Phase II Doxorubicin/Vinorelbine in wtp53 Breast Cancer

描述（由申请人提供）：通过鉴定药物敏感性的分子决定因素，乳腺癌的治疗得到了改善。例如，雌激素和孕激素受体的存在定义了可能对激素疗法如他莫昔芬有反应的患者子集。类似地，那些过表达HER-2/neu的肿瘤最有可能对曲妥珠单抗（赫赛汀）有反应。相比之下，几乎没有任何可靠的决定因素对癌症化疗的敏感性。我们最近完成了一项试点，I期临床试验的基础上，我们的临床前观察，野生型p53的表达可以定义一个子集的患者谁是可能响应于长春花生物碱。我们的临床前工作表明，野生型p53调节微管相关蛋白4（MAP 4）的表达，MAP 4调节微管的聚合状态和抗微管药物（包括紫杉烷和长春花生物碱）的敏感性。然后，我们证明了DNA损伤诱导的野生型p53表达抑制MAP 4和敏感细胞长春花生物碱。我们的I期试验证明了DNA损伤药物（多柔比星）的安全性，随后用抗微管药物（长春瑞滨）进行治疗。此外，该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p53调节的基因，如p21和MAP 4。在这个仔细修订的申请中，我们建议通过在野生型p53乳腺癌中进行多柔比星和长春瑞滨序贯（剂量和顺序间隔由I期结果定义）的II期临床试验来确认和扩展这些观察结果，以确定p53的激活和MAP 4的抑制是否预测对长春花生物碱的反应。

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.