The treatment of breast cancer has improved by identifying molecular determinants of drug sensitivity. For example, the presence of estrogen and progesterone receptors defines a subset of patients likely to respond to hormonal therapies such as tamoxifen. Similarly, those tumors that overexpress HER-2/neu are most likely to respond to trastuzumab (Herceptin). In contrast, there are few if any reliable determinants of sensitivity to cancer chemotherapy. We recently completed a pilot, Phase I clinical trial based on our preclinical observations that the expression of wild type p53 could define a subset of patients who are likely to respond to vinca alkaloids. Our preclinical work demonstrated that wild type p53 regulated the expression of microtubule-associated protein 4 (MAP4), a MAP that regulates the polymerization state of microtubules and sensitivity to antimicrotubule drugs including taxanes and vinca alkaloids. We then demonstrated that DNA damage-induced expression of wild type p53 repressed MAP4 and sensitized cells to vinca alkaloids. Our Phase I trial demonstrated the safety of administering a DNA damaging drug (doxorubicin) followed in sequence by treatment with an antimicrotubule drug (vinorelbine). Furthermore, the laboratory component of this trial demonstrated that doxorubicin treatment could induce the expression of p53 in both peripheral blood mononuclear cells and breast cancer biopsies and that the detection of p53-regulated genes such as p21 and MAP4 was possible. In this carefully revised application, we propose to confirm and extend these observations by conducting a Phase II clinical trial of sequential doxorubicin and vinorelbine (at the dose and sequence interval defined by the Phase I results) in wild type p53 breast cancer to determine whether activation of p53 and repression of MAP4 is predictive of response to vinca alkaloids. ? ?
