Malignant growth leads to an unremitting increase in tumor burden despite treatment with antineoplastic agents. Treatment advances have been largely empirical, with improvements in surgical technique and the delivery of radiation therapy, leading to combined modality therapies that have improved outcomes for many patients. Loss of normal growth regulatory mechanisms and infinite replicative capacity are common features of many human malignancies. Successful targeting of the process whereby malignant cells become or maintain an immortal state should be an effective strategy for a number of cancers. Telomerase inhibition represents a new paradigm for, the treatment of human malignancies. As stated in Specific Aim 3, we will select and characterize human tumor cell lines and pathologic tumor samples from patients with representative tumor types of different stages for telomerase activity and telomere length.
In Specific Aim 6, an in vitro evaluation of compounds identified in the high throughput screen will be examined against normal, tumor, and leukemia cell lines representative of the clinical profile studied in Specific Aim 3 to complement in vitro studies that will be conducted at Geron. Specifically, experiments will be conducted using cell lines and cultured primary tumors to examine the effects of a telomerase inhibitor on growth kinetics, telomerase activity, and telomere length.
In Specific Aim 7 an assay will be developed for the detection of a candidate telomerase inhibitor(s) in biological materials. Pharmacology, drug metabolism, and pharmacokinetic studies will be conducted in order to optimize the bioavailability and activity of the compound in anticipation of performing animal experiments.
In Specific Aim 8 we will select compounds showing in vitro efficacy and evaluate their effects on normal, and immunocompromised mice transplanted with tumor cell lines, primary tumors, or leukemias. Dosing schedules will be optimized and different routes of administration (p.o., i.v,, i.p., s.c.) will be evaluated. The capacity of telomerase inhibitors to block the development of tumors, to regress established tumors with or without chemotherapy, and/or to prevent metastasis will be measured. Quantitative measurements of tumor burden and residual disease will be determined by sensitive serologic, fluorescence, chromophilic, or molecular techniques. Telomerase levels and telomere length will be measured in control and treated tumors as a function of growth rate and time.
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