Long-term genetic studies utilizing backcross and congenic strain analyses coupled with positional cloning strategies and functional studies identified Cdkn2a,Mtor,and Mndal as mouse plasmacytoma susceptibility/resist...Long-term genetic studies utilizing backcross and congenic strain analyses coupled with positional cloning strategies and functional studies identified Cdkn2a,Mtor,and Mndal as mouse plasmacytoma susceptibility/resistance genes.Tumor incidence data in congenic strains carrying the resistance alleles of Cdkn2a and Mtor led us to hypothesize that drug combinations affecting these pathways are likely to have an additive,if not synergistic effect in inhibiting tumor cell growth.Traditional and novel systems-level genomic approaches were used to assess combination activity,disease specificity,and clinical potential of a drug combination involving rapamycin/everolimus,an Mtor inhibitor,with entinostat,an histone deacetylase inhibitor.The combination synergistically repressed oncogenic MYC and activated the Cdkn2a tumor suppressor.The identification of MYC as a primary upstream regulator led to the identification of small molecule binders of the G-quadruplex structure that forms in the NHEIII region of the MYC promoter.These studies highlight the importance of identifying drug combinations which simultaneously upregulate tumor suppressors and downregulate oncogenes.展开更多
基金the Intramural Research Program of the National Institutes of Health,National Cancer Institute,Center for Cancer Research and the MMRF(Multiple Myeloma Research Foundation).
文摘Long-term genetic studies utilizing backcross and congenic strain analyses coupled with positional cloning strategies and functional studies identified Cdkn2a,Mtor,and Mndal as mouse plasmacytoma susceptibility/resistance genes.Tumor incidence data in congenic strains carrying the resistance alleles of Cdkn2a and Mtor led us to hypothesize that drug combinations affecting these pathways are likely to have an additive,if not synergistic effect in inhibiting tumor cell growth.Traditional and novel systems-level genomic approaches were used to assess combination activity,disease specificity,and clinical potential of a drug combination involving rapamycin/everolimus,an Mtor inhibitor,with entinostat,an histone deacetylase inhibitor.The combination synergistically repressed oncogenic MYC and activated the Cdkn2a tumor suppressor.The identification of MYC as a primary upstream regulator led to the identification of small molecule binders of the G-quadruplex structure that forms in the NHEIII region of the MYC promoter.These studies highlight the importance of identifying drug combinations which simultaneously upregulate tumor suppressors and downregulate oncogenes.
