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. Collaborative work has advanced novel applications of CAI. It is active against chronic myelogenous leukemia (CML) cells in culture, reducing activation of the bcr/abl oncogenic fusion protein. New results demonstrate that CAI is active not only in wild type CML, but also in CML resistant to imatinib by through mutation of bcr/abl and also bcr/abl mutants conferring resistance to both imatinib and dasatinib. In both cases, reduction in total and activated bcr/abl was demonstrated. These data should be considered for translation to the clinic. Phase II clinical trials of imatinib and gefitinib in ovarian cancer patients were completed and reported. While neither trial demonstrated clinical benefit, both trials reported presnece of the primary target and modulation of its activation both in tumor and stroma. These findings were obtained using microdissection of the tumor biopsies done on study and at one month, and microdissected tissue was applied to protein array profiling. These findings indicated that either A) the target was neither necessary nor sufficient, B) necessary but not sufficient for clinical benefit to be seen, and/or C) insufficiently modified in the tumor for clinical benefit. These questions led us to hypothesize that rational combinatorial therapy for molecular cooperativity could yield more signal disruption and thus more potential clinical benefit; it was recognized that this may also increase toxicity. 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. A phase II trial in ovarian cancer is accruing and showing similar activity. Extensive translational endpoints were proposed and now analyzed. No notable differences were seen in pharmacokinetics of the two agents alone or in combination, nor were there pharmacogenomic or genetic/genomic correlations. Circulating VEGF was increased as expected; additional endpoints are under assessment. A statistically significant reduction in DCE-MRI endpoints were observed. Serial biopsies from 18 patients have been obtained, sectioned, and histology reviewed. Progressive apoptosis and tumor loss was observed in a number of cases and correlated with those with stable disease or response. Cases have been processed for protein array and biochemial endpoint results are being analyzed presently. 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. Those cases will be analyzed in collaboration with Dr. Tom Conrads, now of U-Pittsburgh. Through collaboration with Dr. John Weinstein of the CCR, we have initiated plans for a clinical trial testing findings in his laboratory that a subset of ovarian cancers are low expressors of asparaginine synthetase (ASNS) and thus susceptible to L-asparaginase exposure. A new formulation, pegylated L-asparaginase is available and a preliminary protocol document has been developed. Work in our group has identified a clear anati-angiogenic activity of asparaginase that will be assessed in endpoints in the clinical trial. Our group has developed an initial trial for molecular targeting of high risk women (BRCA1/2 mutation-associated cancers). The phase I study of the AZD2181 inhibitor of polyADP-ribose polymerase (PARP) in combination with carboplatin has completed accrual of dose level 1 and is continuing. Translational proof of concept and mechanism studies are planned for an expansion cohort and will be addressed in collaboration with CCR colleagues. A queue of studies is under development to advance a concerted effort for treatment of this unique and rare group of women. It will also serve as a nidus from which to re-invigorate breast cancer as a clinical activity in the Branch.
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