DNA Quadruplex Control of hTERT Transcription: A New Therapy for Taxotere Resistant Prostate Cancer

PROJECT SUMMARYTelomerase maintains telomere length and prevents cellular senescenceIt is upregulated inof cancerssuppressed in most non cancer tissuesand is a primary driver of tumor cell immortalityNo clinical agent acting on telomerase has been approved for human useA hurdle for approaches that directly inhibit the action of telomerase is that therapeutic effect is observed only after many population doublings a process that can take monthseven for rapidly dividing cellsG quadruplexesG sand i motifsiMsserve as master switches to control gene expressionHuman telomerase reverse transcriptasehTERTthe catalytic portion of the telomerase holoenzymetranscription can be attenuated through the enhanced folding of the tandem G s in the promoter regionA screen of the NCI diversity set resulted in identification of a family of drug like small molecules that enhance the kinetic folding rate of the Gsilencer elementIn vitro studies support this singular mechanism of actionresulting in reduced telomerase production and telomere shorteningSignificantlytumor cells treated with the identified molecules enter apoptosis in dayssuggesting a unique downstream effectThe rapid onset of hTERT down regulators stands in contrast to the delayed action of classic telomerase inhibitionThe explanation is that hTERT down regulation kills cancer cells primarily through mitochondrial effectsnot downstream telomerase deactivationIn the absence of hTERT down regulationnuclear telomerase is shuttled to the mitochondriaThere it protects mitochondrial function against apoptosis by upregulation of the anti apoptotic peptide BCLand elevation of reactive oxygen speciesROSscavengershTERT down regulation attenuates BCLand ROS scavenger productionresulting in rapid apoptosisProstate cancerPCais the most common cancer in men and the number two killerFor most patientsthe last line of defense is docetaxelTaxotereHoweverresponse rates approachwithinyearshTERT mRNA in the serum or plasma affords greater diagnostic and prognostic accuracy for PCa than the widely used prostate specific antigen assayHuman derived wild type and Taxotere resistantTxRPCa cells are sensitive to hTERT down regulators and enter apoptosis within daysThe forward looking part of this proposal is the translation of the hTERT down regulation compound series onto a commercialization path for the treatment of TxR PCaThe project plan is built on a multiparametricdata driven hit to lead approach to identify molecules with optimized in vitro efficacysafetyand drug like profilesThe culmination of Phase I of this proposal is an in vivo experiment in a validated mouse model of PCaSuccess will enable a lead optimization campaign with an objective of clinical candidate identification PROJECT NARRATIVE A new medicine may save the lives of patients with metastatic prostate cancera disease that will killAmericans inThis therapy leverages the action of DNA quadruplex structures to selectively attenuate expression of the telomerase reverse transcriptase generesulting in cancer cell death in a few daysSuccessful advancement of this therapy on a commercialization path will exemplify a therapeutic paradigm to treat cancer and other lifethreatening diseases marked by abnormal changes in gene expression