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

C/EBP β 拮抗剂在原位乳腺癌中的疗效和 PK/PD

• 批准号: 10681209
• 负责人: Jim Rotolo
• 金额: $ 80.35万
• 依托单位: SAPIENCE THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-05 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10681209
• 关键词: 3-Dimensional; Amino Acids; Apoptosis; Binding; Biological; Biological Assay; Biological Markers; Biopsy; Breast Cancer Model; Breast Cancer therapy; CCAAT-Enhancer-Binding Proteins; CREB1 gene; Cell Death; Cell Nucleus; Cells; Cessation of life; Clinic; Clinical; Clinical Research; Data; Development; Diagnostic; Dimerization; Disease; Dose; ERBB2 gene; Failure; Family; Gene Activation; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Transcription; Immunohistochemistry; In Vitro; Location; Malignant Neoplasms; Mediating; Medical; Metastatic breast cancer; Modeling; Mus; Outcome; Patient Monitoring; Patient Selection; Patients; Penetration; Peptides; Pharmacodynamics; Phase; Phenotype; Phosphorylation; Post-Translational Protein Processing; Prognosis; Protein Isoforms; Proteins; Regimen; Resistance; Role; Serum; Solid Neoplasm; Specimen; Testing; Therapeutic; Tissue-Specific Gene Expression; Tissues; Transactivation; Treatment outcome; Unresectable; Validation; Xenograft procedure; activating transcription factor; antagonist; bZIP Domain; biomarker identification; biomarker performance; biomarker validation; cancer cell; cancer type; design; differential expression; enantiomer; factor C; improved; in vivo; in vivo evaluation; malignant breast neoplasm; mouse model; nano-string; neoplastic cell; novel; novel therapeutics; open label; orthotopic breast cancer; overexpression; participant enrollment; patient derived xenograft model; pharmacodynamic biomarker; pre-clinical; predictive marker; prognostic; programs; prospective; protein protein interaction; response; screening; subcutaneous; success; transcription factor; triple-negative invasive breast carcinoma; tumor; tumor growth; tumorigenesis

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.

抽象的 乳腺癌（BC）仍然是巨大的临床挑战，特别是对于晚期和转移性疾病。 晚期和转移性疾病的预后很严峻，第4期转移性疾病的生存率为5年 22％的中位生存期为3年，每年大约有40,000人死亡。这些证明 临床结果，后期和卑诗省转移性的医疗需求仍然很高。 Sapience的ST101提供 治疗先进或转移性HER2阴性BC的新机会。 ST101的目标是C/EBPβ，这是 一种活跃于癌细胞的新型蛋白质靶标。 C/EBPβ先前被认为是由于 它的（1）在细胞核内的位置，（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相互作用的肽拮抗剂，导致转录 抑制生存因子，从而触发合成致死性和肿瘤凋亡。基于承诺 临床结果，ST101已进入临床阶段。它目前处于开放标签，两部分，阶段1/2 剂量调查研究对先晚期，不可切除和转移性实体瘤的患者的研究 二线疗法。为了进一步支持ST101的发展并提高了其临床成功的机会， 识别ST101活性和 展示了它们在非临床患者衍生的乳腺癌（PDBC）模型中的效用。特定目标＃1将确定 ST101活性的预测生物标志物通过在体外筛选一组PDBC模型，体外， 并将确定与ST101相关的遗传和/或C/EBPβ转化或翻译后修饰 灵敏度（或阻力）。在特定的目标＃2中，将在体内患者中审问已鉴定的生物标志物 - 衍生的异种移植（PDX）小鼠模型，以评估它们是否确实预测了ST101成功还是失败。最后， 特定的目标＃3建议通过组织标本中的差分基因表达（DGE）识别PD生物标志物 在ST101暴露之前和之后，在特定目标＃1和2的特定目标中使用。在临床环境中，这些发现 将在治疗期间用于患者选择和跟踪反应作为参加 ST101的诊断/预后屏幕。生物标志物也将用于优化剂量或方案。