# Development of a cell-penetrating beta-catenin antagonist peptide as a therapeutic candidate for Wnt-driven breast cancer

> **NIH NIH R44** · SAPIENCE THERAPEUTICS, INC. · 2024 · $632,111

## Abstract

ABSTRACT
Dysregulated overexpression and hyperactivation of Wnt/-catenin signaling is found in >20% of all cancers and
in 50% of breast cancer, particularly triple negative breast cancer (TNBC). Yet despite extensive efforts to inhibit
Wnt/-catenin signaling, no drugs that target the Wnt pathway have been approved, mainly due to the inability
of inhibitors drugs to separate oncogenic from homeostatic functions of -catenin. BCL9 is a transcriptional co-
activator that regulates oncogenic β-catenin-mediated gene transactivation. Its overexpression enhances Wnt/β-
catenin signaling, resulting in cell proliferation, migration and invasiveness in vitro, and induces tumor initiation
and progression in vivo. Genetic ablation of Bcl9/Bcl9l in mouse intestinal epithelium reduces tumor growth
without phenotypic abnormalities. Therefore, specific antagonism of the interaction of β-catenin with BCL9 is
hypothesized to prove a safe and efficacious strategy for cancer therapy.
Sapience Therapeutics sought to develop a -catenin antagonist peptide, designed to interact with -catenin.
Our approach introduces amino acid (AA) substitutions to the native HD2 binding domain sequence to enhance
target affinity and includes a short cell penetrating domain (CPD) for intracellular entry. Additionally, to overcome
challenges encountered by traditional peptides, Sapience’s peptides include D-enantiomer AAs (D-AAs), which
dramatically increase stability and bioavailability, while reducing potential immunogenicity.
Through extensive structure-activity relationship (SAR) studies, we screened a library of peptides designed to
disrupt β-catenin’s oncogenic association with BCL9 and selected ST316 as the lead candidate. ST316 displays
potent and selective inhibition of Wnt signaling and induction of cytotoxicity in tumor cells dependent on Wnt
signaling (but not Wnt-independent tumors). Further, ST316 demonstrates stability, superior bioavailability and
solubility and in vivo potency. In Phase I of this SBIR, ST316 demonstrated nanomolar binding affinity to β-
catenin and a low micromolar (2.7µM) EC50 value for inhibition of β-catenin transcriptional activity in vitro. Safety
studies with no histopathological findings at 50mg/kg suggested a therapeutic window of at least 10x.
Following this proof of concept, this Phase II application proposes rigorous IND-enabling toxicology and phar-
macology studies to support clinical development of ST316. Specific Aim #1 will determine the first-in-human
(FIH) ST316 dose by identifying the no adverse effect level (NOAEL) in rats and highest non-severely toxic dose
(HNSTD) in minipigs in 28-day repeat dose GLP toxicity studies. In Specific Aim #2, we propose a series of
experiments to determine the ST316 pharmacologic active dose (PAD) in mouse patient-derived xenograft (PDX)
models, and identify pharmacodynamic (PD) biomarkers associated with the PAD, which can be used clinically
to assess ST316 activity. The PAD will then be used in Sp...

## Key facts

- **NIH application ID:** 10835099
- **Project number:** 5R44CA265503-03
- **Recipient organization:** SAPIENCE THERAPEUTICS, INC.
- **Principal Investigator:** Jim Rotolo
- **Activity code:** R44 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $632,111
- **Award type:** 5
- **Project period:** 2021-09-02 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10835099

## Citation

> US National Institutes of Health, RePORTER application 10835099, Development of a cell-penetrating beta-catenin antagonist peptide as a therapeutic candidate for Wnt-driven breast cancer (5R44CA265503-03). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10835099. Licensed CC0.

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