An Exploratory Study of UCN-01 and Irinotecan in Advanced Triple Negative Breast

UCN-01 和伊立替康治疗晚期三阴性乳腺癌的探索性研究

• 批准号: 7275903
• 负责人: PAULA M. FRACASSO
• 金额: $ 27.84万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-24 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7275903
• 关键词: 3-Phosphoinositide Dependent Protein Kinase-1; 7-Hydroxystaurosporine; AKT1 gene; Anthracycline Antibiotics; Anthracyclines; Biological Markers; Biopsy Specimen; Breast; CDC25A gene; CDC25A protein; CHES1 gene; Cancer Therapy Evaluation Program; Cell Line; Classification; Clinical; Clinical Protocols; Clinical Trials; Complement; Development; Disease Progression; ERBB2 gene; Enrollment; Estrogen Receptors; Estrogens; Frequencies; Gene Amplification; Investigation; Irinotecan/UCN-01; Methodology; Molecular; Monitor; Mutation; National Cancer Institute; PDPK1 gene; PIK3CA gene; PTEN gene; Patients; Pharmacodynamics; Phosphorylation; Phosphotransferases; Polymerase Chain Reaction; Population; Principal Investigator; Progesterone; Progesterone Receptors; Protein Kinase Inhibitors; Protocols documentation; Purpose; Rate; Research; Resistance; Safety; Serine; TP53 gene; Taxane Compound; Threonine; Time; Toxic effect; Woman; base; falls; human PIK3CA protein; improved; inhibitor/antagonist; irinotecan; malignant breast neoplasm; mutant; novel therapeutics; outcome forecast; programs; protein kinase inhibitor; receptor; receptor expression; response; taxane; tumor

DESCRIPTION (provided by applicant): Women with advanced triple negative breast cancer (negative for estrogen and progesterone receptor expression and HER-2 gene/neu amplification) have a very poor prognosis necessitating novel therapeutic strategies to improve survival. Triple negative breast cancer typically falls into the molecular classification of basal-like subtype which has a higher rate of TP53 and/or PTEN mutations. In this investigation, based on a clinical protocol approved by the National Cancer Institute's Cancer Therapy Evaluation Program, we will treat patients with advanced triple negative breast cancer with the combination of irinotecan and UCN-01, a broad spectrum serine-threonine protein kinase inhibitor that targets both 3-phosphoinositide-dependent protein kinase-1(PDK1) and checkpoint kinase, CHK1. The primary aim is to evaluate the efficacy and safety of this combination. The secondary aims are to develop a portfolio of pharmacodynamic and predictive biomarkers that may prove useful for the development of CHK1 and PDK1 inhibitors for the treatment of triple negative breast cancer. The primary aims of this proposal are: 1.To determine the anti-tumor activity (overall response rate, clinical benefit rate, and time to disease progression) of UCN-01 in combination with irinotecan in triple negative advanced breast cancer that has progressed despite prior treatment with an anthracycline and a taxane. 2. To describe the toxicities associated with irinotecan in combination with UCN-01 in triple negative advanced breast cancer. The secondary aims of this proposal are: 1. To analyze the frequency of TP53, PTEN and PIK3CA mutations in triple negative advanced breast cancer and conduct preliminary correlations with treatment response to irinotecan in combination with UCN-01. 2. To better define the population of triple negative breast cancers enrolled into the trial with qRT PCR and immunohistochemical biomarkers for the basal sub-type as well as other breast cancer subtypes. 3. To develop methodologies for pharmacodynamic monitoring of the effect of UCN01 on tumor CHK1 and PDK1 by analyzing the levels of CDC25A, and the phosphorylation status of CDK1(Tyr15), PDK1(Ser241) and AKT1 (Thr308) on basal-type cell lines (as controls) as well as sequential tumor biopsy specimens in patients treated on this study.

描述（由申请人提供）：晚期三阴性乳腺癌（雌激素和孕激素受体表达和HER-2基因/neu扩增阴性）女性的预后非常差，需要新的治疗策略来提高生存率。三阴性乳腺癌通常福尔斯属于基底细胞样亚型的分子分类，其具有较高的TP 53和/或PTEN突变率。在这项研究中，根据美国国家癌症研究所癌症治疗评估计划批准的临床方案，我们将联合伊立替康和UCN-01治疗晚期三阴性乳腺癌患者，UCN-01是一种广谱丝氨酸-苏氨酸蛋白激酶抑制剂，靶向3-磷酸肌醇依赖性蛋白激酶-1（PDK 1）和检查点激酶CHK 1。主要目的是评价该组合的有效性和安全性。次要目的是开发一系列药效学和预测性生物标志物，这些生物标志物可能有助于开发CHK 1和PDK 1抑制剂，用于治疗三阴性乳腺癌。本研究的主要目的是：1.确定UCN-01联合伊立替康治疗三阴性晚期乳腺癌的抗肿瘤活性（总体缓解率、临床获益率和疾病进展时间），这些晚期乳腺癌在既往接受蒽环类药物和紫杉烷类药物治疗后仍发生进展。2.描述伊立替康联合UCN-01治疗三阴性晚期乳腺癌的相关毒性。本提案的次要目的是：1.分析三阴性晚期乳腺癌中TP 53、PTEN和PIK 3CA突变的频率，并与伊立替康联合UCN-01治疗反应进行初步相关性分析。2.使用qRT PCR和基底亚型以及其他乳腺癌亚型的免疫组织化学生物标志物更好地定义入组试验的三阴性乳腺癌人群。3.通过分析基础型细胞系（作为对照）上的CDC 25 A水平以及CDK 1（Tyr 15）、PDK 1（Ser 241）和AKT 1（Thr 308）的磷酸化状态，以及本研究治疗患者的连续肿瘤活检标本，开发UCN 01对肿瘤CHK 1和PDK 1影响的药效学监测方法。