PRE-CLINICAL COMBINATION CHEMO- AND RADIOANTIBODY THERAP

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DESCRIPTION: (Applicant?s Description) Multimodal therapy approaches are needed to bypass tumor protective mechanisms that prevent maximal responses to cytotoxic therapy. Several papers have been published on the efficacy of combined radioimmunotherapy (RAIT) and chemotherapy in experimental animal models. The rationale for the choice of drug, the dose scheduling (simultaneous or sequential) and the spacing between modalities in a sequential schedule has not been addressed. Since each patient?s cancer presents with a specific molecular phenotype, we hypothesize that it will not be possible to use only one combination approach with drug and radioantibody therapy for all patients. By understanding the genetic profile of tumor cells pre therapy and the molecular response of tumor cells to each modality of therapy, it may be possible to tailor combined modality approaches based on the molecular profile and, thus, enhance tumor responses. We propose to focus on the dominant regulators of chemo- and radiation resistance according to current knowledge. The primary traits to be considered are those associated with proliferation (percent S-phase, Ki-67 expression), drug resistance (MDR1, MRP, cerbB2/neu), p53 expression (null, wt, mut-p53), and apoptotic pathways (bcl-2, BAX, FAS). Analysis of expression of these markers will be done in the SKOV-3 ovarian cancer model and the MCF-7 breast cancer model. Over the next 5 years we will address the following three aims: 1) Determine the effect of radioantibody or chemotherapy on the molecular profile of tumors grown in nude mice. Parental tumors, stable transfectants (MDR+, MRP+, p53mut, cerb2/neu+, or BAX+) of the parental tumor, and pharmacologically-generated tumor variants (high Fas, or low bcl-2) will be evaluated. We hypothesize that: (1)The molecular profile of the tumor can be altered by cytotoxic therapy, allowing a window of opportunity for treatment with a second modality; and (2), the initial molecular phenotype will determine the effect that a specific form of therapy has on expression of different tumor markers. 2) Evaluate the therapeutic efficacy of multimodal therapy using radioantibody and 4 standard drugs. Several matrix designs will be considered and the optimal combination and dose-schedule of combined chemoand radioantibody therapy will be determined for each tumor variant. We hypothesize that the molecular phenotype of the tumor will determine the optimal dose-schedule of the two therapeutic modalities. 3) Evaluate expression of drug resistant and apoptotic markers in patients before and within days after RAIT +/- chemotherapy. This work will serve as a first attempt to apply the knowledge gained from the preclinical models by immuno-magnetically isolating tumor cells from patient blood samples, and using RT-PCR, to evaluate expression of drug resistance, and apoptotic markers before and within days after RAIT +/- chemotherapy. Hypothesis: 1) Certain molecular phenotypes will be more responsive than others to the clinical protocols proposed. 2) Therapy-induced changes in marker expression post therapy can be identified clinically in small samples of circulating tumor cells.