We hypothesize that there is a convergence of prosurvival, angiogenesis and motility signals at common pathways in the local tumor microenvironment for therapeutic targeting and monitoring. Our findings suggest that molecular therapeutics targeted against the tumor microenvironment may to be more active when administered to inhibit pathways in series rather than in parallel and also when they affect both the tumor and the local interactive cells.
Aim 1) Initiation and execution of a novel statistically based predictive drug modeling project investigating drug effects on the tumor and its microenvironment. The primary approach to preclinical and clinical development is generally empiric selection of combinations, such as our successful findings with sorafenib and bevacizumab. However, we hypothesized that focused combinatorial studies using clinical available agents can yield combination therapy approaches to examine in the clinic, some of which may not be intuitively selected. We have applied optimized relative high throughput assays to a set of ovca cell lines and 7 pilot targeted agents. Replicates and proteomic characterization of the downstream pathways is pending after which the predictive partial least squares statistical analysis will be applied and models built for validation. Confirmation of success of this pilot project will lead to a more comprehensive examination of agents and shRNA against their primary and potential key targets such that the biochemical cause of activity is identified. These data will be applied to xenograft models and then move into clinical trial development;the laboratory target results will become the endpoints for illustration of mechanism in the trials and, potentially later, as putative predictive biomarkers. This project was the basis for an ASCO Young Investigator Award received by Dr. John Hays, a senior medical oncology fellow in the PIs group, funding a postbaccalaureate fellow under Dr. Hays supervision to expedite these experiments. 2) The CML microenvironment is a key target of dasatinib. Continuation of our studies of the role of exosomes secreted by CML cells acting on endothelial cells has led to the finding that dasatinibs superior action may be due to its Src kinase activity. Our studies indicate that dasatinib, not imatinib, can regulate the tubular differentiation response of endothelial cells to CML cell exosomes. Both agents reduce exosome production and secretion in nontoxic concentrations, but imatinib is neutral or even stimulatory to endothelial cells. Dasatinib treatment abrogates focal contact formation and activation of Src and FAK by endothelial cells by IF and also immunoblot examination;whereas, imatinib has no activity or again is stimulatory. These findings indicate that the src family is key in the positive interaction of CML with the local microenvironment and may define an unanticipated reason that dasatinib may be superior to imatinib in CML therapy. We will continue our collaboration with Kohn lab alumnus, Prof. R. Alessandro at the Univ. Palermo in their studies, proteomic, biochemical, and biological, of CML. They will be following up our in vitro studies with a Matrigel plug in vivo assay of exosome function. 3) Investigation of the role of asparaginase and PARP inhibition in angiogenesis and ovarian cancer. We completed studies of the role of asparaginase in ovarian cancer and angiogenesis, initiated as a translation of the work of others within the CCR. The findings underscored the interactive role of the microenvironment on ovarian cancer survival and led to a pilot phase II clinical trial of pegylated asparaginase. This trial was designed to provide clinical samples for translational examination but closed early due in fulfillment of a toxicity futility rule. Our findings of the interactive role of PARP inhibition with angiogenesis inhibition was initiated based upon findings that gH2AX was required for overcoming hypoxic drive for endothelium. We observed an interaction of a pan-VEGFR inhibitor, cediranib, with a PARP inhibitor and demonstrated a sequence specificity to administration. Further examination of the mechanisms underlying this are on hold due to resource limitations, but will be reinitiated and prostate cells included in the studies. The MOB prostate cancer team is interested in collaborating on this project clinically in recognition of the high PTEN mutation frequency in prostate cancers and the newly discovered role of PTEN in homologous recombination functions.
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