MDR GENE THERAPY FOR DRUG RESISTANCE IN BREAST CANCER

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The objectives of this grant are to transfer and express the human multiple drug resistance (MDR) gene in CD34+ hematopoietic progenitor cells (HPCs) of patients with advanced breast cancer using a safe and efficient retrovirus. The projected result of this treatment is that MDR-transduced cells will ameliorate myelosuppression of subsequent chemotherapy with drugs that are inactivated by MDR (anthracyclines, vincaalkaloids, etoposide and taxol). Normal HPCs have low levels of MDR activity and are, therefore, preferentially sensitive to these drugs. Protocols will be developed and carried out in which MDR gene transfer will be used. The goal of the clinical program is to carry out and monitor the approved protocol and to carry out subsequent phase 1 and 2 protocols developed by the BCTG in collaboration with CTEP. The goals of the laboratory program are to optimize gene transfer by (1) developing new MDR retroviral vectors capable of more efficient transduction and expression of MDR, and (2) establishing optimal ex vivo culture conditions which will permit the most efficient transduction and expression of the MDR gene into hematopoietic progenitors. Specifically, smaller MDR retroviral vectors which may lead to viruses with higher titers will be evaluated, and promoters other than the retroviral long terminal repeat (LTR) will be fused to the MDR cDNA in an attempt to obtain higher levels of expression of the transferred MDR gene. These studies will also have the goal of utilizing different ex vivo culture conditions to expand transduced cell as effectively as possible so that optimal numbers of these cells can be used for marrow reconstitution. Establishment of more efficient vector design, and optimal conditions of MDR transduction and expression may permit fewer CD34+ cells with greater MDR drug resistance to be used in the clinical trials. Subsequent clinical protocols will focus on transduction of peripheral blood progenitor cells (PBPC) with the best MDR retroviral vectors, and optimal conditions for transduction of CD34+ cells to evaluate repeated cycles of higher than conventional doses of combinations of MDR affected drugs. If successful, this program would add a novel modality to the treatment of patients with advanced breast cancer as well as address questions of the relative contributions of marrow, peripheral blood progenitor cells (PBPCs) and endogenous hematopoiesis to marrow recovery.