.
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