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)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Exploratory Grants (P20)
Project #
5P20GM103639-03
Application #
8723255
Study Section
Special Emphasis Panel (ZRR1)
Project Start
Project End
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
City
Oklahoma City
State
OK
Country
United States
Zip Code
73117
Bastian, Anja; Matsuzaki, Satoshi; Humphries, Kenneth M et al. (2017) AG311, a small molecule inhibitor of complex I and hypoxia-induced HIF-1? stabilization. Cancer Lett 388:149-157
Pearsall, Elizabeth A; Cheng, Rui; Zhou, Kelu et al. (2017) PPAR? is essential for retinal lipid metabolism and neuronal survival. BMC Biol 15:113
Boswell-Casteel, Rebba C; Hays, Franklin A (2017) Equilibrative nucleoside transporters-A review. Nucleosides Nucleotides Nucleic Acids 36:7-30
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
Banerjee Mustafi, Soumyajit; Chakraborty, Prabir Kumar; Dwivedi, Shailendra Kumar Dhar et al. (2017) BMI1, a new target of CK2?. Mol Cancer 16:56
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
Nguyen, Charles B; Houchen, Courtney W; Ali, Naushad (2017) APSA Awardee Submission: Tumor/cancer stem cell marker doublecortin-like kinase 1 in liver diseases. Exp Biol Med (Maywood) 242:242-249
Chakraborty, Prabir K; Mustafi, Soumyajit Banerjee; Xiong, Xunhao et al. (2017) MICU1 drives glycolysis and chemoresistance in ovarian cancer. Nat Commun 8:14634
Aravindan, Sheeja; Somasundaram, Dinesh Babu; Kam, Kwok Ling et al. (2017) Retinal Degeneration Protein 3 (RD3) in normal human tissues: Novel insights. Sci Rep 7:13154
Jaiprasart, Pharavee; Yeung, Bertrand Z; Lu, Ze et al. (2017) Quantitative contributions of processes by which polyanion drugs reduce intracellular bioavailability and transfection efficiency of cationic siRNA lipoplex. J Control Release 270:101-113

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