Development of a cell-penetrating beta-catenin antagonist peptide as a therapeutic candidate for WNT-driven breast cancer
Ended Project Grant Awarded Last action
- Award ID
- R44CA265503
- Recipient
-
Sapience Therapeutics, Inc. UEI ERRLJEYAUMC8
- Awarding agency
-
National Cancer Institute
National Institutes of Health, Department of Health and Human Services
- Obligated
- $4,718,915
Award facts
- Assistance listing
- 93.395 Cancer Treatment Research
- Completion date
- Place of performance
- New York, USA
Award details come from USAspending.gov.
Description
- 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 SS-catenin-mediated gene transactivation. Its overexpression enhances WNT/SS- 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 SS-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 SS-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 SS- catenin and a low micromolar (2.7ΜM) EC50 value for inhibition of SS-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 specific aim #3 to evaluate the impact of ST316 on the tumor immune microenvironment (TME), namely macrophage polarization, tumor infiltrating lymphocyte (TIL) expression in tumors and the impact of combination with a PD-1 inhibitor.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $0 | |
| Amendment | $632,111 | |
| Amendment | $0 | |
| Amendment | $0 | |
| Amendment | $1,362,268 | |
| Amendment | $1,362,268 | |
| Original award | $1,362,268 |
Quick answers
Who received award R44CA265503?
R44CA265503 was awarded to Sapience Therapeutics, Inc. by National Cancer Institute (National Institutes of Health) on September 2, 2021.
How much is award R44CA265503 worth?
$4,718,915 has been obligated on R44CA265503.
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