The informed development of new treatments for cancer would be greatly facilitated if tumor cells could be directly sampled at multiple time points following the administration of new drugs or drug combinations. Many new agents are not classic cytotoxics, but specifically target tumor cell biological processes or elements of the tumor stroma. In many cases, the appropriate doses of such agents will not be maximally tolerated, but rather will be the lowest doses found to selectively and thoroughly inhibit the function of their target(s). Accordingly, it is desirable to have direct access to relevant target cells in order to learn about a drug's mechanism of action and its pharmacodynamic or pharmacogenomic properties. Despite much effort, it has proven difficult to directly sample solid tumor masses even once in the context of early-phase clinical trials. The overall goal of this research proposal is to obtain circulating tumor and endothelial cells from the peripheral blood of patients with solid tumors, and to study the effects of therapy with new agents on gene expression, on putative drug targets and on downstream events such as apoptosis. In the Phase I portion of this award we pursued the following specific aims: 1) Isolate and enumerate circulating tumor cells (CTC) and circulating endothelial cell precursors (CEC) in cancer patients undergoing therapy with established and new agents. These studies demonstrated that circulating epithelial tumor cells and endothelial cell precursors can be isolated and enumerated in sufficient numbers to permit analysis of gene expression; and 2) Analyze gene expression in CTC and CEC using microarrav analysis. These studies showed that microarray analysis of CTC and CEC gene expression corresponds to gene expression patterns seen at tumor sites. We now will extend this work to determine the feasibility of using CTC and CEC to monitor the effects of cancer therapy with new agents. In the Phase II portion of this work we will test the hypothesis that circulating tumor and endothelial cells can provide pharmacodynamic surrogates of drug-induced signaling perturbation and apoptosis that can inform the conduct of early-phase clinical trials.
