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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%的人类癌症在KRAS癌基因中含有驱动其生长的突变和转移。最近已经开发出新型KRAS抑制剂，使这些生长信号失效。尽管KRAS抑制剂可以帮助患者延长寿命，但它们不太可能治愈患者。因此，有一个我们需要找到更有效的方法来治疗KRAS突变型癌症。基于癌症的成功在免疫疗法中，一种有吸引力的策略是将靶向疗法与激活免疫原性的药剂联合收割机组合。免疫系统攻击。巨噬细胞是先天免疫系统的细胞，通常是最常见的免疫系统。实体瘤中常见的浸润性免疫细胞。CD 47/SIRPa轴是巨噬细胞的关键调节因子在肿瘤微环境中激活，并作为“不要吃我”的信号。抗CD 47抗体阻断该巨噬细胞免疫检查点可以刺激巨噬细胞活化以对抗癌症。在本提案中，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，因此，KRAS抑制剂将与抗CD 47抗体协同作用以消除KRAS突变型癌症。我们的总体目标是将KRAS靶向疗法转化为治愈性疗法，效应器为了研究KRAS抑制剂和抗CD 47抗体之间的潜在协同作用，我们已经开发了一种新的抗CD 47抗体。评价巨噬细胞介导的癌症破坏的新的体外共培养测定。我们将使用这个分析以测量KRAS抑制剂和抗CD 47抗体之间的协同作用（目的1）。我们将调查通过评估KRAS抑制剂如何改变其他细胞因子的表达和功能， KRAS突变癌细胞表面的免疫调节分子。接下来，我们将测试组合在KRAS突变型癌症的异种移植小鼠模型中评估增强的抗肿瘤免疫力，体内（目标2）。最后，我们将研究联合治疗在免疫功能正常、同基因、肿瘤模型，以了解联合治疗如何改变先天和适应性肿瘤之间的相互作用，免疫系统总的来说，我们提出了一种新的机制，以提高KRAS抑制剂的疗效，融合免疫肿瘤学和精准医学领域。我们希望我们的研究结果能提供合理的解释，快速将这种组合策略转化为临床，使KRAS突变型癌症患者受益。