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 combinations continues and we have added microproteomic techniques with which to analyze drug modulation of signal pathway in tumor samples. Our driving hypothesis is that combinations focusing on signaling steps in series or in parallel may affect the pathway in a fashion such that there will bea need for less drug for the same or better outcome. 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) profiling of signaling events. Target modulation was observed in tumor and stromal 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 linked to gastrointestinal events (p≤0.01), and on-treatment EGFR (p=0.001) and PDGFR (p=0.004) linked to fatigue. The gefitinib study demonstrated increasing EGFR, AKT, p-ERK and p-EGFR in tumor with a trend towards association with increasing overall (p≤0.05), gastrointestinal (p<0.05), and skin toxicity (p=0.03). Our phase I/II trial of sorafenib and bevacizumab, combinatorial anti-angiogenic anti-signaling therapy in series, has yielded 50% partial responses in 16 ovarian cancer patients with benefit in other cancers; the phase II trial in ovarian cancer is accruing and showing similar activity. The phase I study includes a subset of patients in whom biopsies, dynamic contrast enhanced magnetic resonance imaging (DCE MRI) and 18FDG-positron emission tomography (PET) scans were performed at week 0, 2 (monotherapy), and 6 (combination therapy) from which to analyze proof of concept and biological and biochemical activity. No notable differences were seen in pharmacokinetics of the two agents alone or in combination, nor was there an effect on circulating VEGF. DCE-MRI and PET results did not change significantly with treatment in the initial 15 patients analyzed. Serial biopsies from 18 of the targeted 20 patients have been obtained, sectioned, and histology reviewed. Progressive apoptosis and tumor loss was observed in a number of cases. Recuts are being processed for RPPA against angiogenesis and signaling endpoints and immunohistochemistry to measure vascularity, apoptosis, and proliferation index. The ovarian cancer serum proteomics multi-institutional repository trial for women in first remission of advanced stage ovarian cancer is accruing. In addition, our Gynecologic Oncology Group study collecting serum from women undergoing surgical diagnosis of a pelvic mass has completed its accrual of 2000 patients. These samples are to be used to develop a proteomic signature of malignancy v. benign disease. Advances this year in the Clinical Proteomics Reference Laboratory have demonstrated a) quality control algorithm to qualify samples; b) demonstration of a difference in pattern, amplitude, and number of peaks in matched serum and plasma; c) stability of a diagnostic algorithm for 2 years in a breast cancer dataset; and d) confirmation that serum and plasma features are stable with up to 48hr refrigeration before freezing. These findings will be applied to the prospective collections described and to archival clinical samples from the clinical trials. Through collaboration with Dr. John Weinstein of the CCR, we have initiated plans for a clinical trial testing the findings in his laboratory that a subset of ovarian cancers are low expressors of asparaginine synthetase (ASNS). This low enzyme complement makes the tumors more susceptible to L-asparaginase therapy. A new formulation, pegylated L-asparaginase is available and a preliminary protocol document has been developed. Our group is also interested in molecular targeting for high risk women (BRCA1/2 mutation-associated cancers). Recent progress with polyADP-ribose polymerase (PARP) inhibitors suggests that these agents may be selectively toxic to cancers homozygous deleted for BRCA1/2, with resultant inability to repair DNA double strand breaks. This trial is in development, with translational endpoints developed in our laboratory and in collaboration with Drs. Doroshow and Pommier
Showing the most recent 10 out of 23 publications
