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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

基本信息

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
项目类别：
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

项目摘要

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