Project description:Cyclins and cyclin-dependent kinases (CDKs) are hyperactivated in nearly all human tumor types. To identify new approaches for interfering with cyclins/CDKs, we systematically searched for microRNAs (miRNAs) regulating these proteins. We uncovered a group of miRNAs that target nearly all cyclins and CDKs, and demonstrated that these miRNAs are very effective in shutting off cancer cell expansion. By profiling the response of over 120 human cancer cell lines representing 12 tumor types to these cell-cycle-targeting miRNAs, we identified miRNAs particularly effective against triple-negative breast cancers and KRAS-mutated cancers. We also derived expression-based algorithm that predicts response of primary tumors to cell-cycle-targeting miRNAs. Using systemic administration of nanoparticle-formulated miRNAs, we halted tumor progression in seven mouse xenograft models, including three highly aggressive and treatment-refractory patient-derived tumors, without affecting normal tissues. Our results highlight the utility of using cell-cycle-targeting miRNAs for treatment of refractory cancer types.
Project description:Cyclins and cyclin-dependent kinases (CDKs) are hyperactivated in nearly all human tumor types. To identify new approaches for interfering with cyclins/CDKs, we systematically searched for microRNAs (miRNAs) regulating these proteins. We uncovered a group of miRNAs that target nearly all cyclins and CDKs, and demonstrated that these miRNAs are very effective in shutting off cancer cell expansion. By profiling the response of over 120 human cancer cell lines representing 12 tumor types to these cell-cycle-targeting miRNAs, we identified miRNAs particularly effective against triple-negative breast cancers and KRAS-mutated cancers. We also derived expression-based algorithm that predicts response of primary tumors to cell-cycle-targeting miRNAs. Using systemic administration of nanoparticle-formulated miRNAs, we halted tumor progression in seven mouse xenograft models, including three highly aggressive and treatment-refractory patient-derived tumors, without affecting normal tissues. Our results highlight the utility of using cell-cycle-targeting miRNAs for treatment of refractory cancer types.
Project description:Cyclins and cyclin-dependent kinases (CDKs) are hyperactivated in numerous human tumors. To identify means of interfering with cyclins/CDKs, we performed nine genome-wide screens for human microRNAs (miRNAs) directly regulating cell-cycle proteins. We uncovered a distinct class of miRNAs that target nearly all cyclins/CDKs, which are very effective in inhibiting cancer cell proliferation. By profiling the response of over 120 human cancer cell lines, we derived an expression-based algorithm that can predict the response of tumors to cell-cycle-targeting miRNAs. Using systemic administration of nanoparticle-formulated miRNAs, we inhibited tumor progression in seven mouse xenograft models, including three treatment-refractory patient-derived tumors, without affecting normal tissues. Our results highlight the utility of using cell-cycle-targeting miRNAs for treatment of refractory cancer types.
Project description:Most humans are infected with Epstein-Barr virus (EBV), a cancer-causing virus. While EBV generally persists silently in B lymphocytes, periodic lytic (re-)activation of latent virus is central to its life cycle and to most EBV-related diseases. However, a substantial fraction of EBV-infected B cells and tumor cells in a population is refractory to lytic activation. This resistance to lytic activation directly and profoundly impacts viral persistence and effectiveness of oncolytic therapy for EBV+ cancers. To identify the mechanisms that underlie susceptibility to EBV-lytic activation, we used host protein-expression profiling of separated-lytic and -refractory cells.
Project description:Most humans are infected with Epstein-Barr virus (EBV), a cancer-causing virus. While EBV generally persists silently in B lymphocytes, periodic lytic (re-)activation of latent virus is central to its life cycle and to most EBV-related diseases. However, a substantial fraction of EBV-infected B cells and tumor cells in a population is refractory to lytic activation. This resistance to lytic activation directly and profoundly impacts viral persistence and effectiveness of oncolytic therapy for EBV+ cancers. To identify the mechanisms that underlie susceptibility to EBV-lytic activation, we used host protein-expression profiling of separated-lytic and -refractory cells.