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.

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年生存率为100%。 22%，中位生存期为3年，每年导致约40，000人死亡。这些证据表明， 临床结果、晚期和转移性BC仍然是高度未满足的医疗需求。Sapience的ST 101提供了 治疗晚期或转移性HER 2阴性BC的新机会。ST 101的靶点是C/EBPβ， 一种在癌细胞中具有活性的新型蛋白质靶标。C/EBPβ以前被认为是一个“不可用”的目标， 它的（1）细胞核内的位置和（2）依赖于蛋白质-蛋白质相互作用的活性，而不是 酶活性ST 101是肿瘤细胞中C/EBPβ相互作用的肽拮抗剂，导致转录抑制。 抑制存活因子，从而引发合成致死和肿瘤凋亡。基于有前途的预- 临床结果，ST 101已进入临床阶段;目前处于开放标签，两部分，1/2期 在首次治疗失败的晚期、不可切除和转移性实体瘤患者中进行的剂量探索研究， 二线治疗为了进一步支持ST 101的开发并提高其临床成功的机会， Sapience提出鉴定ST 101活性的预测性和药效学（PD）生物标志物， 证明它们在非临床患者来源的乳腺癌（PDBC）模型中的效用。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， 并将鉴定与ST 101相关的遗传和/或C/EBPβ翻译或翻译后修饰 灵敏度（或电阻）。在具体目标#2中，将在体内患者中询问所鉴定的生物标志物- 衍生的异种移植（PDX）小鼠模型，以评估它们是否确实预测ST 101成功或失败。最后， 具体目标#3建议通过组织样本中的差异基因表达（DGE）鉴定PD生物标志物 在ST 101暴露前后，在特定目标#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， ST 101的诊断/预后筛查。生物标志物还将用于优化剂量或方案。