Our team 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 proof of concept and illustrate mechanism of the targeted agents 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 be a need for less drug for the same or better outcome. We reported the demonstration of target presence, target activation, and target modulation in core tissue biopsies obtained on our Phase II trials of imatinib and gefitinib in ovarian cancer patients and Phase I study of bevacizumab and sorafenib in patients with solid tumors. We observed lack of clinical benefit with lack or limited target activity with the single agents. Our revised hypothesis was that rational combination therapy with which to yield molecular cooperativity could result in greater overall signal disruption and thus more potential clinical benefit. Our phase I/II trial of sorafenib and bevacizumab, combination anti-angiogenic anti-signaling therapy in series, resulted in 47% partial responses in 19 ovarian cancer patients, with benefits seen in other cancers. The phase II trial in ovarian cancer continues to accrue bevacizumab-nave women and those with progression on prior bevacizumab-containing regimens;the dual cohorts allow examination of the hypothesis that resistance to anti-angiogenic therapy cannot occur. The bevacizumab nave cohort has entered second stage of accrual and the exposed cohort is still accruing its initial step. Extensive translational endpoints have been incorporated in the phase II study including serial biopsies, functional imaging, pharmacogenomics, cytokine monitoring and others. Functional imaging is repeated on day 3, a time when modulation of vascular flow and glucose uptake have been shown to occur. This is to test whether changes at day 3 will predict clinical outcome in response to the regimen. The other endpoints parallel and extend those done in our phase I analyses and will allow us to cross analyze the trials, increasing the power for analysis of the molecular endpoints. A second study, targeting EGFR and VEGFR2 in parallel with a single agent, vandetanib, has been completed, without clinical activity. Biochemical analyses indicated that vandetanib inhibited EGFR in tissue and had EGFR-inhibitory pharmacodynamics (rash, diarrhea). No inhibition of VEGFR2 was observed in the tissue samples and no PD changes of hypertension, increase in circulating VEGF, or change in vascular permeability by functional imaging. These data indicate that vandetanib did not hit both of its targets in our ovarian cancer cohort. Our examination of asparaginase in vitro has led to the observations that it has a clear and profound inhibitory activity against microvascular cells, ovarian cancer cells, and the interaction between the two. Invasion is inhibited in both cell types and selective adhesion to matrix and sialyl-Lex only in the tumor cells. This is further demonstrated by markedly reduced binding to anti-integrin beta-1 and anti-sialyl-Lex with associated reduction in heterotypic cell-cell adhesion. A manuscript is nearing completion describing these findings. An investigator-initiated phase II study of pegaspargase in ovarian cancer based upon these findings is open to accrual under a CTA with Sigma-Tau Pharmaceuticals. The ovarian cancer serum proteomics multi-institutional repository trial for women in first remission of advanced stage ovarian cancer has been closed to accrual with the initial test set accrued. The core committee has a draft (nonfunded) RFA nearing completion that will publicize access to these samples for validation studies of proteomic and biomarker studies. We have just completed analysis of progranulin, secretory leukocyte protease inhibitor, HE4 and CA125 in the plasma samples collected in our pilot remission monitoring study. We found that the concentration of progranulin in the first or second blood taken after demonstration of clinical complete remission, from 1 6 months after completion of chemotherapy, as a single entity at a single timepoint, segregated those women who progressed before 16-18 months from those who progressed after that time frame (p less than 0.0001). These provocative data will be followed up with a validation analysis. Pilot findings have been submitted for publication. In addition, our Gynecologic Oncology Group study collecting serum from women undergoing surgical diagnosis of a pelvic mass has completed its accrual of over 2000 patients and is awaiting sample release. 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. Our group is now recognized as a center focusing on the treatment of women with BRCA1/2 mutation-associated cancers and BRCA-like cancers, high grade serous ovarian cancer and triple negative breast cancers. Our phase I study of olaparib, an oral inhibitor of polyADP-ribose polymerase (PARP), in combination with carboplatin is nearing completion of dose escalation using one week of olaparib with carboplatin every 3 weeks for the mutation carrier cohort;escalation continues in the two BRCA-like cohorts. After dose finding is completed, expansion cohorts of 10 patients in each group will undergo serial biopsy and blood sampling in order to examine proof of concept and mechanism studies;these will be addressed in collaboration with CCR colleagues. We identified an unmet need to examine sequence specificity of carboplatin and olaparib. Preclinical studies are ongoing and a clinical trial has been submitted to IRB. This trial will be open to all womens cancers, including all mutation carriers. It is designed to use each woman as her own control, randomizing starting with either olaparib or carboplatin and is powered to allow intra-patient, intra-group, and intergroup analysis of the pharmacokinetic and pharmacodynamic endpoints. PD endpoints will include DNA platination and PAR incorporation as well as other homologous recombination and nucleotide excision repair endpoints in an interdisciplinary collaboration. Additional preclinical and clinical studies are under development and approval to advance a concerted effort for treatment of this unique and rare group of women. Our collaborative work on novel applications of CAI against chronic myelogenous leukemia (CML) cells in culture continues. We have demonstrated reduced activation of the bcr/abl oncogenic fusion protein and activity against wild type CML and CML resistant 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.
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