The human genome encodes 538 protein kinases that transfer a γ-phosphate group from ATP to serine, threonine, or tyrosine residues. Many of these kinases are associated with human cancer initiation and progression. The recent development of small-molecule kinase inhibitors for the treatment of diverse types of cancer has proven successful in clinical therapy. Significantly, protein kinases are the second most targeted group of drug targets, after the G-protein-coupled receptors. Since the development of the first protein kinase inhibitor, in the early 1980s, 37 kinase inhibitors have received FDA approval for treatment of malignancies such as breast and lung cancer. Furthermore, about 150 kinase-targeted drugs are in clinical phase trials, and many kinase-specific inhibitors are in the preclinical stage of drug development. Nevertheless, many factors confound the clinical efficacy of these molecules. Specific tumor genetics, tumor microenvironment, drug resistance, and pharmacogenomics determine how useful a compound will be in the treatment of a given cancer. This review provides an overview of kinase-targeted drug discovery and development in relation to oncology and highlights the challenges and future potential for kinase-targeted cancer therapies.

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Kinase-targeted cancer therapies: progress, challenges and future directions

The human aurora family of serine-threonine kinases comprises three members, which act in concert with many other proteins to control chromosome assembly and segregation during mitosis. Aurora dysfunction can cause aneuploidy, mitotic arrest, and cell death. Aurora kinases are strongly expressed in a broad range of cancer types. Aurora A expression in tumors is often associated with gene amplification, genetic instability, poor histologic differentiation, and poor prognosis. Aurora B is frequently expressed at high levels in a variety of tumors, often coincidently with aurora A, and expression level has also been associated with increased genetic instability and clinical outcome. Further, aurora kinase gene polymorphisms are associated with increased risk or early onset of cancer. The expression of aurora C in cancer is less well studied. In recent years, several small-molecule aurora kinase inhibitors have been developed that exhibit preclinical activity against a wide range of solid tumors. Preliminary clinical data from phase I trials have largely been consistent with cytostatic effects, with disease stabilization as the best response achieved in solid tumors. Objective responses have been noted in leukemia patients, although this might conceivably be due to inhibition of the Abl kinase. Current challenges include the optimization of drug administration, the identification of potential biomarkers of tumor sensitivity, and combination studies with cytotoxic drugs. Here, we summarize the most recent preclinical and clinical data and discuss new directions in the development of aurora kinase inhibitors as antineoplastic agents.

https://clincancerres.aacrjournals.org/content/clincanres/14/6/1639.full.pdf

Aurora Kinases as Anticancer Drug Targets

Periostin is considered to be a matricellular protein with expression typically confined to cells of mesenchymal origin. Here, by using in situ hybridization, we show that periostin is specifically up-regulated in bronchial epithelial cells of asthmatic subjects, and in vitro, we show that periostin protein is basally secreted by airway epithelial cells in response to IL-13 to influence epithelial cell function, epithelial–mesenchymal interactions, and extracellular matrix organization. In primary human bronchial epithelial cells stimulated with periostin and epithelial cells overexpressing periostin, we reveal a function for periostin in stimulating the TGF-β signaling pathway in a mechanism involving matrix metalloproteinases 2 and 9. Furthermore, conditioned medium from the epithelial cells overexpressing periostin caused TGF-β–dependent secretion of type 1 collagen by airway fibroblasts. In addition, mixing recombinant periostin with type 1 collagen in solution caused a dramatic increase in the elastic modulus of the collagen gel, indicating that periostin alters collagen fibrillogenesis or cross-linking and leads to stiffening of the matrix. Epithelial cell-derived periostin in asthma has roles in TGF-β activation and collagen gel elasticity in asthma.

https://www.pnas.org/content/pnas/107/32/14170.full.pdf

Roles of epithelial cell-derived periostin in TGF-β activation, collagen production, and collagen gel elasticity in asthma

Periostin, also called osteoblast-specific factor 2 (OSF-2), is a member of the fasciclin family and a disulfide-linked cell adhesion protein that has been shown to be expressed preferentially in the periosteum and periodontal ligaments, where it acts as a critical regulator of bone and tooth formation and maintenance. Furthermore, periostin plays an important role in cardiac development. Recent clinical evidence has also revealed that periostin is involved in the development of various tumors, such as breast, lung, colon, pancreatic, and ovarian cancers. Periostin interacts with multiple cell-surface receptors, most notably integrins, and signals mainly via the PI3-K/Akt and other pathways to promote cancer cell survival, epithelial-mesenchymal transition (EMT), invasion, and metastasis. In this review, aspects related to the function of periostin in tumorigenesis are summarized.

The Multifaceted Role of Periostin in Tumorigenesis

Purpose: This study aimed to develop an Arg-Gly-Asp (RGD) peptide-labeled chitosan nanoparticle (RGD-CH-NP) as a novel tumor targeted delivery system for short interfering RNA (siRNA). Experimental Design: RGD peptide conjugated with chitosan by thiolation reaction was confirmed by proton-NMR (H-NMR). Binding of RGD-CH-NP with ανβ3 integrin was examined by flow cytometry and fluorescence microscopy. Antitumor efficacy was examined in orthotopic mouse models of ovarian carcinoma. Results: We show that RGD-CH-NP loaded with siRNA significantly increased selective intratumoral delivery in orthotopic animal models of ovarian cancer. In addition, we show targeted silencing of multiple growth-promoting genes ( POSTN, FAK , and PLXDC1 ) along with therapeutic efficacy in the SKOV3ip1, HeyA8, and A2780 models using siRNA incorporated into RGD-CH-NP (siRNA/RGD-CH-NP). Furthermore, we show in vivo tumor vascular targeting using RGD-CH-NP by delivering PLXDC1 -targeted siRNA into the ανβ3 integrin–positive tumor endothelial cells in the A2780 tumor-bearing mice. This approach resulted in significant inhibition of tumor growth compared with controls. Conclusions: This study shows that RGD-CH-NP is a novel and highly selective delivery system for siRNA with the potential for broad applications in human disease. Clin Cancer Res; 16(15); 3910–22. ©2010 AACR.

https://clincancerres.aacrjournals.org/content/clincanres/16/15/3910.full.pdf

Targeted gene silencing using RGD-labeled chitosan nanoparticles.

Periostin is a secreted protein that shares a structural homology to the axon guidance protein fasciclin I (FAS1) in insects and was originally named as osteoblast-specific factor-2 (Osf2). Periostin is particularly highly homologus to Betaig-h3, which promotes cell adhesion and spreading of fibroblasts. It has recently been reported that Periostin was frequently overexpressed in various types of human cancers. Although the detailed function of Periostin is still unclear, Periostin-integrin interaction through FAS1 domain is thought to be involved in tumor development. In addition, Periostin stimulates metastatic growth by promoting cancer cell survival, invasion and angiogenesis. Therefore, Periostin can be a useful marker to predict the behavior of cancer. This review summarizes the recent understanding of Periostin roles in tumor development and speculates on the usefulness of Periostin as a therapeutic and diagnostic target for cancer.

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Periostin : Novel diagnostic and therapeutic target for cancer

Aurora-B kinase is a chromosomal passenger protein and is essential for chromosome segregation and cytokinesis. Aurora-B overexpression in various cancer cells induces chromosomal number instability to produce multinuclearity and relates to metastasis. Here, we examined the expression of Aurora-B in oral squamous cell carcinoma (OSCC) to elucidate the relationship between Aurora-B expression and clinico-pathological findings by immunohistochemistry. Aurora-B expression was observed in normal oral squamous epithelia and OSCC cases, but the number of positive cells was significantly higher in OSCC than in normal squamous epithelium (p < 0.01). The labeling index of Aurora-B was significantly correlated with lymph node metastasis (p < 0.01) and histological grades of differentiation (p < 0.01). We also compared Aurora-B expression with Ki-67 expression and a positive correlation was found (p < 0.0001). Moreover, Aurora-B expression is significantly more frequent in multinuclear tumor cells than in total tumor cells. In summary, we found that Aurora-B expression was well correlated with cell proliferation, induction of multinuclear cells, histological differentiation, and metastasis in OSCC. These findings suggest that Aurora-B may be involved in tumor progression and that Aurora-B can be a new diagnostic and therapeutic target for OSCC.

Aurora-B expression and its correlation with cell proliferation and metastasis in oral cancer

Demographic, aetiological and survival differences of oral squamous cell carcinoma in the young and the old in Sri Lanka.

Background: Nodal metastasis is a major prognostic indicator for oral squamous cell carcinoma (OSCC) progression. Recently, it has been revealed that lymphangiogenic growth factor VEGF-C and its receptor Flt-4 play an important role for invasion and metastasis in cancer cells. Aim: To examine VEGF-C expression and its correlation with lymphatic status, including the number of lymph vessels and lymphatic invasion, tumour invasion and metastasis in OSCC. Methods: Intratumoural and peritumoural lymphatic vessels were examined using D2-40 in 54 OSCC cases and correlated with VEGF-C expression and clinicopathological findings. The histological pattern of invasion and pathological findings were compared. Results: High expression of VEGF-C was frequently observed in OSCC and was associated with increased number of lymph vessels and lymphatic invasion. VEGF-C was well correlated with invasion pattern and metastasis. Conclusions: Results suggest that VEGF-C may play an important role for lymphangiogenesis and invasion in the metastatic process and can be a strong predicting factor for metastasis of OSCC.

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VEGF-C is associated with lymphatic status and invasion in oral cancer.

Odontogenic tumors (OTs) constitute a heterogeneous group of lesions with diverse histopathological features and clinical manifestations. The present study is to determine the frequency of odontogenic tumors (OTs) in Sri Lankan population. A total of 1677 cases of OTs were retrieved and analyzed for age, gender and primary site of the tumors. Cases were re-classified according to the 2005 WHO classification of OTs. The relative frequency of different types of tumors was also analyzed and compared with the literature. OTs represent 3.75% of all cases received during a period of 30 years. Ninety-eight percent of these tumors were benign and the rest malignant. Mandible to maxilla ratio is 2.8:1. The posterior part, the molar region, is the most frequently affected site for the mandible whilst it is the anterior region for the maxilla. The age ranges from 1 to 80 years, with a mean age of 30.6 years. Ameloblastoma of solid/multicystic and unicystic types showed a high preponderance for the mandible (>90%) with a ratio of 12.9:1 and 10.8:1, respectively. Out of 1677 cases, 48.7% were ameloblastoma, and other tumors, such as keratocystic odontogenic tumor (KCOT) and odontoma, were 25.7% and 10.1%, respectively. There is a significant change in the frequency of OTs after the inclusion of odontogenic keratocyst as a tumor. Although odontoma is said to be the commonest in western countries, our results showed ameloblastoma as the commonest followed by KCOT, and the relative frequencies of different tumors have changed significantly as a result of inclusion of KCOT in the new classification.

B. S. M. S. Siriwardena

Papers

Periostin : Novel diagnostic and therapeutic target for cancer

Aurora-B expression and its correlation with cell proliferation and metastasis in oral cancer

Demographic, aetiological and survival differences of oral squamous cell carcinoma in the young and the old in Sri Lanka.

VEGF-C is associated with lymphatic status and invasion in oral cancer.

Relative frequency of odontogenic tumors in Sri Lanka: Analysis of 1677 cases.