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该申请是根据特殊利益通知（NOSI）提交的 2被确定为非CA-22-039。三重阴性乳腺癌（TNBC）是生物学上的 3异质和临床上重要的乳腺癌亚型，因为如果被认为是 4截然不同的疾病，TNBC将成为女性癌症死亡的第五个主要原因。 TNBC 5在年轻的大赛妇女，尤其是黑人或非裔美国人中也更为普遍。 6蛋白转化调节已被证明是癌症的潜在脆弱性 7包括TNBC。 EIF4A RNA解旋酶是翻译起始的关键调节剂 8 EIF4F翻译起始复合物。有趣的是，EIF4A有选择地抑制许多人的翻译 9具有高度结构化5'UTRS的癌基因和生长因子mRNA，是一个必不可少的基因 10许多癌细胞系。效应子疗法已经开发了改进的EIF4A抑制剂， 11 Zotatifin（EFT226），目前正在I期临床试验（NCT04092673）中进行评估 12例晚期实质性恶性肿瘤患者。与效应器合作，我们有 13项进行了研究，以确定Zotatifin在合成元中的一般工程中的效率 14个小鼠（GEM）TNBC模型在我们的实验室中开发。在这些模型中有明显的改进 在肿瘤回归和终点的时间到终点的时间15。 16 ZOTATIFIN，具有标准的卡铂或多西他赛。我们现在建议扩大这些 17研究对一系列大致和种族多样化的TNBC PDX模型的研究，特别关注 18从服务不足的人群中得出的那些，以便更好地确定哪些患者可能受益 19在将来的临床试验中进行组合疗法。 EIF4A蛋白表达跨的分析 20 TNBC PDX模型已鉴定出具有明显不同Zotatifin目标的模型 21表达。现在，我们建议优化和阐明单一代理的机制和 22在几个高和低EIF4A PDX的ZOTATIFIN和化学疗法的组合疗法 23个模型并开发生物标志物以预测反应。我们以前在宝石模型中的研究 24确定了髓样免疫微环境的变化，包括降低 25个嗜中性粒细胞和与肿瘤相关的巨噬细胞的复制 26和更多的肿瘤抑制表型。那我们还将研究Zotatifin和 27这些PDX模型中循环和肿瘤相关的髓样细胞的化学疗法。在 28总结，这些临床前研究可能有助于提供关键信息以告知未来的设计 29个临床试验。尽管这些研究最初是针对TNBC的 30应用于其他固体癌症。