Targeting mTORC2 in lung squamous cancer

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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.