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， 仍然严峻，造成了对有效疗法的巨大未满足的医疗需求。 转录因子（TF）代表了有前途的治疗靶点，因为它们在癌症中经常失调。 一种这样的TF - CCAAT/增强子结合蛋白β（C/EBPβ）-在致癌过程中起作用：分化， 炎症、细胞存活、增殖和代谢。C/EBPβ过表达或组成性激活， 各种人类恶性肿瘤，驱动肿瘤细胞增殖和存活。一种肽拮抗剂， Lloyd格林（哥伦比亚大学）的实验室与C/EBPβ结合并抑制其与辅因子的相互作用 致癌基因表达所需的，在体外和体内抗肿瘤活性中证明了概念验证。 许多细胞类型，包括乳腺癌细胞。 Sapience许可并对C/EBPβ拮抗剂肽进行了构效关系分析， 改善了其在生物基质中溶解性、可制造性和稳定性差。一系列修改 产生了一种更有效的治疗候选物，命名为ST 101，具有更大的活性、溶解度、可制造性， 和稳定性，同时降低其预测的免疫原性。具体而言，ST 101 antag- 使肿瘤细胞中的C/EBPβ相互作用消失，导致促存活、增殖和 分化基因，从而触发肿瘤细胞凋亡，无论HER 2状态，甚至在三阴性 乳腺癌（TNBC）细胞。此外，ST 101已在皮下组织中显示出有效的体内抗肿瘤活性。 在新植入的和建立的肿瘤两者中的neous乳腺癌异种移植小鼠模型中。 上述结果支持了我们的假设，即C/EBPβ的肽拮抗剂将被证明是有效的 乳腺癌治疗策略。因此，我们提出了一个计划，以调查ST 101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 ST 101，并选择用于体内阶段的细胞系。然后，我们将描述以下药物的PK/PD特征： ST 101在特定目标#2中的体内，在生物相关的原位乳腺癌模型中，其模拟 在肿瘤的自然环境中的临床生物利用度。最后，具体目标#3将评估opti的有效性， 在具有转移的原位乳腺癌模型中，使用经改良的ST 101给药方案。成功完成 这些目标将确定ST 101的最大有效剂量方案，并支持随后的II期研究。 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.