The Development of Novel Individualized Therapy for Metastatic Triple Negative B

转移性三阴性B的新型个体化治疗的发展

• 批准号: 8385374
• 负责人: Jennifer R Diamond
• 金额: $ 21.5万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-09 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8385374
• 关键词: Accounting; Aftercare; Area; Bioavailable; Biological; Biological Markers; Biopsy; Breast Cancer Cell; Breast Cancer Treatment; Cell Line; Cell division; Cessation of life; Characteristics; Clinical; Clinical Research; Clinical Trials; Code; DNA Sequence; Data; Dependence; Development; Disease; Distant Metastasis; Dose; Dose-Limiting; Drug Kinetics; Enrollment; Exhibits; Family; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Genes; Genomics; Goals; Human; Hypertension; Incidence; Indiana; Individual; Institution; Investigation; Laboratories; Lead; Malignant neoplasm of ovary; Mammary Neoplasms; Mitotic; Modeling; Mutation; Neutropenia; Newly Diagnosed; Nuclear Grade; Oncogenic; Pathway interactions; Patients; Performance; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phase II Clinical Trials; Phenotype; Phosphotransferases; Plasma; Platinum; Pre-Clinical Model; Protein-Serine-Threonine Kinases; Publishing; RNA; Resistance; Reverse Transcriptase Polymerase Chain Reaction; Risk; Salvage Therapy; Sampling; Signal Transduction; Site; Staging; Techniques; Testing; The University of Colorado Cancer Center; Tissues; Toxic effect; Tumor Tissue; Universities; Vascular Endothelial Growth Factors; Work; angiogenesis; anti-cancer therapeutic; arm; aurora kinase; base; cancer care; chemotherapy; clinical efficacy; effective therapy; human STK6 protein; improved; inhibitor/antagonist; kinase inhibitor; malignant breast neoplasm; neoplastic cell; novel; patient population; phase 1 study; pre-clinical; response; small molecule; treatment strategy; triple-negative invasive breast carcinoma; tumor

DESCRIPTION (provided by applicant): Triple-negative breast cancer (TNBC) accounts for 10-15% of all newly diagnosed breast cancer and carries an increased risk of distant metastasis and death from breast cancer compared to other breast cancer subtypes. Despite efforts to develop effective treatment strategies, patients with metastatic TNBC have a median overall survival of around 13 months. This disease represents an area of unmet need in breast cancer treatment. TNBC is associated with a high nuclear grade, sensitivity to anti-mitotic agents, and dependence on angiogenesis. The Aurora kinases are a family of serine-threonine kinases integral to mitotic cell division and are emerging therapeutic anticancer targets. ENMD-2076 is a novel, orally bioavailable, Aurora and angiogenic kinase inhibitor that has antitumor activity in preclinical models of TNBC. This proposal aims to complete a single-arm, dual institution, two-stage phase II clinical trial of ENMD-2076 in patients with advanced or metastatic, previously treated TNBC. This clinical trial will enroll approximately 35 patients at the University of Colorado Cancer Center (UCCC) and the Indiana University (IU). The objectives of this study are to determine the efficacy of this agent in the treatment of advanced TNBC, including pharmacokinetic and pharmacodynamic investigations. This study will include the performance of serial tumor biopsies, pre-treatment and two weeks post-treatment, for pharmacodynamic studies including modulation of the Aurora kinases. A secondary aim of this study is to explore genomic biomarkers predictive of clinical response to ENMD-2076 in this patient population. Studies are ongoing at the UCCC with ENMD-2076 in preclinical models of TNBC to identify classifiers predictive of response which include alterations in p53 signaling and up- and down-regulated cellular pathways which can be assessed by RT- PCR techniques. The overall goal of this proposal is to develop a novel and effective therapy for advanced TNBC, including the investigation of unique biomarker selection strategies which represents a major area of unmet need in human cancer care. PUBLIC HEALTH RELEVANCE: The purpose of this study is to complete a clinical trial investigating ENMD-2076, a novel Aurora and angiogenic kinase inhibitor, in patients with advanced triple-negative breast cancer. Triple- negative breast cancer lacks treatment options that can be tailored to a particular individual's tumor characteristics. This study aims to understand how ENMD-2076 works in triple-negative breast cancer cells and to explore tumor characteristics that can predict clinical benefit from this drug.

描述（由申请人提供）：三阴性乳腺癌（TNBC）占所有新诊断乳腺癌的10-15%，与其他乳腺癌亚型相比，其远处转移和乳腺癌死亡的风险增加。尽管努力开发有效的治疗策略，转移性TNBC患者的中位总生存期约为13个月。这种疾病代表了乳腺癌治疗中未满足需求的一个领域。TNBC与高核等级、对抗有丝分裂剂的敏感性和对血管生成的依赖性相关。Aurora激酶是有丝分裂细胞分裂中不可或缺的丝氨酸-苏氨酸激酶家族，是新兴的治疗性抗癌靶点。ENMD-2076是一种新型的口服生物可利用的Aurora和血管生成激酶抑制剂，在TNBC的临床前模型中具有抗肿瘤活性。该提案旨在完成ENMD-2076在晚期或转移性、既往接受过治疗的TNBC患者中的单臂、双机构、两阶段II期临床试验。本临床试验将在科罗拉多大学癌症中心（UCCC）和印第安纳州大学（IU）入组约35例患者。本研究的目的是确定该药物治疗晚期TNBC的疗效，包括药代动力学和药效学研究。本研究将包括治疗前和治疗后两周进行的系列肿瘤活检，用于药效学研究，包括Aurora激酶的调节。本研究的次要目的是探索预测该患者群体中对ENMD-2076的临床应答的基因组生物标志物。UCCC正在TNBC的临床前模型中使用ENMD-2076进行研究，以鉴定预测应答的分类器，所述应答包括p53信号传导和上调和下调的细胞途径的改变，其可以通过RT-PCR技术进行评估。该提案的总体目标是为晚期TNBC开发一种新的有效疗法，包括研究独特的生物标志物选择策略，这是人类癌症护理中未满足需求的主要领域。 公共卫生关系：本研究的目的是完成ENMD-2076（一种新型Aurora和血管生成激酶抑制剂）在晚期三阴性乳腺癌患者中的临床试验。三阴性乳腺癌缺乏可以针对特定个体的肿瘤特征的治疗选择。这项研究旨在了解ENMD-2076如何在三阴性乳腺癌细胞中发挥作用，并探索可以预测该药物临床益处的肿瘤特征。