Targeting breast cancer microenvironment with small molecule agonist of relaxin receptor

用松弛素受体小分子激动剂靶向乳腺癌微环境

基本信息

批准号：
10650593
负责人：
IRINA AGOULNIK
金额：
$ 17.24万
依托单位：
FLORIDA INTERNATIONAL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-03 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10650593
关键词：
4T1 Affect Agonist Allografting American Animal Model Animals Antibodies Antibody Therapy Antiinflammatory Effect Antineoplastic Agents Biological Availability Breast Cancer Model Breast Cancer Treatment Breast Cancer therapy Cancer Cell Growth Cancer Model Cancer Patient Cell Proliferation Cell Survival Cells Characteristics Chronic Collagen Combined Modality Therapy Continuous Infusion Cytoprotection Cytotoxic T-Lymphocytes Data Development Diagnosis Disease model Dose Drug Kinetics Drug Targeting Drug resistance Drug usage ERBB2 gene Elastin Environment Excision Extracellular Matrix Fibroblasts Fibronectins Fibrosis G-Protein-Coupled Receptors Genomics Goals Growth Half-Life Hormones Immune Immune response Immunocompetent Immunotherapeutic agent Immunotherapy Inbred BALB C Mice Inflammatory Laboratories Laboratory Research Lead Macrophage Malignant Neoplasms Mammary Neoplasms Mediating Metastatic breast cancer Modification Monoclonal Antibodies Mus Neoplasm Metastasis Oral Pathway interactions Patients Penetration Peptides Phagocytosis Pharmacodynamics Pharmacotherapy Population Pre-Clinical Model Primary Neoplasm Property Proteomics Recombinants Relaxin Reporting Resolution Route Signal Transduction Solid Stimulus Stromal Cells Stromal Neoplasm T cell infiltration T-Lymphocyte Testing Therapeutic Tissues Toxic effect Transgenic Mice Transgenic Model Translating Treatment Efficacy Woman anti-PD-L1 anti-cancer anticancer activity anticancer treatment cancer cell cancer invasiveness cancer subtypes cell killing experimental study immune cell infiltrate immune checkpoint immune checkpoint blockade immunogenic improved in vivo malignant breast neoplasm molecular subtypes mouse model novel therapeutic intervention novel therapeutics peptide hormone pharmacokinetics and pharmacodynamics pharmacologic pre-clinical prevent programmed cell death ligand 1 recruit relaxin receptor response side effect small molecule targeted treatment tumor tumor growth tumor microenvironment tumor-immune system interactions

项目摘要

The therapeutics efficacy of an anticancer treatment is often restricted by tumor fibrous tissue and tumor microenvironment. Stromal matrix barriers create a sanctuary for breast cancer, while the prolonged pro-fibrotic stimuli facilitate cancer cell growth and survival by establishing an immunosuppressive environment. Relaxin, a small peptide hormone, demonstrated dual anti-fibrotic and pro-immunogenic effects in various disease models including several solid cancers. Treatment with relaxin significantly reduced the expression of major tumor extracellular matrix components such as collagens, fibronectin, and elastin. The degradation of fibrotic tumor matrix following relaxin treatment led to reduced cancer cell drug resistance. Additionally, it was shown that relaxin can change tumor macrophage population from pro-inflammatory to pro-resolution enabling T cell- mediated cancer cell killing and macrophage phagocytosis. However, due to a short half-life in vivo, delivery of recombinant relaxin requires continuous infusion. Relaxin signals through its cognate G protein-coupled receptor RXFP1, which is expressed in tumor associated fibroblasts and infiltrating immune cells. We propose targeting the integrity of the tumor microenvironment with the first-in-class small molecule agonist of RXFP1 developed in our laboratories. The lead compound, ML290, shows high activity, oral bioavailability, in vivo stability, and excellent pharmacological properties. It is well tolerated by animals, shows no toxicity in vivo, and does not increase cancer cell proliferation and invasiveness nor does it affect extracellular matrix remodeling in healthy tissues. Our preliminary data indicate that the ML290 treatment of mice with HER2-positive breast cancer reduces tumor size and tumor fibrotic content. The overall goal of this project is to demonstrate anticancer activity of relaxin receptor agonist, ML290, in preclinical models of breast cancer, regardless of cancer subtype. We will test the anti-cancer efficacy of ML290 in primary and metastatic breast cancer models, analyze changes in tumor ECM composition, recruitment of immune cells, and genomic/proteomic response in stromal and cancer cells to treatment. We will analyze the effect of combination treatment of ML290 with immune checkpoint blockade and anti-HER2 immunotherapeutics. The pharmacological re-programing of stromal cancer microenvironment by ML290 will provide a new therapeutic approach for breast cancer suppression.

抗癌治疗的疗效常常受到肿瘤纤维组织和肿瘤的限制微环境。基质基质屏障为乳腺癌创造了避难所，而长期的促纤维化刺激通过建立免疫抑制环境促进癌细胞生长和存活。松弛素，一种小肽激素，在多种疾病模型中表现出双重抗纤维化和促免疫原作用包括几种实体癌症。松弛素治疗显着降低了主要肿瘤的表达细胞外基质成分，如胶原蛋白、纤连蛋白和弹性蛋白。纤维化肿瘤的降解松弛素治疗后的基质导致癌细胞耐药性降低。此外，还表明松弛素可以将肿瘤巨噬细胞群从促炎性转变为促消退性，从而使 T 细胞能够介导癌细胞杀伤和巨噬细胞吞噬作用。然而，由于体内半衰期短，重组松弛素需要持续输注。松弛素通过其同源 G 蛋白偶联受体发出信号 RXFP1，在肿瘤相关成纤维细胞和浸润免疫细胞中表达。我们建议瞄准使用 RXFP1 开发的一流小分子激动剂改善肿瘤微环境的完整性我们的实验室。先导化合物 ML290 显示出高活性、口服生物利用度、体内稳定性和优良的药理特性。动物耐受性良好，体内无毒性，增加癌细胞增殖和侵袭性，也不影响健康细胞外基质重塑组织。我们的初步数据表明 ML290 治疗 HER2 阳性乳腺癌小鼠减少肿瘤大小和肿瘤纤维化含量。该项目的总体目标是展示抗癌活性松弛素受体激动剂 ML290 在乳腺癌临床前模型中的应用，无论癌症亚型如何。我们将测试ML290在原发性和转移性乳腺癌模型中的抗癌功效，分析肿瘤的变化 ECM 组成、免疫细胞的募集以及基质细胞和癌细胞中的基因组/蛋白质组反应治疗。我们将分析 ML290 与免疫检查点阻断联合治疗的效果，抗 HER2 免疫治疗。间质癌微环境的药理学重新编程 ML290将为抑制乳腺癌提供新的治疗方法。