Novel approach to attenuate small cell lung cancer growth and metastasis

摘要

Abstract Small cell lung cancer (SCLC) is highly aggressive and metastatic malignancy. Unfortunately, no single targeted therapy has shown clinical activity in SCLC and its 5-year survival rate is only 6-8%. Therefore, there is an urgent need to develop innovative strategies against SCLC. In recent years, microRNAs (miRs) have been shown to play significant roles in cancer at the post-translational/transcriptional level by silencing gene expression. Our preliminary data showed reduced expression of miR-1 in SCLC cell lines as well as patient samples. We also observed that miR-1 is inversely associated with CXCR4 in SCLC cell lines and in patient samples. CXCR4/CXCL12-signaling axis has been explored as a major metastatic signaling axis for various cancers including lung cancer. However, not much is known about the role of miR-1 in regulating CXCR4 in SCLC. Our central hypothesis, based on our preliminary data, is that downregulation of miR-1 contributes to SCLC growth and metastasis by upregulating CXCR4. In this application, we propose to develop nanoformulation platform for dual-targeting polymeric CXCR4 antagonist (PCX) nanoparticles (NPs) containing miR-1 mimics for targeting SCLC. We will pursue three specific aims to test our hypothesis. Aim 1 will focus to establish functional miR-1 and CXCR4 axis in SCLC using cell lines and patient samples. These studies will help us to define the novel role of miR-1 downregulation and CXCR4 upregulation for the early detection of SCLC. Additionally, we will perform global transcriptome (miRNA-Seq/RNA-Seq) integrative analysis to explore novel miRs and their targets in SCLC. Aim 2 will be focused on optimization and characterization of PCX-miR-1NPs in SCLC. Since SCLC is highly aggressive and metastatic, we will evaluate whether PCX-miR-1 NPs simultaneously restore miR-1, block the CXCL12/CXCR4 axis, and thereby inhibit metastasis of SCLC in preclinical mouse models. Aim 3 will be designed to analyze therapeutic efficacy of PCX- miR-1NPs in SCLC spontaneous RP (Rbf/f; Tp53f/f; Rosa) mouse model. Upon nasal infection of Ad-cre, RP mice develop tumors that recapitulate human SCLC characteristics. These tumors are highly aggressive and metastatic, and therefore, PCX-miR-1 NPs will serve as ideal nanoformulation-based therapy for the management of SCLC. In addition, cisplatin treatment has been shown to enhance drug resistance through increase CD133+/CXCR4+ cell populations in lung cancer. In this aim, we will also analyze if PCX-miR-1 NPs enhance cisplatin sensitization by reprogramming cancer-associated fibroblasts. Additionally, we will identify novel targets of miR-1 for SCLC using global transcriptome analysis of PCX-miR-1 and cisplatin treated tumor samples. Altogether, the proposed studies will establish the clinical utility of PCX-miR-1 NPs as a novel therapeutic strategy for the treatment of SCLC patients who are difficult to treat due to their advanced disease stage and/or development of drug resistance and recurrence. Nanotechnogy formulation generated in this project will also have broader application in other aggressive and metastatic cancers that have low miR-1 and high CXCR4 expression.