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

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 tumorandapos;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.NARRATIVE While therapies for early stage breast cancer are often effective, prognosis for later stage and metastatic disease, remain grim: 5-year survival for Stage 4 metastatic disease drops to 22%, with a median survival of 3 years, resulting in ~40,000 deaths annually. We propose to develop a novel therapy for late stage and/or metastatic cancer that interferes with a key element in the cell that drives many of the steps that make cancers develop, metastasize, and present a more aggressive form of the disease. This is expected to provide a promising new therapy for breast cancer, in particular late state and metastatic disease.