The Development of Novel Individualized Therapy for Metastatic Triple Negative B

描述(申请人提供)：三阴性乳腺癌(TNBC)占所有新诊断的乳腺癌的10%-15%，与其他乳腺癌亚型相比，乳腺癌远处转移和死亡的风险增加。尽管努力开发有效的治疗策略，转移性TNBC患者的总生存期中位数约为13个月。这种疾病代表了乳腺癌治疗中一个尚未得到满足的领域。TNBC与高的核级别、对抗有丝分裂药物的敏感性和对血管生成的依赖性有关。极光激酶是丝氨酸-苏氨酸激酶家族，是有丝分裂细胞分裂所必需的，是新兴的抗癌治疗靶点。ENMD-2076是一种新型的口服生物利用型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。这项建议旨在完成ENMD-2076的单臂、双机构、两阶段II期临床试验，用于晚期或转移性、以前接受过TNBC治疗的患者。这项临床试验将在科罗拉多大学癌症中心(UCCC)和印第安纳大学(IU)招募大约35名患者。本研究的目的是确定该药治疗晚期TNBC的疗效，包括药代动力学和药效学研究。这项研究将包括连续的肿瘤活检、治疗前和治疗后两周的表现，以进行药效学研究，包括对Aurora激酶的调节。这项研究的第二个目的是在这一患者群体中探索预测临床对ENMD-2076反应的基因组生物标志物。UCCC和ENMD-2076正在进行TNBC临床前模型的研究，以确定预测反应的分类器，其中包括P53信号和上调和下调的细胞通路的变化，这些可以通过RT-PCR技术进行评估。这项建议的总体目标是为晚期TNBC开发一种新颖而有效的治疗方法，包括研究独特的生物标记物选择策略，这是人类癌症护理中尚未得到满足的一个主要领域。 公共卫生相关性：这项研究的目的是完成一项临床试验，调查新型Aurora和血管生成激酶抑制剂ENMD-2076在晚期三阴性乳腺癌患者中的应用。三阴性乳腺癌缺乏针对特定个体肿瘤特征量身定做的治疗方案。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。

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.