KRAS inhibitors prime cancer cells for macrophage-mediated destruction

KRAS 抑制剂可引发巨噬细胞介导的破坏癌细胞

基本信息

批准号：
10638364
负责人：
KIPP A WEISKOPF
金额：
$ 44.61万
依托单位：
WHITEHEAD INSTITUTE FOR BIOMEDICAL RES
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：
2023-06-01 至 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10638364
关键词：
Adaptive Immune System Adenosine Affect Anti-CD47 Antibodies Binding Biological Assay Blocking Antibodies CD47 gene CD47-SIRPα Cause of Death Cells Clinic Clinical Trials Coculture Techniques Combined Modality Therapy Complement Dichloromethylene Diphosphonate Down-Regulation Eating Effector Cell Engraftment Evaluation Flow Cytometry Genetic Goals Growth Histologic Human Immune Immune Evasion Immune checkpoint inhibitor Immune system Immunocompetent Immunooncology Immunosuppression In Vitro Innate Immune Response Innate Immune System Investigation K-ras mouse model KRAS2 gene Ligands Link Liposomes Macrophage Macrophage Activation Malignant Neoplasms Measures Mediating Membrane Proteins Modeling Mus Mutation Myelogenous Neoplasm Metastasis Oncogenes Oncogenic PTPNS1 gene Patients Pharmaceutical Preparations Pre-Clinical Model Signal Transduction Solid Neoplasm Surface Testing Therapeutic Translating Tumor Immunity Xenograft Model Xenograft procedure adaptive immune response anti-tumor immune response arm cancer cell cancer immunotherapy cancer therapy cancer type curative treatments effective therapy experimental study immune activation immune cell infiltrate immune checkpoint immunoregulation in vivo inhibitor metabolomics mouse model mutant novel pharmacologic precision medicine receptor side effect success synergism targeted treatment treatment strategy tumor tumor microenvironment

项目摘要

Project Summary Approximately 20% of all human cancers contain a mutation in the KRAS oncogene that drives their growth and metastasis. Novel KRAS inhibitors have recently been developed that disable these growth signals. Although they help patients live longer, KRAS inhibitors are unlikely to cure patients. For this reason, there is a need to identify more effective ways to treat KRAS mutant cancers. Based on the success of cancer immunotherapy, an appealing strategy has been to combine targeted therapies with agents that activate the immune system to attack. Macrophages are cells of the innate immune system and are often the most common infiltrating immune cell in solid tumors. The CD47/SIRPa axis is a key regulator of macrophage activation in the tumor microenvironment and acts as a “don’t eat me” signal. Anti-CD47 antibodies that block this macrophage immune checkpoint can stimulate macrophage activation against cancer. In this proposal, we hypothesize that KRAS inhibitors make cancer cells more vulnerable to macrophage-mediated destruction, and consequently, that KRAS inhibitors will synergize with anti-CD47 antibodies to eliminate KRAS mutant cancers. Our overall goal is to convert KRAS-targeted therapies into curative therapies by engaging macrophages as effectors. To investigate potential synergy between KRAS inhibitors and anti-CD47 antibodies, we have developed a novel in vitro co-culture assay to evaluate macrophage-mediated destruction of cancer. We will use this assay to measure synergy between KRAS inhibitors and anti-CD47 antibodies (Aim 1). We will investigate the mechanism of synergy by assessing how KRAS inhibitors change the expression and function of other immunoregulatory molecules on the surface of KRAS mutant cancer cells. Next, we will test the combination therapy in xenograft mouse models of KRAS mutant cancer to evaluate for enhanced anti-tumor immunity in vivo (Aim 2). Finally, we will investigate the effects of the combination therapy in immunocompetent, syngeneic tumor models to understand how the combination therapy alters interactions between the innate and adaptive immune systems. Overall, we propose a novel mechanism to enhance the efficacy of KRAS inhibitors by merging the fields of immuno-oncology and precision medicine. We expect our findings to provide the rationale for rapidly translating this combination strategy to the clinic to benefit patients with KRAS mutant cancer.

项目摘要大约20％的人类癌症中包含KRAS癌基因的突变，以驱动其生长和转移。最近已经开发出新的KRAS抑制剂，这些抑制剂禁用了这些生长信号。尽管它们可以帮助患者寿命更长，但KRAS抑制剂不太可能治愈患者。因此，有一个需要确定更有效的方法来治疗KRAS突变癌。基于癌症的成功免疫疗法是一种吸引人的策略，是将靶向疗法与激活该药物相结合的策略免疫系统要攻击。巨噬细胞是先天免疫系统的细胞，通常是最大的在实体瘤中常见的免疫细胞浸润。 CD47/SIRPA轴是巨噬细胞的关键调节器在肿瘤微环境中激活，并充当“不要吃我”的信号。阻塞的抗CD47抗体该巨噬细胞免疫检查点可以刺激针对癌症的巨噬细胞激活。在这个建议中，我们假设KRAS抑制剂使癌细胞更容易受到巨噬细胞介导的破坏的影响，并且因此，KRAS抑制剂将与抗CD47抗体协同作用，以消除KRAS突变癌。我们的总体目标是通过将巨噬细胞作为巨噬细胞作为治疗疗法的转化为治疗疗法效应子。为了研究KRAS抑制剂和抗CD47抗体之间的潜在协同作用，我们已经开发了一种新型体外共培养测定法，以评估巨噬细胞介导的癌症破坏。我们将使用此测定法测量KRAS抑制剂和抗CD47抗体之间的协同作用（AIM 1）。我们将调查通过评估KRAS抑制剂如何改变其他的表达和功能，协同作用机理 KRAS突变癌细胞表面上的免疫调节分子。接下来，我们将测试组合 KRAS突变癌的特征小鼠模型中的治疗，以评估增强的抗肿瘤免疫力 Vivo（AIM 2）。最后，我们将研究联合疗法在免疫能力，合成性中的影响肿瘤模型了解组合疗法如何改变先天和适应性之间的相互作用免疫系统。总体而言，我们提出了一种新的机制来提高KRAS抑制剂的效率合并免疫肿瘤和精密医学领域。我们希望我们的发现能提供理由将这种组合策略迅速转化为诊所，以使KRAS突变癌患者受益。