P-1: Targeting Aurora Kinase in Aggressive B-cell non-Hodgkin's Lymphomas

P-1：针对侵袭性 B 细胞非霍奇金淋巴瘤的 Aurora 激酶

• 批准号: 8381185
• 负责人: DARUKA MAHADEVAN
• 金额: $ 27.93万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8381185
• 关键词: Aneuploidy; Animals; Apoptosis; Arizona; B-Cell NonHodgkins Lymphoma; C-terminal; Cancer Center; Cell Culture Techniques; Cell Cycle; Cell Line; Cell Survival; Centrosome; Chromosome Segregation; Clinical Trials; Collaborations; Cultured Tumor Cells; Data; Drug Delivery Systems; Drug Kinetics; Family; Follicular Lymphoma; Gene Expression Profile; Genes; Genomic Instability; Human; Inferior; Inhibitory Concentration 50; Length; Lymphoma; Mantle Cell Lymphoma; Microtubules; Mitotic; Mitotic spindle; Molecular; Molecular Profiling; Mouse Cell Line; Mus; N-terminal; Non-Hodgkin' s Lymphoma; Oncogenic; Patients; Pharmacodynamics; Phase; Phosphotransferases; Prognostic Factor; Protein-Serine-Threonine Kinases; RNA Interference; Relapse; Reverse Transcriptase Polymerase Chain Reaction; Safety; Signal Transduction; Specimen; Techniques; Testing; Therapeutic; Tissue Microarray; Tissues; Validation; Xenograft Model; aurora kinase; design; drug discovery; human STK6 protein; inhibitor/antagonist; large cell Diffuse non-Hodgkin' s lymphoma; leukemia/lymphoma; novel; overexpression; phase 1 study; phase 2 study; research clinical testing; rituximab; safety study; tumor

Aurora kinases are a family of serine/threonine (S/T) kinases (Aurora A, B, C) that function predominantly in the mitotic-phase of the cell cycle. All 3 Auroras possess a highly conserved C-terminal kinase domain with a variable length N-terminal extension. These kinases regulate the completion of centrosome separation, bipolar spindle assembly, chromosome segregation and cytokenesis. Aberrant over-expression of Aurora A and B are oncogenic as they over-ride the mitotic and spindle check points leading to aneuploidy and genomic instability. Previously, we utilized small interference RNA (RNAi) techniques to validate Aurora A as an oncogenic target. We then evaluated the lymphoma, leukemia molecular profiling project (LLMPP) gene expression profile of ~100 mantle cell lymphoma (MCL) patients and demonstrated that over-expression of Aurora A and B, as 'signature genes for proliferation', predicts for an inferior overall survival and hence is a poor prognostic factor. Further, we showed that Aurora A is over-expressed in several of human MCL and DLBCL cell lines, Therefore, targeting Aurora with a specific small molecular inhibitor (SMI) might be of therapeutic value in aggressive B-cell non-Hodgkin's lymphomas (NHL). Hence, we utilized a structurebased drug discovery approach to design and synthesize a specific ATP-competitive Aurora SMI (SGI-498). Treatment of MCL and DLBCL cell lines with SGI-498 led to reduced cell viability and apoptosis in the 5- 10|aM IC50 range. Large animal safety studies have been conducted and an IND application is in progress (in collaboration with Supergen). Collectively these data show that Aurora is an excellent oncogenic drug target in aggressive subsets of B-cell NHL. Despite encouraging data in cell lines, there has not been a comprehensive study evaluating the expression of Aurora kinases in fresh tumor specimens of aggressive B-cell NHL nor a clinical test of efficacy in lymphoma patients. Therefore, the hypotheses to be tested in this Project 1 are: (1). Aurora A and B are over-expressed in fresh human aggressive B-cell NHL (mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL) and transformed follicular lymphoma (TFL)) tissues, (2). Aurora inhibitor SGI-498 is effective in promoting apoptosis in cell culture and tumor regression in a mouse xenograft model(s) of NHL and (3). SGI-498 will be safe and effective in treating patients with relapsed aggressive B-cell NHL in a early Phase clinical trial.

极光激酶是丝氨酸/苏氨酸 (S/T) 激酶 (Aurora A、B、C) 家族，主要在 细胞周期的有丝分裂期。所有 3 个 Aurora 都具有高度保守的 C 端激酶结构域 可变长度的N-末端延伸。这些激酶调节中心体分离的完成， 双极纺锤体组装、染色体分离和细胞分裂。 Aurora A 异常过度表达 B 和 B 是致癌的，因为它们超越有丝分裂和纺锤体检查点，导致非整倍性 基因组不稳定。此前，我们利用小干扰 RNA (RNAi) 技术来验证 Aurora A 为 致癌靶点。然后我们评估了淋巴瘤、白血病分子谱项目（LLMPP）基因 约 100 名套细胞淋巴瘤 (MCL) 患者的表达谱，并证明 Aurora A 和 B 作为“增殖的标志基因”，预测总体生存率较差，因此是 不良预后因素。此外，我们发现 Aurora A 在几种人类 MCL 和 DLBCL 细胞系，因此，用特定的小分子抑制剂 (SMI) 靶向 Aurora 可能是有效的 对侵袭性 B 细胞非霍奇金淋巴瘤 (NHL) 的治疗价值。因此，我们利用了基于结构的 药物发现方法设计和合成特定的 ATP 竞争性 Aurora SMI (SGI-498)。 用 SGI-498 处理 MCL 和 DLBCL 细胞系导致 5-细胞活力降低和细胞凋亡 10|aM IC50 范围。大型动物安全性研究已经开展，IND申请正在进行中（in 与 Supergen 合作）。总的来说，这些数据表明 Aurora 是一个极好的致癌药物靶点 在 B 细胞 NHL 的侵袭性亚群中。 尽管细胞系中的数据令人鼓舞，但尚未进行全面的研究评估表达 极光激酶在侵袭性 B 细胞 NHL 的新鲜肿瘤标本中的作用，也没有临床功效测试 淋巴瘤患者。因此，本项目1要检验的假设为： (1)．极光 A 和 B 是 在新鲜人侵袭性 B 细胞 NHL（套细胞淋巴瘤 (MCL)、弥漫性大 B 细胞 淋巴瘤（DLBCL）和转化滤泡性淋巴瘤（TFL））组织，（2）。极光抑制剂 SGI-498 是 有效促进细胞培养中的细胞凋亡和 NHL 小鼠异种移植模型中的肿瘤消退 和（3）。 SGI-498 在早期治疗复发性侵袭性 B 细胞 NHL 患者方面将是安全有效的 一期临床试验。