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

开发细胞穿透性 β-连环蛋白拮抗剂肽作为 Wnt 驱动乳腺癌的候选治疗药物

• 批准号: 10707593
• 负责人: Jim Rotolo
• 金额: $ 136.23万
• 依托单位: SAPIENCE THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-02 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10707593
• 关键词: Ablation; Advanced Development; Adverse effects; Affinity; Amino Acid Substitution; Amino Acids; Animal Testing; BCL9 gene; Binding; Biological Availability; Biological Markers; Breast; Breast Cancer Model; Breast Cancer Treatment; Cancerous; Cell Proliferation; Cell Survival; Cell physiology; Cells; Cessation of life; Clinical; Data; Development; Dose; Drug Targeting; Genes; Genetic; Genetic Transcription; Growth; Guidelines; Human; In Vitro; Infiltration; Intravenous infusion procedures; Lymphocyte; Macrophage; Malignant Neoplasms; Mediating; Metastatic Neoplasm to Lymph Nodes; Miniature Swine; Mus; Oncogenic; Pathway interactions; Patients; Penetration; Peptide Library; Peptides; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology Study; Pharmacology and Toxicology; Phase; Phenotype; Prognosis; Proteins; Rattus; Recurrence; Research Design; Series; Signal Pathway; Signal Transduction; Small Business Innovation Research Grant; Solubility; Sprague-Dawley Rats; Structure-Activity Relationship; Testing; Therapeutic; Tissues; Toxic effect; Toxicokinetics; Toxicology; Transactivation; Transcription Coactivator; Tumor Escape; Tumor Immunity; Tumor-Infiltrating Lymphocytes; WNT Signaling Pathway; Xenograft procedure; antagonist; anti-tumor immune response; beta catenin; cancer therapy; chemotherapy; clinical development; clinically relevant; cytotoxicity; design; enantiomer; experimental study; first-in-human; immunogenicity; in vitro activity; in vivo; inhibitor; inhibitor therapy; intestinal epithelium; lead candidate; malignant breast neoplasm; migration; nanomolar; neoplastic cell; overexpression; participant enrollment; patient derived xenograft model; pharmacodynamic biomarker; pharmacologic; programmed cell death ligand 1; receptor; safety study; standard of care; success; therapeutic candidate; therapeutic target; triple-negative invasive breast carcinoma; tumor; tumor growth; tumor initiation; tumor microenvironment; tumor progression; tumor-immune system interactions

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 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.

摘要