Dimerizer-mediated regulation of gene expression in vivo.

Several systems have been developed that allow transcription of a target gene to be chemically controlled, usually by an allosteric modulator of transcription factor activity. An alternative is to use chemical inducers of dimerization, or "dimerizers," to reconstitute active transcription factors from inactive fusion proteins. The most widely used system employs the natural product rapamycin, or a biologically inert analog, as the dimerizing drug.

Dimerizer-mediated regulation of gene expression in vitro.

Several systems have been developed that allow transcription of a target gene to be chemically controlled, usually by an allosteric modulator of transcription factor activity. An alternative is to use chemical inducers of dimerization, or "dimerizers," to reconstitute active transcription factors from inactive fusion proteins. The most widely used system employs the natural product rapamycin, or a biologically inert analog, as the dimerizing drug.

Dimerizer-mediated regulation of gene expression.

Several systems have been developed that allow transcription of a target gene to be chemically controlled, usually by an allosteric modulator of transcription factor activity. An alternative is to use chemical inducers of dimerization, or "dimerizers," to reconstitute active transcription factors from inactive fusion proteins. The most widely used system employs the natural product rapamycin, or a biologically inert analog, as the dimerizing drug.

Analysis of the pharmacodynamic activity of the mTOR inhibitor ridaforolimus (AP23573, MK-8669) in a phase 1 clinical trial.

Purpose: As part of a phase 1 dose-escalation trial, the pharmacodynamic activity of the mammalian target of rapamycin (mTOR) inhibitor ridaforolimus was assessed in multiple tissues by measuring levels of phosphorylated 4E binding protein-1 (p-4E-BP1) or S6, two downstream markers of mTOR activity.

Methods: 32 patients (pts) were dosed intravenously with ridaforolimus once daily for 5 consecutive days (QD × 5) every 2 weeks. The pharmacodynamic activity of ridaforolimus was assessed in peripheral blood mononuclear cells (PBMCs; 32 pts), skin (28 pts), and tumor specimens (3 pts) collected before and after dosing by measuring levels of p-4E-BP1 by immunoblot analysis or pS6 by immunohistochemistry.

Phase II study of the mammalian target of rapamycin inhibitor ridaforolimus in patients with advanced bone and soft tissue sarcomas.

Purpose: Ridaforolimus is an inhibitor of mammalian target of rapamycin, an integral component of the phosphatidyl 3-kinase/AKT signaling pathway, with early evidence of activity in sarcomas. This multicenter, open-label, single-arm, phase II trial was conducted to assess the antitumor activity of ridaforolimus in patients with distinct subtypes of advanced sarcomas.

Patients And Methods: Patients with metastatic or unresectable soft tissue or bone sarcomas received ridaforolimus 12.

Ridaforolimus for patients with progressive or recurrent malignant glioma: a perisurgical, sequential, ascending-dose trial.

Purpose: This perisurgical phase 1 study evaluated the pharmacokinetics, pharmacodynamics, and safety of the mammalian target of rapamycin (mTOR) inhibitor ridaforolimus in patients (N = 10) with progressive or recurrent primary grade IV malignant glioma, who failed standard therapy. The primary objective of the study was to determine the maximum tolerated dose (MTD) of ridaforolimus.

Methods: Treatment was administered intravenously at doses of 12.

Ridaforolimus (AP23573; MK-8669), a potent mTOR inhibitor, has broad antitumor activity and can be optimally administered using intermittent dosing regimens.

The mTOR pathway is hyperactivated through oncogenic transformation in many human malignancies. Ridaforolimus (AP23573; MK-8669) is a novel rapamycin analogue that selectively targets mTOR and is currently under clinical evaluation. In this study, we investigated the mechanistic basis for the antitumor activity of ridaforolimus in a range of human tumor types, exploring potential markers of response, and determining optimal dosing regimens to guide clinical studies.

Phase IB study of the mTOR inhibitor ridaforolimus with capecitabine.

Purpose: Synergistic/additive cytotoxicity in tumor models and widespread applicability of fluoropyrimidines in solid tumors prompted the study of the combination of the mammalian target of rapamycin (mTOR) inhibitor, non-prodrug rapamycin analog ridaforolimus, with capecitabine.

Patients And Methods: Thirty-two adult patients were treated. Intravenous ridaforolimus was given once weekly for 3 weeks and capecitabine was given from days 1 to 14 every 4 weeks.

A phase I trial to determine the safety, tolerability, and maximum tolerated dose of deforolimus in patients with advanced malignancies.

Purpose: This was a phase I trial to determine the maximum tolerated dose and toxicity of deforolimus (AP23573, MK-8669), an inhibitor of mammalian target of rapamycin (mTOR). The pharmacokinetics, pharmacodynamics, and antineoplastic effects were also studied.

Experimental Design: Deforolimus was administered intravenously over 30 min every 7 days according to a flat dosing schedule.

Dimerizer regulation of AADC expression and behavioral response in AAV-transduced 6-OHDA lesioned rats.

Recombinant AAV vectors containing a dimerizer-inducible system of transcriptional activation provide a strategy for control of therapeutic gene expression in the CNS. Here we explored this system for regulated expression of human aromatic L-amino acid decarboxylase (hAADC) in a rodent model of Parkinson disease. Expression of hAADC, the enzyme that converts L-dopa to dopamine, was dependent on reconstitution of a functional transcription factor (TF) by the dimerizer rapamycin.

Detection and frequency estimation of rare variants in pools of genomic DNA from large populations using mutational spectrometry.

DNA variants underlying the inheritance of risk for common diseases are expected to have a wide range of population allele frequencies. The detection and scoring of the rare alleles (at frequencies of <0.01) presents significant practical problems, including the requirement for large sample sizes and the limitations inherent in current methodologies for allele discrimination.