We pioneered the concept of oral signal transduction therapy and disease stabilization endpoints with our work with CAI. Expansion of our approach to signal transduction therapy continues with inclusion of microproteomic techniques with which to analyze drug modulation of signal pathway in tumor samples. Phase II clinical trials of imatinib and gefitinib in ovarian cancer patients have been completed. Both trials included microdissection followed by reverse phase protein array (RPPA) proteomic profiling of key signaling events in tumor and stroma. We optimized technique for acquisition, storage, and processing of sentinel tumor lesions and obtained biopsies on-study and at 1 mo of therapy. Neither trial had remarkable clinical outcomes, however, in both trials target modulation was observed in tumor tissue by RPPA and a statistical association was observed between signaling events and extent of toxicity. Imatinib patients had pre-treatment phospho(p)-kit and EGFR potentially linked to gastrointestinal events (p !U 0.01), and on-treatment EGFR (p=0.001) and PDGFR (p=0.004) were linked to fatigue. The gefitinib study demonstrated increasing EGFR, AKT, p-ERK and p-EGFR in tumor on treatment with a trend toward being associated with increasing overall toxicity (p!U0.05), gastrointestinal toxicity (p less than 0.05), and skin toxicity (p=0.03). Accumulation of ascites and pleural effusions on our imatinib protocol was unexpected and severe in a subset of patients; we found a strong association with increased concentrations of plasma IL-6 in those patients, strongly suggesting the imatinib therapy upregulated cytokine production. Our phase I/II trial of sorafenib and bevacizumab, combinatorial anti-angiogenic anti-signaling therapy has yielded partial responses in ovarian cancer and benefit in other cancers; a phase II trial in ovarian cancer is to open shortly. The phase I study includes a subset of patients in whom triplet biopsies, DCE-MRI, and PET scans are obtained from which to analyze proof of concept and biological and biochemical activity of this combination. Ovarian cancer serum proteomics is advancing with a multi-institutional trial for the collection of serum samples from women in first remission of advanced stage ovarian cancer accruing. In addition, through our Gynecologic Oncology Group study, serum from women undergoing surgical diagnosis of a pelvic mass is being collected from which to develop a proteomic signature of malignancy v. benign disease. Serum samples from these two studies will be used for training and blinded validation of serum proteomic signatures of disease recurrence and malignancy, respectively. Advances this year in the mass spectrometry/bioinformatics work with the NCI/SAIC Clinical Proteomics Reference Laboratory have demonstrated a) quality control algorithm to qualify samples before use; b) incorporation of an internal MS control; c) stability of the diagnostic algorithm for over one year (breast cancer dataset); and d) preliminary data in functional analysis. These findings will be applied to the prospective collections described and to archival clinical samples from the clinical trials. Thus, we have translated both exciting proteomic technology advances to direct clinical investigation.
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