Efficacy and PK/PD of a C/EBP beta antagonist in orthotopic breast cancer

摘要 虽然早期乳腺癌的治疗通常是有效的，但晚期和转移性疾病的预后， 形势依然严峻，为有效治疗创造了巨大的未得到满足的医疗需求。 转录因子是很有希望的治疗靶点，因为它们在癌症中经常是不受调控的。 一种这样的TF-CCAAT/增强子结合蛋白(C/EBpβ)-在肿瘤发生过程中发挥作用：分化， 炎症、细胞存活、增殖和新陈代谢。C/eBPβ过度表达或结构性激活 各种人类恶性肿瘤，推动肿瘤细胞的增殖和存活。一种肽拮抗剂，由The 劳埃德·格林实验室(哥伦比亚大学)与C/EBPβ结合并抑制其与辅助因子的相互作用 致癌基因表达所需的，在体外和体内证明了抗肿瘤活性 多种细胞类型，包括乳腺腺癌细胞。 Sapience获得许可并进行了C/eBPβ拮抗肽的构效关系分析 改善其在生物基质中的溶解性、可制造性和稳定性。一系列的修改 产生了一种更有效的治疗候选药物，名为ST101，具有更高的活性，溶解性，可制造性， 比母体化合物更稳定，同时降低了其预期的免疫原性。具体地说，ST101 ANTAG- 激活肿瘤细胞中的C/eBPβ相互作用，导致对促生存、增殖和 分化基因，从而触发肿瘤细胞凋亡，无论HER2状态如何，甚至在三重阴性 乳腺癌(TNBC)细胞。此外，ST101还在体内的一种皮下组织中表现出了强大的抗肿瘤活性。 新移植和已建立肿瘤中的新生乳腺癌小鼠模型。 上述结果支持我们的假设，即C/EBPβ的多肽拮抗剂将被证明是有效的 乳腺癌治疗策略。因此，我们提出了一项计划，研究ST101作为一种 治疗乳腺癌的新方法，特别关注转移性疾病。在具体目标#1中，我们建议 筛选一组乳腺癌细胞系以确定不同乳腺癌亚型对 ST101，选择细胞株(S)作为体内时相细胞。然后我们将描述PK/PD配置文件的特征 ST101在体内的特定目的#2，在生物相关的原位乳腺癌模型中，模拟 肿瘤自然环境下的临床生物利用度。最后，具体目标3将评估Opti-One的效果。 改良ST101给药方案在原位乳腺癌转移模型中的应用。成功完成 这些目标将确定ST101的最有效剂量方案，并支持后续的第二阶段 提案，以支持IND申请。

ABSTRACT While therapies for early stage breast cancer are often effective, prognosis for later stage and metastatic disease, remain grim, creating a great unmet medical need for effective therapies. Transcription factors (TFs) represent promising therapeutic targets as they are often dysregulated in cancer. One such TF – CCAAT/enhancer-binding protein  (C/EBPβ) – has roles in oncogenic processes: differentiation, inflammation, cell survival, proliferation and metabolism. C/EBPβ is overexpressed or constitutively activated in various human malignancies, driving tumor cell proliferation and survival. A peptide antagonist, designed by the lab of Lloyd Greene (Columbia University) to associate with C/EBPβ and inhibit its interactions with co-factors required for oncogenic gene expression, demonstrated proof-of-concept in vitro and in vivo anti-tumor activity in many cell types, including breast adenocarcinoma cells. Sapience licensed and performed a structure-activity relationship analysis on the C/EBPβ antagonist peptide to improve upon its poor solubility, manufacturability and stability in biological matrices. A series of modifications produced a more potent therapeutic candidate, named ST101, with greater activity, solubility, manufacturability, and stability than the parent compound, while reducing its predicted immunogenicity. Specifically, ST101 antag- onizes C/EBPβ interactions in tumor cells, resulting in transcriptional inhibition of pro-survival, proliferation, and differentiation genes, thereby triggering tumor apoptosis, regardless of HER2 status, and even in triple negative breast cancer (TNBC) cells. Moreover, ST101 has demonstrated potent anti-tumor activity in vivo in a subcuta- neous breast cancer xenograft mouse model in both newly implanted and established tumors. The above results support our hypothesis that a peptide antagonist of C/EBPβ will prove to be an effective strategy for breast cancer therapy. Accordingly, we propose a plan to investigate the potential of ST101 as a novel approach to treat breast cancer, with particular focus on metastatic disease. In Specific Aim #1, we propose to screen a panel of breast cancer cell lines to determine the sensitivity of different breast cancer subtypes to ST101 and select cell line(s) to be used for the in vivo phase. We will then characterize the PK/PD profile of ST101 in vivo in Specific Aim #2, in a biologically-relevant orthotopic breast cancer model, which simulates clinical bioavailability at the tumor's natural milieu. Finally, Specific Aim #3 will evaluate the efficacy of the opti- mized ST101 dosing regimen in an orthotopic breast cancer with metastasis model. Successful completion of these aims will identify a maximally effective dosing regimen for ST101 and support a subsequent Phase II proposal, in support of an IND application.