Applications

Pre-clinical drug screening

Unique utility of LTL tumor tissue lines for preclinical anticancer drug screening

Biological similarity The Living Tumor Lines are established directly from patient biopsy or surgically excised tumor tissue, and are biologically representative of original patient tumors in terms of histology, specific molecular markers, genetic/epigenetic alterations, and drug sensitivity.

Large collection The LTL provides tumor tissue lines covering a wide range of cancer types and subtypes. Various models with different biological or genetic features (low/high grade, slow/fast growing, metastatic/non-metastatic, genetic/epigenetic alterations) are available.

Clinical relevance LTL tumor tissue lines with high metastatic ability maintain the biology of advanced clinical disease and provide relevant models for testing the efficacy of anticancer drugs. Such metastatic tumor tissue lines reflect the malignancies in patients more accurately than conventional cell lines, and hence will be more predictive of clinical responses to established or novel drugs.

Target specificity For targeted anticancer drugs, we can provide detailed information on gene and molecular marker expression. These human tumor lines can be characterized for known drug targets using available methods (e. g. tissue microarrays, gene expression profiles).

For more information, please see Services\Pre-clinical drug testing

Publications

Sifeng Qu, Kendric Wang, Hui Xue, Yuwei Wang, Rebecca Wu, Chengfei Liu, Allen C. Gao, Peter W. Gout, Colin C. Collins, Yuzhuo Wang. Enhanced anticancer activity of a combination of docetaxel and Aneustat (OMN54) in a patient-derived, advanced prostate cancer tissue xenograft model. Mol Oncol. 2014 Mar;8(2):311-22. Full text

Dong Lin, Alexander W. Wyatt, Hui Xue, Yuwei Wang, Xin Dong, Anne Haegert, Rebecca Wu, Sonal Brahmbhatt, Fan Mo, Lina Jong, Robert H. Bell, Shawn Anderson, Antonio Hurtado-Coll, Ladan Fazli, Manju Sharma, Himisha Beltran, Mark Rubin, Michael Cox, Peter W. Gout, James Morris, Larry Goldenberg, Stanislav V. Volik, Martin E. Gleave, Colin C. Collins, and Yuzhuo Wang. High Fidelity Patient-Derived Xenografts for Accelerating Prostate Cancer Discovery and Drug Development. Cancer Res. 2014 Feb 15;74(4):1272-83. Full text

Stany MO,  Vathipadiekal V, Ozbun L, Stone RL, Mok S, Xue H, Kagami T, Wang Y, McAlpine JN, Bowtell D,  Gout PW,  Miller DM, Gilks CB, Huntsman DG, Ellard S, Wang YZ, Vivas-Mejia P, Lopez-Berestein G, Sood AK, and Birrer MJ, Identification of Novel Therapeutic Targets in Microdissected Clear Cell Ovarian Cancers. PLoS ONE 6(7): e21121. doi:10.1371/journal.pone.0021121. Full text

Kortmann U, McAlpine JN, Xue H, Guan J, Ha G, Tully S, Shafait S, Lau A, Cranston An, O'Connor MJ, Huntsman DG, Wang Y, Gilks CB (2011). Tumor growth inhibition by olaparib in BRCA2 germline-mutated patient-derived ovarian cancer tissue xneografts. Clinical Cancer Research 2011 Fe 15; 17(4):783-91.Full text

Tung WL, Wang Y, Gout PW, Liu DM, Gleave M, Wang YZ (2010). Use of Irinotecan for Treament of Small Cell Carcinoma of the Prostate. The Prostate 2010 OCT 14 [Epub ahead of print] Full text

Cheng H, Clarkson PW, Gao D, Pacheco M, Wang YZ, Nielsen TO (2010). Therapeutic antibodies targeting CSF1 impede macrophage recruitment in a xenograft model of tenosynovial giant cell tumor. Sarcoma. 2010, [in press] Full text

Andersen RJ, Mawji NR, Wang J, Wang G, Haile S, Myung JK, Watt K, Tam T, Yang YC, Bañuelos CA, Williams DE, McEwan IJ, Wang Y, Sadar MD  (2010). Regression of castrate-recurrent prostate cancer by a small-molecule inhibitor of the amino-terminus domain of the androgen receptor. Cancer Cell. 2010 Jun 15;17(6):535-46. full text

McPherson S, Hussain S, Balanathan P, Hedwards S, Niranjan B, Grant M, Chandrasiri U, Toivanen U, Wang YZ, Taylor R, Risbridger G (2010). Estrogen receptor beta activated apoptosis in benign hyperplasia and cancer of the prostate is androgen-independent and TNFα-mediated. PNAS 107(7): 3123-3128. Full text

Guan J, Lo M, Dockery P, Mahon S, karp S, Buckley S, Lam S,  Gout PW, Wang YZ (2009). The xc- Cystine Transporter as a Therapeutic Target for Small Cell Lung Cancer: Use of Sulfasalazine. Cancer Chemotherapy and Pharmacology, 64(3): 463-72. Full text

Press JZ, Kenyon JA, Xue H, Miller MA, De Luca A, Miller DM, Huntsman DG, Gilks CB, McAlpine JN, Wang YZ (2008) Xenografts of primary human gynecological tumors grown under the renal capsule of NOD/SCID mice show genetic stability during serial transplantation and respond to cytotoxic chemotherapy. Gynecologic oncology 110: 256-64

Personalized Cancer Therapy

Cancers consist of subpopulations of cells which can differ markedly in their response to treatment. Since each patient’s cancer is unique, cancer therapy should be tailored to individiual cancers. Choosing the most effective chemotherapeutic regimen for a patient is one of the major challenges faced by oncologists today. Patients usually have varying responses to a particular regimen. In addition, there are a multitude of different strategies to choose from (varying in terms of side effects and costs). If a selected regimen is unsuccessful, the high toxicity of treatments may exclude the patient from undergoing alternative treatments.

At The Living Tumor Centre, scientists have developed a patient-specific, predictive system for evaluating the drug response/resistance of cancers in individual patients, using primary grafts from patient cancers to test a variety of conventional and novel disease-specific chemotherapeutic regimens. In collaboration with oncologists, surgeons and pathologists, we aim to identify the most effective chemotherapeutic strategies for individual patients.

For more information, please see Sevices\Personalized Cancer Therapy

Media

Getting personal with cancer treatment----an interview with the International Innovation. [PDF file]

Publications

Gout PW, Wang YZ. Drug sensitivity testing for personalized lung cancer therapy. J Thorac Dis 2012 Feb;4(1):17-8. Full text

Dong X, Guan J, English JC, Flint J, Yee J, Evans K, Murray N, Macaulay C, Ng RT, Gout PW, Lam WL, Laskin J, Ling V, Lam S, Wang Y (2010). Patient-derived first generation xenografts of non-small cell lung cancers: promising tools for predicting drug responses for personalized chemotherapy. Clinical Cancer Research 16(5):1442-51.

In vivo models for translational cancer research

The LTL tumor tissue lines provide an optimal in vivo platform for the discovery of biomarkers for early detection, diagnosis, drug sensitivity and prognosis, and for discovery of potential therapeutic targets.

The LTL tumor tissue models maintain a greater biological heterogeneity than the conventionally used cancer cell lines and subcutaneous xenograft models. The highly vascularized renal graft site provides increased nutrient supply for transplanted tissue in comparison with tissues grafted at the subcutaneous site. Tissues grown under the renal capsule encounter a more hospitable environment due to the enriched blood supply and experience lower selective pressures, allowing for the survival of a wider range of cancer cell subpopulations derived from the original heterogeneous patient tumor.

The array of heterogeneous LTL tumor lines can be selectively enriched for distinct biological features (e.g. fast growth, strong metastatic potential, drug resistance) providing important models for studying critical features of cancer biology and their underlying mechanisms.

The LTL collection includes a wide variety of tumor types and subtypes. For more information, please see Patient-derived cancer tissue xenografts and Services & Collaboration.

Publications

Dong Lin, Hui Xue, Yuwei Wang, Rebecca Wu, Akira Watahiki, Xin Dong, Hongwei Cheng, Alexander W Wyatt, Colin C Collins, Peter W Gout, and Yuzhuo Wang. Next generation patient-derived prostate cancer xenograft models. Asian J Andro. 2014 May-Jun;16(3):407-12. Full text

Yan Ting Chiang, Peter W Gout, Colin C Collins and Yuzhuo Wang. Prostate cancer metastasis-driving genes: hurdles and potential approaches in their identification. Asian J Androl. 2014 Feb 28. doi: 10.4103/1008-682X.122875 Full text

Francesco Crea, Akira Watahiki, Luca Quagliata, Hui Xue, Larissa Pikor, Abhijit Parolia, Yuwei Wang, Dong Lin, Wan L. Lam, William L. Farrar, Takao Isogai, Rudolf Morant, Serenella Castori-Eppenberger, Kim N. Chi, Yuzhuo Wang and Cheryl D. Helgason. Identification of a long non-coding RNA as a novel biomarker and potential therapeutic target for metastatic prostate cancer. Oncotarget. 2014 Feb 15;5(3):764-74. Full text

Yan Ting Chiang, Kendric Wang, Ladan Fazli, Robert Z. Qi, Martin E. Gleave, Colin C. Collins, Peter W. Gout and Yuzhuo Wang. GATA2 as a potential metastasis-driving gene in prostate cancer. Oncotarget. 2014 Jan 30;5(2):451-61. Full text

Hongtuan Zhang, Can Qi, Andi Wang, Bing Yao, Liang Li, Yuzhuo Wang and Yong Xu. Prognostication of prostate cancer based on NUCB2 protein assessment: NUCB2 in prostate cancer. J Exp Clin Cancer Res. 2013 Oct 16;32(1):77. Full text

Francesco Crea, Pier Luc Clermont, Abhijit Parolia, Yuzhuo Wang and Cheryl D. Helgason. The non-coding transcriptome as a dynamic regulator of cancer metastasis. Cancer Metastasis Rev. 2013 Dec 18. [Epub ahead of print] Full text

Hisae Nakamura, Yuwei Wang, Hui Xue, Mark T. Romanish, Dixie L. Mager, Cheryl D. Helgason, and Yuzhuo Wang. Genisteinversus ICI182, 780: AnAllyor Enemy in Metastatic Progression of Prostate Cancer. Prostate. 2013 Dec;73(16):1747-60. Full text

Stephen Yiu Chuen Choi, Colin C Collins, Peter W Gout and Yuzhuo Wang. Cancer-generated lactic acid: a regulatory, immunosuppressive metabolite? J Pathol. 2013 Aug;230(4):350-5. Full text

Ariadna Mendoza-Naranjo, Amal El-Naggar, Daniel H. Wai, Priti Mistry, Nikola Lazic, Fernanda Rocha Rojas Ayala, Isabela Werneck da Cunha, Pablo Rodriguez-Viciana, Hongwei Cheng, Jose H. Tavares Guerreiro Fregnani, Patrick Reynolds, Robert J. Arceci, Andrew Nicholson, Timothy J. Triche, Fernando A. Soares, Adrienne M. Flanagan, Yuzhuo Z. Wang, Sandra J. Strauss and Poul H. Sorensen. ERBB4 confers metastatic capacity in Ewing sarcoma. EMBO Mol Med. 2013 Jul;5(7):1019-34. Full text

Yue Yu, Liangliang Liu, Ning Xie, Hui Xue, Ladan Fazli, Ralph Buttyan, Yuzhuo Wang, Martin Gleave, and Xuesen Dong. Expression and Function of the Progesterone Receptor in Human Prostate Stroma Provide Novel Insights to Cell Proliferation Control. J Clin Endocrinol Metab. 2013 Jul;98(7):2887-96.Full text

Akira Watahiki, Robyn J. Macfarlane, Martin E. Gleave, Francesco Crea, Yuzhuo Wang, Cheryl D. Helgason and Kim N. Chi. Plasma miRNAs as Biomarkers to Identify Patients with Castration-Resistant Metastatic Prostate Cancer. Int J Mol Sci. 2013 Apr 10;14(4):7757-70Full text

Alexander W Wyatt, Fan Mo, Yuzhuo Wang and Colin C Collins. The diverse heterogeneity of molecular alterations in prostate cancer identified through next-generation sequencing. Asian J Andro. 2013 May;15(3):301-8. Full text

Dong Lin, Peter W. Grout, Yuzhuo Wang, Lessons from in-vivo models of castration-resistant prostate cancer. Curr Opin rol. 2013 May;23(3):214-9 Full text

Low CG, Luk IS, Lin D, Fazli L, Yang K, Xu Y, Gleave M, Gout PW, Wang Y. BIRC6 protein, an inhibitor of apoptosis: role in survival of human prostate cancer cells. PLoS One. 2013;8(2): Epub 2013 Feb 8. Full text

Daniel T. Johnson, Richard Luong, Suk Hyung Lee, Yue Peng, Atossa Shaltouki, Jane T. Lee, Dong Lin, Yuzhuo Wang and Zhijie Sun. Deletion of Leucine Zipper Tumor Suppressor 2 (Lzts2) Increases Susceptibility to Tumor Development. J Biol Chem. 2013 Feb 8;288(6):3727-38. Full text

Xin Dong, Dong Lin, Chris Low, Emily A Vucic, John C. English, John Yee, Nevin Murray, Wan L. Lam, victor Ling, Stephen Lam, Peter W. Gout, Yuzhuo Wang. Elevated Expression of BIRC6 Protein in Non–Small-Cell Lung Cancers is Associated with Cancer Recurrence and Chemoresistance. J Thorac Oncol. 2013 Feb;8(2):161-70. Full text

Lapuk AV, Wu C, Wyatt AW, McPherson A, McConeghy BJ, Brahmbhatt S, Mo F, Zoubeidi A, Anderson S, Bell RH, Haegert A, Shukin R, Wang Y, Fazli L, Hurtado-Coll A, Jones EC, Hach F, Hormozdiari F, Hajirasouliha I, Boutros PC, Bristow RG, Zhao Y, Marra MA, Fanjul A, Maher CA, Chinnaiyan AM, Rubin MA, Beltran H, Sahinalp SC, Gleave ME, Volik SV, Collins CC. From sequence to molecular pathology, and a mechanism driving the neuroendocrine phenotype in prostate cancer. J Pathol. 2012 Jul;227(3):286-97. Full text

Stephen Yiu Chuen Choi, Peter W. Gout, Colin C. Collin, Yuzhuo Wang. Epithelial immune cell-like transition (EIT): A proposed transdifferentiation process underlying immune-suppressive activity of epithelial cancers. Differentiation. 2012 Jun;83(5):293-8. Full text

Collins CC, Volik SV, Lapuk A, Wang Y, Gout PW, Wu C, Xue H, Cheng H, Haegert A, Bell RH, Brahmbhatt S, Anderson S, Fazli L, Hurtado-Coll A, Rubin MA, Demichelis F, Beltran H, Hirst M, Marra MA, Maher CA, Chinnaiyan AM, Gleave ME, Bertino JR, Lubin M, Wang YZ. Next Generation Sequencing of Prostate Cancer from a Patient Identifies a Deficiency of Methylthioadenine Phosphorylase (MTAP), an Exploitable Tumor Target. Mol Cancer Ther. 2012 Jan 17. [Epub ahead of print] Full text

Watahiki A, Wang Y, Morris J, Dennis K, O'Dwyer HM, Gleave M, Gout PW, Wang Y. MicroRNAs associated with metastatic prostate cancer. PLoS One. 2011;6(9):e24950. Epub 2011 Sep 30.fulltext

Kuchenbauer F, Mah SM, McPherson A,  Heuser M,  Argiropoulos B, Morin RD,  Berg T, Lai D, Murani, AL Hogge DE,  Ruschmann J,  Starczynowski DT, Karsan A,  O’Connor MD,  Eaves C,  Watahiki A, Wang YZ,  Aparicio SA, Ganser A,  KrauterJ, Johnnidis JB, Marra MA, Carmargo FD and Humphries RK. Comprehensive analysis of mammalian miRNA species and their role in myeloid cells. Blood. 2011 May 31. [Epub ahead of print]full text

Nakamura H, Wang Y,  Kurita T, Adomat  H,  Cunha  GR and  Wang YZ. Genistein increases Epidermal Growth Factor Receptor signaling and promotes tumor progression in advanced human prostate cancer.  PLoS ONE 6(5): e20034. doi:10.1371/journal.pone.0020034, 2011. full text

Lin D, Bayani J, Wang Y, Sadar MD, Yoshimoto M, Gout PW, Squire J, Wang YZ (2010). Development of Metastatic and Non-Metastatic Tumor Lines From a Patient’s Prostate Cancer Specimen - Identification of a Small Subpopulation With Metastatic Potential in the Primary Tumor. The Prostate 70:1636 -1644, 2010full text

Chiu H, Yong TMK, Wang J, Wang Y, Vessella RL, Ueda T, Wang YZ, Sadar MD (2010). Induction of Neuronal Apoptosis Ihibitory Protein Expression in Response to Andogen Deprivation in Prostate cancer. Cancer Letters 292:176-185 Full text

Lin D, Watahiki A, Bayani J, Zhang F, Liu L, Ling V, Sadar MD, English J, Fazli L, So A, Gout PW, Gleave M, Squire JA, Wang YZ (2008). ASAP1, a gene at 8q24, is associated with prostate cancer metastasis. Cancer Research 68(11):4352-9.

Cutz JC, Guan J, Bayani J, Yoshimoto M, Xue H, Sutcliffe M, English J, Flint J, LeRiche J, Yee J, Squire JA, Gout PW, Lam S, Wang YZ (2006). Establishment in severe combined immunodeficiency mice of subrenal capsule xenografts and transplantable tumor lines from a variety of primary human lung cancers: potential models for studying tumor progression-related changes. Clinical Cancer Research 12(13):4043-54 Cutz

Wang Y, Revelo MP, Sudilovsky D, Cao M, Chen WG, Goetz L, Xue H, Sadar M, Shappell SB, Cunha GR, Hayward SW (2005) Development and characterization of efficient xenograft models for benign and malignant human prostate tissue. Prostate. 2005 Jul 1;64(2):149-59.

Lee CH, Xue H, Sutcliffe M, Gout PW, Huntsman DG, Miller DM, Gilks CB, Wang YZ (2005). Establishment of subrenal capsule xenografts of primary human ovarian tumors in SCID mice: potential models. Gynecologic oncology 96:48-55.

Wang Y, Xue H, Cutz JC, Bayani J, Mawji NR, Chen WG, Goetz LJ, Hayward SW, Sadar MD, Gilks CB, Gout PW, Squire JA, Cunha GR, Wang YZ (2005). An orthotopic metastatic prostate cancer model in SCID mice via grafting of a transplantable human prostate tumor line. Laboratory Investigation 85:1392-404.