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

> **NIH NIH R43** · SAPIENCE THERAPEUTICS, INC. · 2020 · $255,240

## Abstract

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 tumor'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.

## Key facts

- **NIH application ID:** 10079655
- **Project number:** 1R43CA250786-01A1
- **Recipient organization:** SAPIENCE THERAPEUTICS, INC.
- **Principal Investigator:** Jim Rotolo
- **Activity code:** R43 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $255,240
- **Award type:** 1
- **Project period:** 2020-08-05 → 2021-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10079655

## Citation

> US National Institutes of Health, RePORTER application 10079655, Efficacy and PK/PD of a C/EBP beta antagonist in orthotopic breast cancer (1R43CA250786-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10079655. Licensed CC0.

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