Lung cancer remains a major health problem in the world. Despite advances in treatment strategies the overall 5-year survival rate is only 14%. Therefore, novel therapies are needed. One attractive therapeutic approach is to identify a molecular target that is overexpressed in lung cancer and which regulates the expression of several cellular proteins that support cancer growth and metastasis. By inhibiting such a molecular target a global inhibitory effect on the expression of several proteins in a cancer cell will be produced resulting in anticancer activity. HuR, a member of the embryonic lethal abnormal vision (ELAV) protein family, is one such protein that controls the translation of numerous proteins and overexpressed in human cancers. HuR is a nucleo-cytoplasmic shuttling protein that specifically binds to mRNA that has AU rich (ARE) sites at the 3'end and transports the mRNA to the cytoplasm for protein translation. In addition to mRNA transportation, HuR plays a role in mRNA stabilization and protein translation. Studies have shown mRNA's of several growth factors, cell-cycle regulators, and transcription- regulating proteins have AREs and are bound and regulated by HuR. Additionally, HuR expression has been demonstrated to be a poor prognostic marker in patients diagnosed with cancer of the ovary, breast and colon. Although studies investigating HuR in cancer exist, the role of HuR in lung cancer, especially in non-small cell lung cancer (NSCLC), has not been investigated. In addition, very few therapeutic studies targeting HuR for cancer therapy have been investigated. On the basis of the existing literature and our own preliminary data demonstrating HuR overexpression in human lung cancer tissues we hypothesize that HuR is a novel druggable target for cancer therapy and its inhibition will downregulate multiple oncoproteins that play a role in tumor progression resulting in enhanced tumor killing. Additionally, combining HuR-targeted therapy with small molecule inhibitors will produce enhanced anticancer activity. To test our hypothesis we have identified the following specific aims:
Aim 1 : Cellular and molecular characterization of HuRSiRNA-Tf-nanoparticles (HuR-TfNPs) treatment on human lung tumor and normal cell lines in vitro.
Aim 2 : Evaluate the efficacy of HuR-TfNPs on lung metastasis in a tumor xenograft mouse model.
Aim 3 : Determine the efficacy of HuR-TfNPs treatment in combination with small molecule inhibitors in vitro and in vivo. The outcome of our studies will result in advanced preclinical testing and translation to the clinic.

Public Health Relevance

Current treatments for lung cancer have not significantly improved patient survival. Therefore there is a need for testing new therapies that are based on novel mechanisms of action, is broadly applicable, and yet minimally toxic. The goal of this project is to target HuR, an mRNA-binding protein that is overexpressed in lung cancer, using tumor-targeted nanoparticles.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA167516-02
Application #
8601528
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Fu, Yali
Project Start
2013-01-01
Project End
2017-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
2
Fiscal Year
2014
Total Cost
$339,880
Indirect Cost
$88,069
Name
University of Oklahoma Health Sciences Center
Department
Pathology
Type
Schools of Medicine
DUNS #
878648294
City
Oklahoma City
State
OK
Country
United States
Zip Code
73117
Griffith, James; Andrade, Daniel; Mehta, Meghna et al. (2017) Silencing BMI1 radiosensitizes human breast cancer cells by inducing DNA damage and autophagy. Oncol Rep 37:2382-2390
Muralidharan, Ranganayaki; Babu, Anish; Amreddy, Narsireddy et al. (2017) Tumor-targeted Nanoparticle Delivery of HuR siRNA Inhibits Lung Tumor Growth In Vitro and In Vivo By Disrupting the Oncogenic Activity of the RNA-binding Protein HuR. Mol Cancer Ther 16:1470-1486
Amreddy, Narsireddy; Babu, Anish; Panneerselvam, Janani et al. (2017) Chemo-biologic combinatorial drug delivery using folate receptor-targeted dendrimer nanoparticles for lung cancer treatment. Nanomedicine 14:373-384
Babu, Anish; Ramesh, Rajagopal (2017) Multifaceted Applications of Chitosan in Cancer Drug Delivery and Therapy. Mar Drugs 15:
Babu, Anish; Amreddy, Narsireddy; Muralidharan, Ranganayaki et al. (2017) Chemodrug delivery using integrin-targeted PLGA-Chitosan nanoparticle for lung cancer therapy. Sci Rep 7:14674
Srivastava, Akhil; Amreddy, Narsireddy; Babu, Anish et al. (2016) Nanosomes carrying doxorubicin exhibit potent anticancer activity against human lung cancer cells. Sci Rep 6:38541
Panneerselvam, Janani; Srivastava, Akhil; Muralidharan, Ranganayaki et al. (2016) IL-24 modulates the high mobility group (HMG) A1/miR222 /AKT signaling in lung cancer cells. Oncotarget 7:70247-70263
Mehta, Meghna; Basalingappa, Kanthesh; Griffith, James N et al. (2016) HuR silencing elicits oxidative stress and DNA damage and sensitizes human triple-negative breast cancer cells to radiotherapy. Oncotarget 7:64820-64835
Babu, Anish; Muralidharan, Ranganayaki; Amreddy, Narsireddy et al. (2016) Nanoparticles for siRNA-Based Gene Silencing in Tumor Therapy. IEEE Trans Nanobioscience 15:849-863
Muralidharan, Ranganayaki; Babu, Anish; Amreddy, Narsireddy et al. (2016) Folate receptor-targeted nanoparticle delivery of HuR-RNAi suppresses lung cancer cell proliferation and migration. J Nanobiotechnology 14:47

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