Targeting breast cancer microenvironment with small molecule agonist of relaxin receptor

抗癌治疗的疗效往往受到肿瘤、纤维组织和肿瘤的制约。 微环境。基质屏障为乳腺癌创造了一个避难所，而长期的促纤维化 刺激通过建立免疫抑制环境来促进癌细胞的生长和存活。松弛素，一种 小肽激素，在各种疾病模型中表现出抗纤维化和促免疫原性双重作用 包括几种实体癌症。松弛素治疗显著降低主要肿瘤的表达 细胞外基质成分，如胶原蛋白、纤维连接蛋白和弹性蛋白。纤维性肿瘤的降解 松弛素治疗后的基质导致癌细胞耐药性降低。此外，还表明， 松弛素可将肿瘤巨噬细胞群从促炎状态转变为支持分解状态，使T细胞- 介导的癌细胞杀伤和巨噬细胞吞噬作用。然而，由于体内半衰期很短，给药 重组松弛素需要持续输注。松弛蛋白通过其同源G蛋白偶联受体传递信号 RXFP1，表达于肿瘤相关成纤维细胞和浸润性免疫细胞。我们建议有针对性地 一流小分子激动剂RXFP1对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 优良的药理作用。它对动物的耐受性很好，在体内没有毒性，也没有 增加健康人癌细胞增殖和侵袭力，也不影响细胞外基质重塑 纸巾。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。这个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，与癌症亚型无关。我们会 在原发和转移乳腺癌模型中检测ML290的抗癌效果，分析肿瘤的变化 间质和癌细胞的ECM组成、免疫细胞的募集和基因组/蛋白质组反应 治疗。我们将分析ML290联合免疫检查点阻断和联合治疗的效果 抗HER2免疫疗法。丹参对间质癌微环境的药理学重塑 ML290将为乳腺癌抑制提供一种新的治疗途径。

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.