Phase II Doxorubicin/Vinorelbine in wtp53 Breast Cancer

描述(申请人提供)：通过识别药物敏感性的分子决定因素，乳腺癌的治疗得到了改进。例如，雌激素和孕激素受体的存在定义了一组可能对他莫昔芬等激素治疗有反应的患者。同样，那些过度表达HER-2/neu的肿瘤最有可能对曲妥珠单抗(Herceptin)有反应。相比之下，几乎没有可靠的癌症化疗敏感性决定因素。我们最近完成了一项试点的I期临床试验，基于我们的临床前观察，野生型p53的表达可以定义一组可能对长春花碱有反应的患者。我们的临床前工作表明，野生型p53调节微管相关蛋白4(MAP4)的表达，MAP4是一种调节微管聚合状态的MAP，并调节对包括紫杉烷和长春花碱在内的抗微管药物的敏感性。然后我们证明了DNA损伤诱导野生型P53的表达抑制了MAP4，并使细胞对长春花碱敏感。我们的第一阶段试验证明了依次给予DNA损伤药物(阿霉素)和抗微管药物(长春瑞滨)治疗是安全的。此外，这项试验的实验室部分表明，阿霉素治疗可以诱导外周血单核细胞和乳腺癌活检组织中P53的表达，并且可以检测到P53调节的基因，如p21和MAP4。在这项精心修订的应用中，我们建议通过对野生型p53乳腺癌进行阿霉素和长春瑞滨序贯临床试验(剂量和序列间隔由I期结果定义)来确认和扩大这些观察结果，以确定P53的激活和MAP4的抑制是否预测长春花碱的反应。

DESCRIPTION (provided by applicant): 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.