We pioneered the concept of signal transduction therapy with CAI and have completed our phase II study of single agent CAI in ovarian cancer and are nearing completion of our combination study with paclitaxel. We continue to find activity with limited toxicity. The phase II study demonstrates a 33% rate of response and disease stabilization of up to 18 months in women with measurable recurrent ovarian cancer. One partial response and 4 minor responses were observed. Toxicity has been mild and the pharmacokinetic monitoring suggests only a small number of patients are not optimally dosed at 250 mg/m2 per day administered in the morning, fasting. Serial plasma samples were assessed for circulating concentrations of VEGF, IL-8 and MMP-2. No consistent correlation between circulating concentrations and toxicity, pharmacokinetics and/or outcome were observed. Our phase I study of daily CAI with 3 weekly paclitaxel is completing accrual at the highest dose level with neuropathy and delayed neutrophil recovery the most common side effects. G-CSF use has been less common with the daily CAI and pulse paclitaxel regimen than with similar drug doses with only one week of CAI of each 3 wk cycle. Consistent findings of clinical benefit (partial responses and disease stabilization) have been observed, especially in ovarian cancer, cervix cancer, and melanoma. Collaboration continues investigating the application of CAI for ophthalmologic use. Excellent scleral permeability has been found in ex vivo models and it has been shown to be problematic when used in implant form due to its hygroscopic nature altering release over time. No direct ocular toxicity has been identified to date in the rabbit models with implants and the screening observations in the patients on the phase II trial have yielded no drug-related ophthalmologic toxicity. New preclinical directions for CAI include combinatorial therapy. Supra-additive activity in vitro was observed in combination with cyclooxygenase II inhibition. These effects were seen when cells were treated with EGF and the effects were also observed at the biochemical level. A phase I trial is anticipated from these findings. We are expanding our approach to signal transduction therapy to apply microproteomics for the analysis of signal pathway modulation in situ in cancer. Microdissection and proteomic tissue lysate array profiling are ongoing to assess the clinical effects in the tumor of the activity of STI-571 and ZD1839 administered to women with recurrent ovarian cancer accrued to recently opened studies. Sentinel tumor lesions are biopsied prior to initiation of therapy and then at 1 month. Stroma and tumor have been microdissected and will be subjected to protein array to analyze the initial and downstream activity of regulation of these pathways. Component parts of this project are the development of tissue lysate array reagents for the assessment of angiogenesis-related markers (see also Project: Signaling Pathways as Molecular Targets in Angiogenesis and the Microenvironment). This approach permits the opportunity to evaluate in situ the effects of circulating drug on the putative tumor and stromal targets to test microenvironment interaction and molecular target hypotheses.
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