Targeting mTORC2 in lung squamous cancer

项目总结/摘要 肺癌是美国癌症相关死亡的主要原因， 老兵尽管肺腺癌的靶向治疗可以改善总生存率，但没有类似的 在肺鳞状细胞癌（LUSC）方面已经取得了进展，LUSC占病例的30%， 与吸烟密切相关，并且高度转移。相反，免疫检查点抑制剂 该疗法在治疗LUSC患者方面取得了一些成功。然而，大多数患者对 这样的待遇。因此，存在未满足的临床需求，以更好地理解LUSC并开发新的LUSC。 分子靶向治疗难治的这类肺癌的治疗。 在寻找肺鳞癌的弱点时，我们最近重新分析了TCGA LUSC 数据集。我们发现，虽然个别驱动突变是罕见的，PIK 3CA突变/扩增， PTEN缺失和RICTOR扩增的组合占LUSC的40%以上。 肿瘤的由于PI 3 K和PTEN都调节PIP 3水平，PIP 3水平激活mTORC 2和AKT，因此， 研究结果表明，PI 3 K-AKT通路是过度活跃的，靶向mTORC 2可以抑制整个PI 3 K-AKT通路。 LUSC肿瘤中的信号通路。 在本申请中，我们发现mTORC 2功能丧失（LOF）显著改变了肿瘤细胞的生长。 代谢，抑制体内肿瘤生长，影响抗肿瘤免疫环境。我们还 发现选择性抑制血管内皮中的mTORC 1会增加肿瘤浸润 淋巴细胞因此，内皮mTORC 1抑制与肿瘤抑制的组合 mTORC 2的表达将为抗肿瘤免疫创造有利的微环境，增强T细胞 募集（mTORC 1）和活性（mTORC 2），提供了一种靶向治疗策略， LUSC。在目的1中，我们将研究mTORC 2抑制对抗肿瘤免疫的影响。 微环境在目标2中，我们将研究内皮mTORC 1在招募LUSC中的作用。 浸润性T细胞在目标3中，我们提出：（i）通过低剂量 RAD 001（内皮中mTORC 1的选择性抑制）和（ii）通过 siRictor纳米颗粒（NP）（抑制mTORC 2）在LUSC中的作用，无论是作为单药，还是联合用药 与检查点抑制剂或低剂量RAD 001的三向组合以增加TIL， 通过siRictor-NPs和抗PD 1。 该项目的成功将提高我们对引发和 肺鳞状细胞癌的进展，特别是肿瘤细胞中的mTORC 2信号传导如何影响 免疫微环境免疫微环境的研究对LUSC特别重要，因为 免疫疗法成为这些患者的主要治疗方法之一。此外，该项目的成功将 具有显著的翻译潜力，因为纳米颗粒策略用于最近的COVID-19疫苗。 本申请中提出的研究将为抑制 mTORC 2使用纳米颗粒对肿瘤生长和抗肿瘤免疫应答的影响。

Project Summary/Abstract Lung cancer is the leading cause of cancer-related deaths in the US and disproportionally affects Veterans. Although targeted therapies for lung adenocarcinoma improve overall survival, no similar advances have been made in lung squamous carcinoma (LUSC), which represents 30% of cases, strongly associated with smoking, and highly metastatic. In contrast, immune checkpoint inhibitor therapy has some success in treating LUSC patients. However, majority of patients do not respond to such treatment. Thus, there is an unmet clinical need to better understand LUSC and develop new treatments in this subclass of lung cancer that is refractory to molecular targeted therapies. In searching for vulnerabilities in squamous lung cancer, we recently re-analyzed TCGA LUSC datasets. We found that while individual driver mutations are rare, PIK3CA mutation/amplification, PTEN deletion, and RICTOR amplification combined accounts for more than 40% of the LUSC tumors. As both PI3K and PTEN regulates PIP3 levels, which activates mTORC2 and AKT, these findings indicate that PI3K-AKT pathway is hyperactive, and targeting mTORC2 may inhibit the entire pathway in the LUSC tumors. In this application, we discovered that mTORC2 loss-of-function (LOF) significantly altered tumor metabolism, inhibited tumor growth in vivo, and impacted antitumor immune environment. Further, we found that selective inhibition of mTORC1 in vascular endothelium increases tumor infiltrating lymphocytes. Thus, the combination of endothelial mTORC1 inhibition coupled with tumor inhibition of mTORC2 will create a favorable microenvironment for anti-tumor immunity, enhancing T-cell recruitment (mTORC1) and activity (mTORC2), providing a targeted therapy treatment strategy for LUSC. In Aim 1, we will investigate the effects of mTORC2 inhibition on antitumor immune microenvironment. In Aim 2, we will investigate the role of endothelial mTORC1 on recruiting LUSC infiltrating T cells. In Aim 3, we propose (i) to increase tumor infiltrating lymphocytes by low-dose RAD001 (selective inhibition of mTORC1 in endothelium) and (ii) improve T cell effector function by siRictor nanoparticles (NP) (inhibition of mTORC2) in LUSC, either as a single agent, in combination with checkpoint inhibitors, or three-way combination of low-dose RAD001 to increase TILs, followed by siRictor-NPs and anti-PD1. Success of this project will improve our understanding of the molecular mechanisms of initiation and progression to lung squamous cancer, especially how mTORC2 signaling in tumor cells influences immune microenvironment. Study of immune microenvironment is particularly important for LUSC, as immunotherapy becomes one main treatment for these patients. Further, success of this project will have significant translational potential, as nanoparticle strategy is used in recent COVID-19 vaccines. The proposed studies in this application will provide proof-of-concept for the impact of inhibiting mTORC2 using a nanoparticle on tumor growth and antitumor immune responses.