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 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 imatinib and gefinitib administered to women with recurrent ovarian cancer accrued to ongoing studies. Sentinel tumor lesions are biopsied prior to initiation of therapy and then at 1 month. Stroma and tumor have been microdissected and subjected to protein array to analyze the initial and downstream activity of regulation of key nodes in these pathways. The gefinitib study also incorporates acquisition of skin in order to investigate the validity of skin as a surrogate marker of response to therapy. Preliminary tissue lysate array results from the imatinib study shows that PDGFR and c-kit are expressed in more abundance and more frequently than expected. Changes are seen in both tumor and stroma in response to drug, however, the lack of prolonged treatment in the patient cohort makes correlative assessment difficult. Accumulation of ascites and pleural effusions was unexpected and severe in a subset of patients. Imatinib has been shown to be anti-angiogenic in preclinical and clinical studies. Assessment of plasma VEGF, PDGF-AB, PDGF-BB, and IL-6 showed statistically significant increased concentrations in patients with ascites, strongly suggesting that imatinib therapy upregulated production of these proangiogenic cytokines. Further studies on this hypothesis are ongoing. Preliminary results of the gefitinib study suggest that total and activated AKT and ERK may correlate with tumor drug sensitivity. Two new trials are expected to accrue shortly for which preclinical studies have been completed: assessment of nucleotide excision repair in patients treated with Yondeelis and assessment of angiogenic, survival and proliferation pathways in patients to receive bevacizumab and sorafenib. The tissue lysate array 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. A multi-institutional trial has been designed for the collection of serum samples from women in first remission of advanced stage ovarian cancer. These samples will be used for training and blinded validation of serum proteomic signatures of disease recurrence. Thus, we have translated both exciting proteomic technology advances to clinical investigation.
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