Phase II Doxorubicin/Vinorelbine in wtp53 Breast Cancer

wtp53 乳腺癌的 II 期阿霉素/长春瑞滨

• 批准号: 6872340
• 负责人: DEBORAH L TOPPMEYER
• 金额: $ 26.84万
• 依托单位: UNIV OF MED/DENT NJ-R W JOHNSON MED SCH
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-02-05 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6872340
• 关键词: SDS polyacrylamide gel electrophoresis; breast neoplasms; clinical research; dosage; doxorubicin; drug screening /evaluation; female; fluorescent in situ hybridization; gene expression; human subject; microtubule associated protein; p53 gene /protein; pharmacokinetics; polymerase chain reaction; vinblastine; vinca alkaloids; western blottings; women' s health

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.

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他莫昔芬等激素疗法有反应的患者子集。同样，那些过度表达 HER-2/neu 的肿瘤最有可能对曲妥珠单抗（赫赛汀）产生反应。相比之下，对癌症化疗的敏感性几乎没有可靠的决定因素。我们最近完成了一项试点 I 期临床试验，该试验基于我们的临床前观察，即野生型 p53 的表达可以定义可能对长春花生物碱产生反应的患者子集。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，该 MAP 调节微管的聚合状态以及对包括紫杉烷和长春花生物碱在内的抗微管药物的敏感性。然后我们证明 DNA 损伤诱导的野生型 p53 表达抑制 MAP4 并使细胞对长春花生物碱敏感。我们的 I 期试验证明了先使用 DNA 损伤药物（阿霉素），然后再使用抗微管药物（长春瑞滨）进行治疗是安全的。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中 p53 的表达，并且可以检测 p53 调节的基因，例如 p21 和 MAP4。在这个经过仔细修改的申请中，我们建议通过在野生型 p53 乳腺癌中进行序贯阿霉素和长春瑞滨（按照 I 期结果定义的剂量和序列间隔）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 MAP4 的抑制是否可以预测对长春花生物碱的反应。