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

1本申请是根据特别利益通知（NOSI）提交的。 2被识别为NOT-CA-22-039。三阴性乳腺癌（TNBC）是一种生物学上 3异质性和临床上重要的乳腺癌亚型，因为如果它被认为是 4种不同的疾病，TNBC将成为女性癌症死亡的第五大原因。TNBC 5在年轻的绝经前妇女中也更普遍，特别是黑人或非洲裔美国人。 6蛋白质翻译调控已被证明是癌症的潜在脆弱性 7包括TNBC。eIF 4A RNA解旋酶是翻译起始的关键调节因子，作为翻译起始的一部分。 8 eIF 4F翻译起始复合物。有趣的是，eIF 4A选择性地抑制许多转录因子的翻译。 9种癌基因和生长因子mRNA，具有高度结构化的5 'UTR，是肿瘤细胞中的必需基因。 10多种癌细胞系。eFFECTOR Therapeutics已经开发了一种改进的eIF 4A抑制剂， 11 Zotatifin（eFT 226），目前正在进行I期临床试验（NCT 04092673）， 12例晚期恶性实体瘤患者。通过与eFFECTOR的合作，我们 13项研究旨在确定Zotatifin在同基因遗传工程中的疗效。 我们实验室开发了14种小鼠（GEM）TNBC模型。在这些模型中， 在联合治疗后观察到肿瘤消退和至终点的时间为15 16佐他替芬与卡铂或多西他赛的标准治疗。我们现在建议扩大这些 17项针对一系列种族和民族多样化的TNBC PDX模型的研究，特别关注 18个来自服务不足的人群，以更好地确定哪些患者可能受益 19例来自未来临床试验中的联合治疗。eIF 4A蛋白表达分析 20个TNBC PDX模型已识别出具有显著不同佐他替芬靶标水平的模型 21表情。我们现在建议优化和阐明单一药物的机制， 22例在几种高和低eIF 4A PDX中使用佐他替芬和化疗的联合治疗 23种模型，并开发生物标志物来预测反应。我们以前对GEM模型的研究 24例确定的骨髓免疫微环境变化，包括骨髓细胞浸润减少， 25中性粒细胞和肿瘤相关巨噬细胞复极化至免疫抑制性较低的 26和更多的肿瘤抑制表型。因此，我们还将研究Zotatifin的作用， 在这些PDX模型中对循环和肿瘤相关骨髓细胞的化疗。在 总之，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篇临床试验虽然这些研究最初集中在TNBC上，但它们可能具有更广泛的 30应用于其他实体癌。

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.