THE RNA HELICASE EIF4A IS A THERAPEUTIC VULNERABILITY IN TRIPLE-NEGATIVE BREAST CANCER

RNA解旋酶EIF4A是三阴性乳腺癌的治疗漏洞

• 批准号: 10582328
• 负责人: Nicholas Mitsiades
• 金额: $ 20万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10582328
• 关键词: 5' Untranslated Regions; African American population; Biological Markers; Black American; Breast Cancer Model; COVID-19; Cancer Etiology; Cancer cell line; Carboplatin; Cessation of life; Chemicals; Clinical; Clinical Trials; Collaborations; Combined Modality Therapy; Disease; Essential Genes; Eukaryotic Initiation Factor-4F; Future; Genetic Engineering; Growth Factor; Infiltration; Laboratories; Malignant Neoplasms; Messenger RNA; Modeling; Mus; Myelogenous; Myeloid Cells; Oncogenes; Patient-derived xenograft models of breast cancer; Patients; Pharmaceutical Preparations; Phase I Clinical Trials; Phenotype; Premenopause; Property; Proteins; RNA Helicase; Series; Solid; Solid Neoplasm; Structure; Therapeutic; Time; Translation Initiation; Translational Regulation; Translations; Tumor-associated macrophages; Underserved Population; Woman; cancer subtypes; chemotherapy; design; docetaxel; ethnic diversity; improved; inhibitor; interest; malignant breast neoplasm; mouse model; neutrophil; patient derived xenograft model; preclinical study; predicting response; protein expression; racial diversity; response; standard of care; triple-negative invasive breast carcinoma; tumor; tumor-immune system interactions

1 This application is being submitted in response to the Notice of Special Interest (NOSI) 2 identified as NOT-CA-22-039. Triple negative breast cancer (TNBC) is a biologically 3 heterogeneous and clinically important breast cancer subtype because if it were considered a 4 distinct disease, TNBC would rank as the 5th leading cause of cancer deaths in women. TNBC 5 also is more prevalent in younger premenopausal women especially Black or African Americans. 6 Protein translational regulation has been demonstrated to be a potential vulnerability in cancer 7 including TNBC. The eIF4A RNA helicase is a key regulator of translation initiation as part of the 8 eIF4F translation initiation complex. Interestingly, eIF4A selectively inhibits the translation of many 9 oncogene and growth factor mRNAs with highly structured 5’UTRs and is an essential gene in 10 many cancer cell lines. eFFECTOR Therapeutics has developed an improved eIF4A inhibitor, 11 Zotatifin (eFT226), that is currently being evaluated in a Phase I clinical trial (NCT04092673) in 12 patients with advanced solid tumor malignancies. In collaboration with eFFECTOR, we have 13 performed studies to determine the efficacy of Zotatifin in syngeneic genetically engineered 14 mouse (GEM) TNBC models developed in our laboratory. In these models a marked improvement 15 in tumor regression and time to end point was observed following combination treatment of 16 Zotatifin with standard-of-care either carboplatin or docetaxel. We now propose to expand these 17 studies to a series of racially and ethnically diverse TNBC PDX models with a special focus on 18 those derived from underserved populations in order to better identify which patients might benefit 19 from combination therapy in future clinical trials. Analysis of eIF4A protein expression across 20 TNBC PDX models has identified models with markedly different levels of Zotatifin target 21 expression. We now propose to optimize and elucidate mechanisms of single agent and 22 combination therapy with Zotatifin and chemotherapy across several high and low eIF4A PDX 23 models and to develop biomarkers to predict response. Our previous studies in GEM models 24 identified changes in the myeloid immune microenvironment including decreased infiltration of 25 neutrophils and repolarization of tumor associated macrophages to a less immunosuppressive 26 and more tumor inhibitory phenotype. Thus, we will also study effects of Zotatifin and 27 chemotherapy on circulating and tumor associated myeloid cells in these PDX models. In 28 summary, these preclinical studies may help provide key information to inform the design of future 29 clinical trials. Although these studies are initially focused on TNBC they may have a broader 30 application to other solid cancers.

1 本申请是为了响应特别利益通知 (NOSI) 而提交的 2 被鉴定为 NOT-CA-22-039 三阴性乳腺癌 (TNBC) 是一种生物学上的癌症。 3 异质性且临床上重要的乳腺癌亚型，因为如果它被认为是一种 作为第四种不同的疾病，TNBC 将成为女性癌症死亡的第五大原因。 5 在年轻的绝经前女性中也更为普遍，尤其是黑人或非裔美国人。 6 蛋白质翻译调控已被证明是癌症的潜在弱点 7 包括 TNBC，eIF4A RNA 解旋酶是翻译起始的关键调节因子。 8 eIF4F 翻译起始复合物暗示，eIF4A 选择性抑制许多翻译。 9 个癌基因和生长因子 mRNA 具有高度结构化的 5'UTR，是 eFFECTOR Therapeutics 开发了一种改进的 eIF4A 抑制剂，针对 10 多种癌细胞系。 11 Zotatifin (eFT226)，目前正在 I 期临床试验 (NCT04092673) 中进行评估 我们与 eFFECTOR 合作，治疗了 12 名晚期实体瘤患者。 13 项研究旨在确定 Zotatifin 在同基因基因工程中的功效 我们实验室开发了 14 个小鼠 (GEM) TNBC 模型，这些模型有显着的改进。 联合治疗后观察到肿瘤消退和达到终点的时间为 15 16 Zotatifin 联合卡铂或多西紫杉醇标准治疗 我们现在建议扩大这些范围。 针对一系列种族和民族多样化的 TNBC PDX 模型进行了 17 项研究，特别关注 18 来自服务不足的人群，以便更好地确定哪些患者可能受益 19 未来临床试验中联合治疗的 eIF4A 蛋白表达分析。 20 个 TNBC PDX 模型已识别出 Zotatifin 靶点水平显着不同的模型 21表达我们现在建议优化和阐明单剂和 22 佐他替芬和化疗的联合治疗跨越多个高和低 eIF4A PDX 23 个模型并开发生物标志物来预测反应。 24 发现了骨髓免疫微环境的变化，包括细胞浸润减少 25 中性粒细胞和肿瘤相关巨噬细胞复极化至免疫抑制程度较低 26 及更多肿瘤抑制表型因此，我们还将研究 Zotatifin 和的作用。 27 在这些 PDX 模型中对循环和肿瘤相关骨髓细胞进行化疗。 28总结，这些临床前研究可能有助于提供关键信息，为未来的设计提供信息 29 临床试验虽然这些研究最初集中于 TNBC，但它们可能有更广泛的研究。 30 种在其他实体癌中的应用。