CONTACT INFORMATION http://www.loyola.org
Takeshi Shimamura
Ph.D.
  • Assistant Professor
  • Molecular Pharmacology and Therapeutics
Research Keywords
  • Cancer/Carcinogenesis
  • Signal Transduction
  • Drug Resistance
Research Summary

Investigating the signaling pathways and transcriptome in non-small cell lung cancer (NSCLC) to overcome drug resistance

Lung cancer is the leading cause of cancer-related death in the U.S. ¬In NSCLC, activating EGFR mutations are responsive to reversible EGFR tyrosine kinase inhibitors TKIs, including gefitinib and erlotinib. Despite initial responses, acquired resistance invariably develops and is mediated by the emergence of the secondary T790M mutation and by focal amplification of c-MET, in approximately 50% and 15% of patients, respectively. The resistance mechanisms for the remaining 35% of cases remain elusive. A recent clinical study demonstrated that half of the remaining 35% of these resistant NSCLCs present with an epithelial to mesenchymal transition (EMT) phenotype. However, it remains elusive if EMT is a primary mechanism of TKI resistance.

Consequently, we are interested in investigating if EMT is a primary mechanism of EGFR TKI resistance and how EMT modulates signaling cascades leading to the acquired resistance to EGFR TKIs in NSCLC addicted to mutant EGFR for survival and growth. This project was initiated by Dr. Shimamura as a part of Dana-Farber/Harvard Cancer Center Lung SPORE Career development project. Using proteomics and genomics techniques, we are currently investigating if inhibiting specific signaling pathway could re-sensitize the EMT-mediated EGFR TKI resistant NSCLC cells to EGFR TKIs with the ultimate goal of lending further credence to novel early phase clinical trials using the inhibitors.

My laboratory is also interested in developing strategies to pharmacologically inhibit mutant KRAS-driven NSCLC. Approximately 15 - 30% of NSCLC patients harbor an oncogenic KRAS mutation associated with resistance to conventional treatment regimens. Oncogenic activation of Kras in the murine lung compartment produces adenocarcinoma and several human lung cancer cell lines harboring mutant KRAS are dependent on KRAS activity for survival; therefore oncogenic mutant KRAS is a highly attractive therapeutic target in NSCLC. However, targeting mutant KRAS with small molecules inhibitors has not proven successful. In collaboration with several laboratories around the world, our laboratory is investigating several novel targets in the subset of NSCLC with mutant KRAS in a hope to find a novel therapeutic strategy.

In our laboratory, students are expected to learn techniques and theories in molecular, cellular and cancer biology with specific emphasis in integrating bioinformatics and proteomics to their research projects.

For our most recent publications, please visit
http://www.researchgate.net/profile/Takeshi_Shimamura/

Research Areas: Lung cancer, signal transduction, transcription factor, EMT, resistance, EGFR, KRAS, oncogene addiction and mutation.

Publications

Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumorsAkbay,E. A.; Koyama,S.; Carretero,J.; Altabef,A.; Tchaicha,J. H.; Christensen,C. L.; Mikse,O. R.; Cherniack,A. D.; Beauchamp,E. M.; Pugh,T. J.; Wilkerson,M. D.; Fecci,P. E.; Butaney,M.; Reibel,J. B.; Soucheray,M.; Cohoon,T. J.; Janne,P. A.; Meyerson,M.; Hayes,D. N.; Shapiro,G. I.; Shimamura,T.; Sholl,L. M.; Rodig,S. J.; Freeman,G. J.; Hammerman,P. S.; Dranoff,G.; Wong,K. K.Cancer discovery 2013 ;3(12):1355-1363

Efficacy of BET bromodomain inhibition in Kras-mutant non-small cell lung cancerShimamura,T.; Chen,Z.; Soucheray,M.; Carretero,J.; Kikuchi,E.; Tchaicha,J. H.; Gao,Y.; Cheng,K. A.; Cohoon,T. J.; Qi,J.; Akbay,E. A.; Kimmelman,A. C.; Kung,A. L.; Bradner,J. E.; Wong,K. K.Clinical cancer research : an official journal of the American Association for Cancer Research 2013 ; ( ):

Interleukin-6 upregulates expression of ADAMTS-4 in fibroblast-like synoviocytes from patients with rheumatoid arthritisMimata,Y.; Kamataki,A.; Oikawa,S.; Murakami,K.; Uzuki,M.; Shimamura,T.; Sawai,T.International journal of rheumatic diseases 2012 ;15(1):36-44

Ganetespib (STA-9090), a nongeldanamycin HSP90 inhibitor, has potent antitumor activity in in vitro and in vivo models of non-small cell lung cancerShimamura,T.; Perera,S. A.; Foley,K. P.; Sang,J.; Rodig,S. J.; Inoue,T.; Chen,L.; Li,D.; Carretero,J.; Li,Y. C.; Sinha,P.; Carey,C. D.; Borgman,C. L.; Jimenez,J. P.; Meyerson,M.; Ying,W.; Barsoum,J.; Wong,K. K.; Shapiro,G. I.Clinical cancer research : an official journal of the American Association for Cancer Research 2012 ;18(18):4973-4985

Interleukin 13 mediates signal transduction through interleukin 13 receptor alpha2 in pancreatic ductal adenocarcinoma: role of IL-13 Pseudomonas exotoxin in pancreatic cancer therapyShimamura,T.; Fujisawa,T.; Husain,S. R.; Joshi,B.; Puri,R. K.Clinical cancer research : an official journal of the American Association for Cancer Research 2010 ;16(2):577-586

IL-13 cytotoxin has potent antitumor activity and synergizes with paclitaxel in a mouse model of oral squamous cell carcinomaKioi,M.; Shimamura,T.; Nakashima,H.; Hirota,M.; Tohnai,I.; Husain,S. R.; Puri,R. K.International journal of cancer.Journal international du cancer 2009 ;124(6):1440-1448

Novel role of IL-13 in fibrosis induced by nonalcoholic steatohepatitis and its amelioration by IL-13R-directed cytotoxin in a rat modelShimamura,T.; Fujisawa,T.; Husain,S. R.; Kioi,M.; Nakajima,A.; Puri,R. K.Journal of immunology (Baltimore, Md.: 1950) 2008 ;181(7):4656-4665

Interleukin-4 cytotoxin therapy synergizes with gemcitabine in a mouse model of pancreatic ductal adenocarcinomaShimamura,T.; Royal,R. E.; Kioi,M.; Nakajima,A.; Husain,S. R.; Puri,R. K.Cancer research 2007 ;67(20):9903-9912

Regulation of mast cell development by inflammatory factorsHu,Z. Q.; Zhao,W. H.; Shimamura,T.Current medicinal chemistry 2007 ;14(28):3044-3050

The IL-4 and IL-13 pseudomonas exotoxins: new hope for brain tumor therapyShimamura,T.; Husain,S. R.; Puri,R. K.Neurosurgical Focus 2006 ;20(4):E11

Interleukin-13 receptor alpha2 chain: a potential biomarker and molecular target for ovarian cancer therapyKioi,M.; Kawakami,M.; Shimamura,T.; Husain,S. R.; Puri,R. K.Cancer 2006 ;107(6):1407-1418

Mechanisms of strain-dependent development of mast cells from mouse splenocytesHu,Z. Q.; Zhao,W. H.; Shimamura,T.Immunology and cell biology 2006 ;84(2):184-191

Interleukin-4-triggered, STAT6-dependent production of a factor that induces mouse mast cell apoptosisHu,Z. Q.; Zhao,W. H.; Shimamura,T.; Galli,S. J.European journal of immunology 2006 ;36(5):1275-1284

Inhibitory effect of catechin against the superantigen staphylococcal enterotoxin B (SEB)Hisano,M.; Yamaguchi,K.; Inoue,Y.; Ikeda,Y.; Iijima,M.; Adachi,M.; Shimamura,T.Archives of Dermatological Research 2003 ;295(5):183-189

Induction of osteogenic protein-1 expression by interleukin-1beta in cultured rabbit articular chondrocytesYoshida,S.; Kubota,Y.; Toba,T.; Horiuchi,S.; Shimamura,T.The Tohoku journal of experimental medicine 2002 ;197(2):101-109

The polarization of T(h)1/T(h)2 balance is dependent on the intracellular thiol redox status of macrophages due to the distinctive cytokine productionMurata,Y.; Shimamura,T.; Hamuro,J.International immunology 2002 ;14(2):201-212

The skewing to Th1 induced by lentinan is directed through the distinctive cytokine production by macrophages with elevated intracellular glutathione contentMurata,Y.; Shimamura,T.; Tagami,T.; Takatsuki,F.; Hamuro,J.International immunopharmacology 2002 ;2(5):673-689

Dynamics of interleukin (IL)-18 in serum, synovial fluid and synovial membrane in the patients with rheumatoid arthritisMunakata,T.; Uzuki,M.; Shimamura,T.; Sawai,T.Ryumachi.[Rheumatism] 2001 ;41(3):625-634

Immunomodulatory effect of gold sodium thiomalate on murine acquired immunodeficiency syndromeYamaguchi,K.; Ushijima,H.; Hisano,M.; Inoue,Y.; Shimamura,T.; Hirano,T.; Muller,W. E.Microbiology and immunology 2001 ;45(7):549-555

Biography

Dr. Shimamura received his Ph.D. from Western Michigan University, Kalamazoo Michigan. Dr. Shimamura’s postdoctoral work was conducted in Drs. Geoffrey I. Shapiro and Kwok-Kin Wong’s labs in the Dana-Farber Cancer Institute, Harvard Medical School, from 2004 to 2008, where he studied targeted-therapies and resistance mechanisms in the treatment for non-small cell lung cancer (NSCLC). In 2008, he was promoted as an Instructor in Medicine, Dana-Farber Cancer Institute, Brigham and Women’s Hospital, Harvard Medical School.

Dr. Shimamura joined the research faculty of the Oncology Institute at Loyola University of Chicago in late 2011. His primary research interest is in the area of signaling pathways of NSCLC and small-cell lung cancer (SCLC) undergoing epithelial to mesenchymal transition (EMT).

Dr. Shimamura is the author of more than 30 publications. He has made several original observations, including that NSCLC cells driven by activating EGFR mutations are exquisitely sensitive to HSP90 inhibitors, and that EGFR irreversible inhibitors show potency limitations against mutant EGFR with acquired T790M mutations. Using integrative genomics and proteomics, Dr. Shimamura has also demonstrated that Src pathway plays a pivotal role for the survival of the NSCLC with mutant Kras and LKB1 deletion.

Languages
  • Japanese