Patients with metastatic non-small cell lung cancer (NSCLC) remain incurable with few options. New therapies are critically needed. In this project we propose to translate a fundamental understanding of microRNAs (miRNAs) in NSCLC. The EGFR/RAS and p53 pathways are the most frequently dysregulated pathways in NSCLC and are regulated in part by two miRNAs, miR-34 and let-7, tumor suppressors that regulate key lung cancer oncogenes such as KRAS and are lost or poorly expressed in many lung tumors. miR-34 is directly up- regulated by p53 and is one of the most important outputs of p53 signaling. We will test the hypothesis that a novel miRNA-based therapeutic strategy focused on miR-34 reverses NSCLC tumor phenotypes. Preliminary data generated from our lab shows that MRX34, a nanoparticle encapsulated mir34 molecule, provides a benefit in Kras and in Kras;p53 mutant NSCLC mouse models. Our goal is to evaluate MRX34 in patients with metastatic NSCLC while incorporating novel imaging methods to determine drug delivery and effect.
In Specific Aim 1 we will investigate miR-34 therapeutics in NSCLC mouse models. We have preliminarily shown that miR-34 administered to KRAS or KRAS;p53 mutant tumor cells blocks proliferation and induces apoptosis, including when delivered systemically as MRX34 to Kras or Kras;p53 mutant mouse models. We propose to investigate efficacy and optimal dosingand scheduling of MRX34 using mouse models; test the effects of MRX34 in combination with drugs known to be active against NSCLC in vitro in KRAS; p53 NSCLC cell lines and in vivo and test if MRX34 treatment shows therapeutic potential in EGFRL858R;p53, and erlotinib- resistant EGFRT790M;p53 mutant mice (in collaboration with Dr. Katie Politi [Project 3]).
In Specific Aim 2 we will investigate if MRX34 is delivered to the appropriate tissues and engages its targets. We propose to discover serum and tumor biomarkers in the Kras and Kras;p53 mutant mice treated with MRX34 that will be useful for PK, PD, and efficacy analyses in the clinical trial proposed in Aim 3; to apply 18F-ICMT-11 PET imaging of caspase-3 to measure MRX34-induced apoptosis in lung tumors in Kras;p53 mice. We will radiolabel MRX34 particles with F-18 and if successful, incorporate this as an imaging endpoint to validate magnitude and kinetics of particle delivery to in these models.
In Specific Aim 3 we will conduct a clinical trial with MRX34 in patients with NSCLC preselected based on genotype, evaluating response/efficacy and PD endpoints to assess drug delivery and drug:target effects using both novel imaging tools developed in Aim 2 (18F-labelled MRX34 nanoparticle) as well as direct tumor signal transduction effects using 18F-ICMT-11 (caspase) as an exploratory biomarker for drug-induced apoptosis. Patient biopsies will be genotyped for the KRAS, EGFR and p53 status, and tumor and serum miR-34 (and let-7) levels determined. These data will be correlated with outcome and could inform patient selection in these and future trials.

Public Health Relevance

Patients with metastatic non-small cell lung cancer (NSCLC) remain incurable with few options despite recent advances in tumor biology. Thus, new therapies based on a better understanding of the biology of lung cancer are a major public health goal. Here we propose to reverse the lung tumor phenotype with a novel microRNA- based therapeutics strategy using a microRNA mimic, MRX34, first in proof of principle experiments in mouse models and then in human clinical trials with imaging and biomarker endpoints.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
1P50CA196530-01
Application #
8931834
Study Section
Special Emphasis Panel (ZCA1-RPRB-7 (M1))
Project Start
2015-08-26
Project End
2020-07-31
Budget Start
2015-08-26
Budget End
2016-07-31
Support Year
1
Fiscal Year
2015
Total Cost
$287,464
Indirect Cost
Name
Yale University
Department
Type
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06510
Adams, Brian D; Parsons, Christine; Walker, Lisa et al. (2017) Targeting noncoding RNAs in disease. J Clin Invest 127:761-771
Zhu, Ruoqing; Zhao, Ying-Qi; Chen, Guanhua et al. (2017) Greedy outcome weighted tree learning of optimal personalized treatment rules. Biometrics 73:391-400
Villarroel-Espindola, Franz; Yu, Xiaoqing; Datar, Ila et al. (2017) Spatially resolved and quantitative analysis of VISTA/PD-1H as a novel immunotherapy target in human non-small cell lung cancer. Clin Cancer Res :
Buck, Michael D; Sowell, Ryan T; Kaech, Susan M et al. (2017) Metabolic Instruction of Immunity. Cell 169:570-586
Rimm, David L; Han, Gang; Taube, Janis M et al. (2017) A Prospective, Multi-institutional, Pathologist-Based Assessment of 4 Immunohistochemistry Assays for PD-L1 Expression in Non-Small Cell Lung Cancer. JAMA Oncol 3:1051-1058
Liu, Huafeng; Li, Xin; Hu, Li et al. (2017) A crucial role of the PD-1H coinhibitory receptor in suppressing experimental asthma. Cell Mol Immunol :
Rehman, Jamaal A; Han, Gang; Carvajal-Hausdorf, Daniel E et al. (2017) Quantitative and pathologist-read comparison of the heterogeneity of programmed death-ligand 1 (PD-L1) expression in non-small cell lung cancer. Mod Pathol 30:340-349
Rojewski, Alana M; Zuromski, Kelly L; Toll, Benjamin A (2017) Strategies for smoking cessation among high risk populations to prevent lung cancer. Expert Rev Respir Med 11:85-87
Smithy, James W; Moore, Lauren M; Pelekanou, Vasiliki et al. (2017) Nuclear IRF-1 expression as a mechanism to assess ""Capability"" to express PD-L1 and response to PD-1 therapy in metastatic melanoma. J Immunother Cancer 5:25
Stevens, Laura E; Cheung, William K C; Adua, Sally J et al. (2017) Extracellular Matrix Receptor Expression in Subtypes of Lung Adenocarcinoma Potentiates Outgrowth of Micrometastases. Cancer Res 77:1905-1917

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