Project 3: Inhibiting FAK to enhance immune checkpoint inhibitor therapy in LKB1-mutant lung adenocarcinoma

项目3：抑制FAK增强免疫检查点抑制剂治疗LKB1突变型肺腺癌

• 批准号: 10411668
• 负责人: Adam I. Marcus
• 金额: $ 54.89万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10411668
• 关键词: Antibody Therapy; CD8-Positive T-Lymphocytes; Cancer Patient; Cell Adhesion; Cell Communication; Clinical; Collagen; Combined Modality Therapy; Data; Fibroblasts; Focal Adhesion Kinase 1; Genes; Genetically Engineered Mouse; Genomics; Goals; Immune checkpoint inhibitor; Immunotherapeutic agent; Immunotherapy; Invaded; KRAS2 gene; KRASG12D; Lead; Luciferases; Lung Adenocarcinoma; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of pancreas; Metastatic Neoplasm to Lymph Nodes; Modeling; Mus; Mutate; Mutation; Neoplasm Metastasis; Non-Small-Cell Lung Carcinoma; Pathway interactions; Patients; Pharmacology; Phase II Clinical Trials; Phenotype; Pilot Projects; Pre-Clinical Model; Primary Neoplasm; Publishing; Regimen; Regulation; Resistance; STK11 gene; Salvage Therapy; Subgroup; Symptoms; Testing; Therapeutic; Time; Tumor Burden; Tumor Suppressor Proteins; Tumor-infiltrating immune cells; anti-PD-1; anti-PD1 antibodies; base; cancer cell; cell motility; checkpoint therapy; clinical development; clinically relevant; cohort; efficacy evaluation; immune checkpoint; improved; inhibitor; inhibitor therapy; kinase inhibitor; lymph nodes; molecular targeted therapies; mouse model; mutant; neoplastic cell; novel; novel therapeutics; patient population; pembrolizumab; preclinical trial; prevent; recruit; response; restoration; synergism; targeted agent; tumor; tumor growth; tumor progression

Project Summary Project 3 of the Emory Lung Cancer P01 application focuses on focal adhesion kinase (FAK) in LKB1-mutant lung adenocarcinoma (LUAD) for the clinical development of combination therapy to enhance the efficacy of immune checkpoint inhibitors (ICI). The tumor suppressor LKB1 is the 3rd most frequently mutated gene in lung adenocarcinoma. This tumor subgroup is resistant to ICI therapy and is not amenable to molecularly targeted therapies. Our goal is to develop novel therapeutic regimens that will benefit patients with LKB1-mutant lung cancer. We discovered that LKB1 regulates LUAD cell motility and represses FAK to oversee cell adhesion, invasion, and collagen remodeling. Our clinically relevant Lkb1-mutant genetically engineered mouse model (GEMM) showed that FAK is activated in collective invasion packs (CIPs) of cancer cells at the invasion front of the primary tumor, with a similar phenotype as in lung cancer patients. These collective invasion packs are surrounded by heterotypic cancer-associated fibroblasts (CAFs) and contain a densely remodeled collagen matrix. Our initial pre-clinical trial with this mouse model indicated that these tumors are exquisitely sensitive to FAK inhibition monotherapy. Importantly, FAK inhibitor therapy increases CD8+T cell infiltration and enhances ICI in pancreatic cancer. Our pilot study revealed synergy between FAK inhibitor and anti-PD-1 antibody in preventing tumor growth and metastasis in a new metastatic syngeneic model. Here, FAK inhibition eliminates collective invasion packs, surrounding CAFs, and restores STING expression (a focus of Project 2), increasing CD8+ T cell infiltration to CIPs. These data lead to the central hypothesis that LKB1 inactivation in LUAD represents an acquired tumor vulnerability that can be synergistically targeted with a FAK inhibitor in combination with ICI therapy. We propose that FAK inhibition disrupts the heterotypic CAF:tumor-cell interaction within the collective invasion packs, resulting in increased CD8+ T-cell infiltration. To test this, we will conduct a Phase II clinical trial with the FAK inhibitor in combination with an anti-PD-1 antibody (pembrolizumab) in patients with LKB1-mutant advanced lung adenocarcinoma. We will also evaluate the underlying mechanism using our GEMM and syngeneic model to determine if pharmacologic FAK inhibition enhances the response to ICI, resulting in CD8+ T-cell recruitment to collective invasion packs. Along with Project 1 (FAK regulated glutaminolysis and immune checkpoint regulation) and Project 2 (restoration of STING to enhance ICI), the successful completion of this project will accelerate the implementation of a novel combination therapy approach specially tailored toward lung cancer patients with LKB1-mutant tumors.

项目摘要 Emory肺癌P01应用的项目3侧重于LKB1突变物中的焦点粘附激酶（FAK） 肺腺癌（LUAD）用于联合疗法的临床发展，以增强 免疫检查点抑制剂（ICI）。肿瘤抑制剂LKB1是肺中第三个最常见的突变基因 腺癌。该肿瘤亚组对ICI治疗具有抗性，不适合分子靶向 疗法。我们的目标是开发新型治疗方案，该治疗方案将使LKB1突变肺的患者受益 癌症。我们发现LKB1调节LUAD细胞运动，并抑制FAK以监督细胞粘附， 入侵和胶原蛋白重塑。我们临床上相关的LKB1突变遗传学的小鼠模型 （GEMM）表明，FAK在癌细胞的集体入侵包（CIPS）中被激活 原发性肿瘤，具有与肺癌患者相似的表型。这些集体入侵包是 被异型癌症相关的成纤维细胞（CAF）包围，并包含密集重塑的胶原蛋白 矩阵。我们使用该小鼠模型的最初临床前试验表明，这些肿瘤对 FAK抑制单一疗法。重要的是，FAK抑制剂疗法增加CD8+T细胞浸润并增强 胰腺癌的ICI。我们的试点研究表明，FAK抑制剂和抗PD-1抗体之间的协同作用 在新的转移性合成模型中预防肿瘤生长和转移。在这里，FAK抑制作用消除了 集体入侵包，周围的CAF和恢复刺痛表达（项目2的重点），增加 CD8+ T细胞对CIPS的浸润。这些数据导致了一个中心假设，即LUAD中的LKB1失活 代表可获得的肿瘤脆弱性，可以与FAK抑制剂协同靶向组合 进行ICI疗法。我们建议FAK抑制作用破坏了异型CAF：肿瘤细胞的相互作用 集体入侵包，导致CD8+ T细胞浸润增加。为了测试这一点，我们将进行II期 通过FAK抑制剂与抗PD-1抗体（Pembrolizumab）结合使用FAK抑制剂的临床试验 LKB1突变晚期肺腺癌。我们还将使用我们的基本机制评估 GEMM和合成模型以确定药理学FAK抑制是否增强了对ICI的反应， 导致CD8+ T细胞募集到集体入侵包中。与项目1一起（FAK监管 谷氨酰胺分解和免疫检查点调节）和项目2（恢复sting以增强ICI）， 该项目的成功完成将加速实施一种新型组合疗法 专门针对患有LKB1突变肿瘤的肺癌患者量身定制。