Dr. Yuzhuo Wang, PhD
675 West 10th Avenue, Vancouver, V5Z 1L3
Our long-term objectives are to (i) identify new biomarkers for improved diagnosis and prognosis of human cancers, including cancers of the prostate, ovary and lung, and (ii) develop novel, more effective therapies for the diseases.
A major focus of our research is directed toward prostate cancer (PCa) metastasis. Once prostate cancer has metastasized it is a terminal disease. Its management is impeded by a lack of reliable biomarkers for predicting metastatic potential of primary prostate cancers and molecular targets for effective therapy of metastatic prostate cancer. Development of metastasis is thought to stem from changes in the expression of certain genes. In search of such metastasis-associated genes (e.g. protein coding or non-coding ones), we have developed pairs of transplantable metastatic sublines (e.g. PCa1-met) (Wang et al, 2005b) and non-metastatic counterparts (e.g. PCa2) (Lin et al, 2008) from the same patients' primary prostate cancer specimens, using our well-established subrenal capsule and orthotopic xenograft technology. The paired metastatic and non-metastatic tumor sublines are subjected to differential analyses (e.g., Serial Analysis of Gene Expression, Solexa Sequencing) to detect up-regulated and down-regulated genes. To identify metastasis-associated genes, we search for differentially expressed genes that are (i) associated with alterations in gene copy number (gains or losses) or gene amplification and (ii) commonly detected in pairs of metastatic and non-metastatic tumor sublines. Subsequently, the selected genes are validated for clinical relevance by determining whether their differential expression in clinical prostate cancer samples correlates with the metastatic status of the samples, using antibodies and/or fluorescent in situ hybridization. The qualifying genes are then examined, alone or in conjunction, for possible use as targets for metastatic prostate cancer therapy, using in vitro and in vivo functional assays. Using the above approach, we have successfully revealed a number of metastasis-associated genes, including ASAP1, which encodes an Arf GTPase-activating protein. This gene, not previously associated with prostate cancer, was upregulated in the metastatic subline. The SAGE finding was confirmed by real time RT-PCR. Importantly, immunohistochemical studies showed that increased ASAP1 protein expression was found to be associated with prostate cancer carcinogenesis, while high expression of the protein was associated with metastasis. This was confirmed by a study using clinical samples. We further demonstrated that ASAP1 is functionally important in prostate cancer metastasis. In addition to ASAP1, there are a number of promising genes that are under extensive study in the laboratory.
Another major area of our studies focuses on the development, and application of Patient-Derived Cancer Xenograft Models, particularly on their use in New Anti-Cancer Drug Development. At present, the most commonly used preclinical cancer xenograft models are based on use of cultured human cell lines. Such cell line xenograft models, while valuable for basic research, in general do not adequately predict the efficacy of anticancer agents in the clinic and have been highlighted as a key obstacle in the translation of major advances in basic cancer research into meaningful clinical benefits. Even if all the preclinical tests are successful, only about 5% of proposed anti-cancer agents can pass FDA approval. The high rate of ineffective compounds entering clinical testing indicates a need for better ways of predicting efficacy of drugs before they are tested in humans.
Cancers are complex cellular systems usually consisting of various subpopulations of neoplastic cells, a variety of normal cells as well as stromal components. In contrast, established cancer cell lines consist only of neoplastic cells and usually are highly homogeneous; they therefore do not exhibit the typical cellular heterogeneity of cancer tissue. In view of this, cancer models based on xenografts of human cancer tissue are expected to mimic clinical disease more closely than xenografts of cultured cancer cell lines. Various research groups have focused on growing intact tumor tissues from patients in vivo, i.e. subcutaneously and orthotopically. However, successful growth of tumors in these graft sites was only achieved sporadically (tumor take rates < 20%) and only when the tumors were highly advanced (Cutz et al, 2006; Lee et al, 2005; Wang et al, 2005a). Recently, we have, at the Living Tumor Laboratory (www.livingtumorlab.com), developed a procedure for successfully grafting and serially transplanting primary human cancer tissues in an in vivo experimental condition. It is based on grafting of the tumor tissue into the subrenal capsule graft site. The high vascularity of this site, compared to the subcutaneous and orthotopic sites, allows a more adequate supply of nutrients to the tumor tissue. Using this methodology, we have consistently achieved high tumor take rates (>95%) for a variety of low and higher grade malignancies, including cancers of the prostate (Lin et al, 2008; Wang et al, 2005a; Wang et al, 2005b), ovary (Lee et al, 2005; Press et al, 2008), kidney (Liou et al, 2004), lung (Cutz et al, 2006; Guan et al, 2009; Dong et al.,2010), pancreas (Watahiki et al, 2006) and others (unpublished data). Significantly, the cancer tissue xenografts and transplantable tumor lines derived from such xenografts are histologically highly similar to the donor tissues and retain important genetic and epigenetic features as well as responses to treatment with drugs (Cutz et al, 2006; Lee et al, 2005; Press et al, 2008). Such a comprehensive collection of transplantable tumor lines (currently, over 130 tumor lines established from cancers of human prostate, ovary, lung, kidney and pancreas) are therefore most adequate as models for the original cancers and suitable for evaluation of novel and existing therapeutics under experimental conditions. We use the patients' tumor tissue xenografts for (i) discovery and validation of potential biomarkers and/or targets for therapy of metastatic cancers, (ii) personalized cancer therapy, and (iii) preclinical drug efficacy studies in anti-cancer therapeutics development.
Fang Zhang, Research Associate
Hisae Nakamura, Dept. of Oncology, UBC
Hongwei Chang, Research Associate
JC Cutz, Molecular Pathology Fellow 2005-2006