Systemic chemotherapy is one of the remaining avenues available to an oncologist treating unresectable non-small cell lung cancer (NSCLC). Unfortunately, NSCLC indicated anticancer therapeutics do not provide significant patient survival benefits and have toxic side effects. These drugs will extend the time-to-progression of metastatic disease by small margins yet do little to decrease NSCLC mortality. An underlying theme to the current proposal is that one can obtain significant improvements in NSCLC chemotherapy with a more detailed molecular understanding of drug disposition and response. To obtain this understanding we will use a combination of structural biology and functional assays to study a human integral membrane protein directly linked to gemcitabine uptake within normal and neoplastic cells. The equilibrative nucleoside transporter (hENT) family is broadly distributed in human tissues, is known to transport a wide array of nucleoside antimetabolites, and is directly linked to chemotherapeutic outcomes. Specific goals we seek to address in this proposal include (1) determine the structure of hENT at atomic resolution, (2) develop in vitro functional assays using purified protein, and (3) characterize hENT functional determinants using three human lung cancer cell lines. Outcomes from these studies will be tuned to determine the molecular basis by which hENT regulatoin and transport of therapeutics occus. The broad vision is that these novel molecular insights can be advanced to clinical outcomes that guide treatment decisions in nucleoside based drug treatment of NSCLC.

Public Health Relevance

These studies will investigate the function of a key membrane protein involved in drug response and disposition in the treatment of human cancer. Understanding how protein sequence and function for this protein relate to drug efficacy will provide a means by which to improve cancer chemotherapy and drug selection during treatment.

Agency
National Institute of Health (NIH)
Type
Exploratory Grants (P20)
Project #
5P20GM103639-03
Application #
8723255
Study Section
Special Emphasis Panel (ZRR1)
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
City
Oklahoma City
State
OK
Country
United States
Zip Code
73117
Ramraj, Satish Kumar; Aravindan, Sheeja; Somasundaram, Dinesh Babu et al. (2016) Serum-circulating miRNAs predict neuroblastoma progression in mouse model of high-risk metastatic disease. Oncotarget 7:18605-19
Zhang, Zhi; Subramaniam, Sabareesh; Kale, Justin et al. (2016) BH3-in-groove dimerization initiates and helix 9 dimerization expands Bax pore assembly in membranes. EMBO J 35:208-36
Huang, Qingling; Schneeberger, Valentina E; Luetteke, Noreen et al. (2016) Preclinical Modeling of KIF5B-RET Fusion Lung Adenocarcinoma. Mol Cancer Ther 15:2521-2529
Nguyen, Charles B; Kotturi, Hari; Waris, Gulam et al. (2016) (Z)-3,5,4'-Trimethoxystilbene Limits Hepatitis C and Cancer Pathophysiology by Blocking Microtubule Dynamics and Cell-Cycle Progression. Cancer Res 76:4887-96
Corbin, Joshua M; Overcash, Ryan F; Wren, Jonathan D et al. (2016) Analysis of TMEFF2 allografts and transgenic mouse models reveals roles in prostate regeneration and cancer. Prostate 76:97-113
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
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
Ha, Ji Hee; Ward, Jeremy D; Radhakrishnan, Rangasudhagar et al. (2016) Lysophosphatidic acid stimulates epithelial to mesenchymal transition marker Slug/Snail2 in ovarian cancer cells via Gαi2, Src, and HIF1α signaling nexus. Oncotarget 7:37664-37679
Kim, Tae-Dong; Jin, Fang; Shin, Sook et al. (2016) Histone demethylase JMJD2A drives prostate tumorigenesis through transcription factor ETV1. J Clin Invest 126:706-20
Amreddy, Narsireddy; Muralidharan, Ranganayaki; Babu, Anish et al. (2015) Tumor-targeted and pH-controlled delivery of doxorubicin using gold nanorods for lung cancer therapy. Int J Nanomedicine 10:6773-88

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