Therapeutic approaches for LKB1-deficient non-small cell lung cancer

 描述(申请人提供)：非小细胞肺癌(NSCLC)是全球癌症死亡的主要原因。近年来，针对具有特定基因组改变的患者亚群的定制治疗取得了显著进展，例如针对10%-15%携带EGFR突变的患者的EGFR酪氨酸激酶抑制剂，以及通过使用阻断PD-1/PD-L1免疫检查点途径的药物。不幸的是，只有少数患者从这些方法中受益。LKB1(STK11)是非小细胞肺癌中第二大常见的肿瘤抑制因子，在20-30%的肺腺癌中缺失，每年导致30,000-40,000人死亡。为LKB1缺陷(LD)NSCLC量身定做的治疗策略有一个主要的未得到满足的需求。项目研究人员已经证明，LKB1缺失与转移潜能增加、化疗耐药性以及最近的免疫抑制表型和对检查点抑制剂的耐药性有关。根据我们的初步发现，我们假设a)LKB1缺失直接导致明显的免疫抑制表型，潜在的潜在机制包括抗原提呈减少和/或细胞因子产生改变；b)可以开发治疗方案来增强抗肿瘤免疫反应和克服对检查点抑制的耐药性。我们将在以下目标中检验这些假设。在目标1中，我们将描述 LD-NSCLC的免疫抑制表型，通过a)在临床前模型中研究LD相关的肿瘤内免疫抑制的机制，包括抗原呈递减少和免疫抑制细胞因子如IL-6和VEGF的产生的改变；以及b)比较LD和LKB1完整(LI)非小细胞肺癌患者肿瘤的免疫表型。接下来，在目标2中，我们将利用从目标1获得的见解来开发更有效的免疫治疗方法，通过测试a)直接和间接细胞因子抑制，b)细胞因子抑制与抗PD1的组合，以确定我们是否可以克服与LD相关的对检查点抑制的抵抗；以及c)与放射治疗(RT)和其他增强抗原提呈的方法的组合。最后，在目标3中，我们将把这项工作转化为临床，使用最近激活的随机临床试验，在104名非小细胞肺癌患者中单独或与RT联合测试抗PD抗体Pembrolizumab。这将使我们能够测试我们关于LD-NSCLC对PD-1抑制的相对耐药性的临床前观察，并确定RT是否可以增强LD NSCLC患者的抗肿瘤免疫和克服PD-1抑制剂的耐药性。临床意义：LD-NSCLC导致的死亡比胰腺癌更多，对新的治疗方法和对其独特生物学的洞察有关键的未得到满足的需求。我们已经组建了一个由领先研究人员组成的多学科团队来满足这些需求，他们在肺癌基因组学、免疫疗法、病理学、小鼠模型和放射治疗方面拥有深厚的专业知识，准备迅速将发现直接转化为非小细胞肺癌患者的临床进步。

 DESCRIPTION (provided by applicant): Non-small cell lung cancer (NSCLC) is the leading cause of cancer mortality worldwide. In recent years dramatic progress has been made in tailoring therapies for subgroups of patients harboring specific genomic alterations, such as EGFR tyrosine kinase inhibitors for the 10-15% of patients bearing EGFR mutations, and through the use drugs blocking the PD-1/PD-L1 immune checkpoint pathway. Unfortunately, only a minority of patients benefit from these approaches. LKB1 (STK11) is the second most commonly altered tumor suppressor in NSCLC, and is lost in 20-30% of lung adenocarcinoma, resulting in 30,000-40,000 deaths annually. There is a major unmet need for therapeutic strategies tailored for LKB1-deficient (LD) NSCLC. Project investigators have demonstrated that LKB1 loss is associated with increased metastatic potential, chemotherapy resistance, and, more recently, with an immunosuppressed phenotype as well as resistance to checkpoint inhibitors. Given our initial findings, we hypothesize that a) LKB1 loss directly drives a distinctve immunosuppressed phenotype, and that potential underlying mechanisms include reduced antigen presentation and/or altered cytokine production; and b) therapeutic regimens can be developed to enhance the antitumor immune response and overcome resistance to checkpoint inhibition. We will test these hypotheses in the following aims. In Aim 1, we will characterize the immunosuppressed phenotype of LD-NSCLC, by a) investigating the mechanisms underlying the LD-associated intratumor immunosuppression in preclinical models, including reduced antigen presentation and altered production of immunosuppressive cytokines such as IL-6 and VEGF; and b) comparing the immune phenotype in LD and LKB1-intact (LI) tumors from NSCLC patients. Next, in Aim 2, we will use insights gained from Aim 1 to develop more effective immunotherapy approaches, by testing a) direct and indirect cytokine suppression, b) combinations of cytokine suppression with anti-PD1, to determine whether we can overcome the LD-associated resistance to checkpoint inhibition; and c) combinations with radiotherapy (RT) and other approaches enhancing antigen presentation. Finally, in Aim 3, we will translate this work into the clinic using a recently activated randomized clinical trial testing the anti-PD- antibody pembrolizumab, alone or combined with RT in 104 NSCLC patients. This will enable us to test our preclinical observations regarding the relative resistance of LD-NSCLC to PD-1 inhibition, and determine whether RT can enhance anti-tumor immunity and overcome PD-1 inhibitor resistance in LD NSCLC patients. Clinical significance: LD-NSCLC causes more deaths than pancreatic cancer, and there are critical unmet needs for new treatment approaches and insights into its distinct biology. We have assembled a multidisciplinary team of leading investigators to tackle these needs, with deep expertise in lung cancer genomics, immunotherapy, pathology, mouse models and radiotherapy that is poised to rapidly translate discoveries directly into clinical advances for NSCLC patients.