The Development of Novel Individualized Therapy for Metastatic Triple Negative B

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，乳腺癌远处转移和死亡的风险更高。尽管努力开发有效的治疗策略，但转移性TNBC患者的中位总生存期约为13个月。这种疾病是乳腺癌治疗中一个未满足需求的领域。TNBC与核分级高、对抗有丝分裂药物敏感以及对血管生成的依赖有关。Aurora激酶是有丝分裂细胞分裂不可或缺的丝氨酸-苏氨酸激酶家族，是新兴的抗癌治疗靶点。ENMD-2076是一种新型的口服生物可利用的极光和血管生成激酶抑制剂，在临床前TNBC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、先前治疗过的TNBC患者中的单臂、双机构、两期II期临床试验。该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）招募约35名患者。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。该研究将包括一系列肿瘤活检，治疗前和治疗后两周的表现，用于药效学研究，包括极光激酶的调节。本研究的第二个目的是探索预测该患者群体对ENMD-2076临床反应的基因组生物标志物。UCCC正在临床前TNBC模型中使用ENMD-2076进行研究，以确定预测反应的分类器，包括p53信号的改变以及可以通过RT- PCR技术评估的上调和下调的细胞通路。本提案的总体目标是为晚期TNBC开发一种新颖有效的治疗方法，包括研究独特的生物标志物选择策略，这代表了人类癌症治疗中未满足需求的主要领域。

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.