**6. Conclusion and perspective**

Breakdown of the extracellular matrix scaffold and the concomitant cellular migration, mitogenesis, and morphogenesis that is driven by the HGF-Met system makes way for the construction and reconstruction of tissues during development and wound healing. Perhaps because of this, tumor cells use the HGF-Met pathway as a machine particularly for their spreading, metastasis, and evasion of microenvironmental predicaments. Therefore, activation and inhibition of the HGF-Met pathway are likely to be therapeutic approaches for the treatment of non-neoplastic diseases with tissue damage and for malignant diseases, respectively. HGF exhibits therapeutic effects for the protection and healing of tissues against tissue damage and pathology. Clinical trials using recombinant HGF or HGF gene drugs have been approved for the treatment of diseases with unmet needs.

Based on the basic knowledge of the significance of the HGF-Met pathway in tumor biology and pathology, during the last several years the one-to-one relationship between HGF and Met has facilitated the discovery and development of drug candidates that selectively inhibit HGF-Met in different ways. Preclinical and clinical development of drugs targeting HGF-Met will move into practice in the near future as new anticancer drugs. However, although drug discoveries in molecular-targeted cancer therapy have been beneficial for patients with malignancies, the appearance of persistent characteristics of malignant tumors in regard to resistance to anticancer therapies and drugs remains an obstacle to disease-free survival. The choice of the better, or best, way to inhibit HGF-Met signaling, i.e., ligand inhibition, receptor inhibition, biologics, mAb, or small synthetic, would gradually become clearer following clinical experiences.

#### **7. Acknowledgement**

The studies from the authors' laboratories were supported by Grants from the Ministry of Education, Culture, Science, Sports, and Technology of Japan, the Program for Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation, and the Hokkou Foundation for the Promotion of Cancer Research.

#### **8. References**

324 Advances in Cancer Therapy

et al., 2006). Anti-Met mAb R13 and R28 synergistically inhibited HGF binding to MET and elicited antibody-dependent cellular cytotoxicity (van der Horst et al., 2009). The combination of R13/28 inhibited tumor growth in various colon tumor xenograft models. MetMab reduced Met phosphorylation, and this was associated with inhibition of orthotopic tumor growth and improvement of survival in a pancreatic xenograft model (Jin et al., 2008). MetMab is currently in phase I/II human clinical trials in comparison with erlotinib for patients with NSCLC (HYPERLINK "http://www.clinicaltrials.gov"

As small synthetic Met tyrosine kinase inhibitors, SU11274 and PHA665752 provided the basic notion that small synthetic Met tyrosine kinase inhibitors selectively inhibit Met activation and suppress tumor growth (Christensen ; 2003; Sattler et al., 2003; Berthou et al; 2004; Ma et al., 2005; Smolen et al., 2006). Subsequent research and development led to the discovery of various types of synthetic tyrosine kinase inhibitors with different structures, chemical properties, and target specificity. Based on the wealth of accumulated knowledge gained from the success of preclinical and clinical development of small synthetic tyrosine kinase inhibitors, more than 10 small synthetic Met tyrosine kinase inhibitors have been

PF-02341066 targets Met as well as anaplastic lymphoma kinase (ALK) (Sattler & Salgia, 2009). MP470 inhibits PDGFR, Kit, and Met tyrosine kinases. In combination with erlotinib, MP470 inhibited prostate cancer cell proliferation and tumor xenograft growth (Qi et al., 2009). E7050 targets both Met and VEGFR2 (Nakagawa et al., 2009). JNJ-38877605 shows a >1,000-fold selectivity for the Met kinase, compared to a >200-fold selectivity for related receptor tyrosine kinases (Eder et al., 2009). AMG 208 selectively inhibits both ligand-dependent and ligand-independent Met activation. BMS777607 has completed a phase I/II study in metastatic cancer patients (Schroeder et al., 2009). Phase I clinical trials were discontinued for SGX523 after renal toxicity was observed in patients receiving relatively low doses ( HYPERLINK "http://www.sgxpharma.com" www.sgxpharma.com). PF02341066 and XL184 have progressed the furthest of all Met inhibitors in clinical development. PF-02341066 has greater Met selectivity compared with PF-04217903 (Timofeevski et al., 2009). Preclinical studies indicate PF-02341066 is highly effective against the product of the EML4-ALK translocation found in a subset of NSCLC patients (Shaw et al., 2009). PF-02341066t is currently in phase I, II, and III clinical trials ( HYPERLINK "http://www.clinicaltrials.gov" www.clinicaltrials.gov). XL184 targets Met, VEGFR2, and Ret. A current phase III trial is investigating the efficacy of XL184 as a first-line treatment, compared to a placebo, in patients with medullary thyroid cancer ( HYPERLINK

Breakdown of the extracellular matrix scaffold and the concomitant cellular migration, mitogenesis, and morphogenesis that is driven by the HGF-Met system makes way for the construction and reconstruction of tissues during development and wound healing. Perhaps because of this, tumor cells use the HGF-Met pathway as a machine particularly for their spreading, metastasis, and evasion of microenvironmental predicaments. Therefore, activation and inhibition of the HGF-Met pathway are likely to be therapeutic approaches

www.clinicaltrials.gov).

**5.2 Small synthetic kinase inhibitors** 

entered into clinical trials (Table 1).

"http://www.clinicaltrials.gov" www.clinicaltrials.gov).

**6. Conclusion and perspective** 


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**15**

*UK* 

Sally P. Wheatley

**Nuclear Survivin: Cellular** 

*School of Biomedical Sciences, University of Nottingham* 

**Consequences and Therapeutic Implications** 

Survivin is a cancer associated protein that is present in all embryonic cells, but whose expression is normally limited to actively proliferating cells in adults. During mitosis it is part of a conserved complex of chromosomal passenger proteins (CPPs), which is essential for chromosome biorientation and cell division (Ruchaud et al., 2007). Defects in CPP function cause errors in mitosis and cytokinesis and can lead to genomic instability, or "aneuploidy", a status indicative of tumorigenesis. First discovered by Altieri and coworkers (Ambrosini et al., 1998), survivin is the fourth most upregulated mRNA in the cancer transcriptome (Velculescu et al., 1999), and in many tumours its expression is detected throughout the cell cycle. Importantly increased survivin abundance correlates with tumour resistance to conventional radiation and chemotherapies, a correlation recapitulated in cultured cells in the laboratory (Chakravarti et al., 2004; Colnaghi et al., 2006). While involvement in mitosis alone is a valid reason for considering a protein as a biomarker, or a target for cancer therapy, the oncotherapeutic potential of survivin is compounded by the fact that it is also an inhibitor of cell death (for review see Altieri, 2008). The principle aim of this article is to highlight the manifestations of survivin expression in

the nucleus and to discuss how these might be exploited for oncotherapeutic gain.

**2. Subcellular localisation of survivin as a prognostic marker in cancer** 

Numerous clinical studies have reported differential localisation of survivin in the cytoplasm, the nucleus, or both in tumours and have correlated this with disease severity and patient survival, with the aim to determine the prognostic value of its localisation retrospectively. However, despite the plethora of data collected, the prognostic significance of the subcellular distribution of survivin in cancer remains unclear. In 2005 a review of the subject returned a hung jury, revealing more opposing conclusions and contradictions than commonalities (Li et al., 2005); see also (Xie et al., 2006). As most of these clinical-based studies used histopathological samples, the lack of uniformity in sample collection and preservation between labs, together with differences in antibody protocols and the subjective nature of the analysis are likely to have contributed to the variation within these data (Li et al., 2005). Differences in data acquisition and interpretation aside, survivin localisation does vary between tumour types, and if one considers more detailed factors within specific types of cancer, such as its grade, stage of differentiation, and whether it is

**1. Introduction** 

agonist to an antagonist. *Proceeding National Academy of Science USA,* 104: 14592-14597

