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

摘要 乳腺癌(BC)仍然是一个巨大的临床挑战，特别是对于晚期和转移性疾病。 晚期和转移性疾病的预后是严峻的，4期转移性疾病的5年存活率是 22%，中位生存期为3年，每年造成约40,000人死亡。从以下几点可以看出 临床结果、晚期和转移性BC仍然是一个高度未得到满足的医疗需求。Sapience的ST101提供 治疗晚期或转移性HER2阴性BC的新机会。ST101的目标是C/EBPβ，它是 一种活跃在癌细胞中的新的蛋白质靶点。C/eBPβ之前被认为是一个无法下药的目标，因为 它(1)位于细胞核内，(2)活性取决于蛋白质-蛋白质相互作用，而不是 酶活性。ST101是肿瘤细胞中C/EBPβ相互作用的多肽拮抗剂，导致转录 抑制生存因子，从而触发合成杀伤力和肿瘤细胞凋亡。基于前景看好的PRE- 临床结果，ST101已经进入临床阶段；它目前处于开放标签、两部分、1/2阶段 首次和首次失败的晚期、不能切除和转移性实体肿瘤患者的剂量发现研究 二线治疗。为了进一步支持ST101的发展，提高其临床成功的机会， Sapience建议识别ST101活性的预测性和药效学(PD)生物标志物，并 在非临床患者来源的乳腺癌(PDBC)模型中展示它们的有效性。具体目标#1将确定 通过在体外三维培养中筛选一组PDBC模型来预测ST101活性的生物标志物， 并将确定与ST101相关的基因和/或C/EBPβ翻译或翻译后修饰 敏感性(或抵抗力)。在特定的目标2中，已识别的生物标记物将在活体患者身上进行询问- 衍生异种移植(PDX)小鼠模型，以评估它们是否真的预测ST101的成功或失败。最后， 具体目标#3提出通过组织标本的差异基因表达来鉴定帕金森病生物标志物(S) 在ST101暴露前后的特定目标#1和#2期间使用。在临床环境中，这些发现 将用于患者选择和跟踪治疗期间的反应，作为伴随 ST101的诊断/预后筛查。这些生物标志物也将被用来优化剂量或方案。

ABSTRACT Breast cancer (BC) remains an immense clinical challenge, particularly for late stage and metastatic disease. Prognosis for late-stage and metastatic disease is grim, with 5-year survival for Stage 4 metastatic disease at 22%, with a median survival of 3 years, resulting in approximately 40,000 deaths annually. As evident by these clinical outcomes, late stage and metastatic BC remains a high unmet medical need. Sapience’s ST101 provides a new opportunity to treat advanced or metastatic HER2-negative BC. The target of ST101 is C/EBPβ, which is a novel protein target active in cancer cells. C/EBPβ was previously considered an ‘undruggable’ target due to its (1) location inside of the nucleus of a cell and (2) activity dependent on protein-protein interactions, and not enzymatic activity. ST101 is a peptide antagonist of C/EBPβ interactions in tumor cells, resulting in transcriptional inhibition of survival factors, thereby triggering synthetic lethality and tumor apoptosis. Based on promising pre- clinical results, ST101 has moved into the clinical phase; it is currently in an open-label, two-part, phase 1/2 dose-finding study in patients with advanced, unresectable and metastatic solid tumors who have failed first- and second-line therapies. To further support the development of ST101 and improve its chances of clinical success, Sapience proposes to identify predictive and pharmacodynamic (PD) biomarkers for ST101 activity and demonstrate their utility in non-clinical patient-derived breast cancer (PDBC) models. Specific Aim #1 will identify predictive biomarkers of ST101 activity by screening a panel of PDBC models in 3-dimensional culture in vitro, and will identify genetic and/or C/EBPβ translational or post-translational modifications that correlate with ST101 sensitivity (or resistance). In Specific Aim #2, the identified biomarkers will be interrogated in in vivo patient- derived xenograft (PDX) mouse models, to assess whether they indeed predict ST101 success or failure. Finally, Specific Aim #3 proposes to identify PD biomarker(s) via differential gene expression (DGE) in tissue specimens used during Specific Aims #1 and #2, before and after ST101 exposure. In a clinical setting, these discoveries will be utilized for patient selection and tracking responses during treatment as an accompanying diagnostic/prognostic screen for ST101. The biomarkers would also be used to optimize dose or regimen.